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Merck Provides Update on KEYTRUDA (pembrolizumab) Indication in Third-Line Gastric Cancer in the US – Business Wire

Tuesday, July 6th, 2021

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the company plans to voluntarily withdraw the U.S. accelerated approval indication for KEYTRUDA for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [combined positive score (CPS 1)] as determined by a U.S. Food and Drug Administration (FDA)-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, human epidermal growth factor receptor 2 (HER2)/neu-targeted therapy.

The decision was made in consultation with the FDA following the April 29 Oncologic Drugs Advisory Committee evaluation of this third-line gastric cancer indication for KEYTRUDA as a monotherapy because it failed to meet its post-marketing requirement of demonstrating an overall survival benefit in a Phase 3 study. As agreed with the FDA, Merck will initiate the withdrawal in six months. Patients being treated with KEYTRUDA for metastatic gastric cancer in the third- or further-line setting should discuss their care with their health care provider. This decision does not affect other indications for KEYTRUDA.

While there remains an unmet need for heavily pre-treated patients with advanced gastric cancer, we recognize that the treatment landscape has evolved and we respect the FDAs efforts to continually evaluate accelerated approvals, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. Our research with KEYTRUDA has contributed to recent advances in the treatment of gastric cancer, and we are continuing to advance studies to help more patients with this disease.

KEYTRUDA will continue to play an important role in the treatment of certain patients with gastric cancer:

These indications are approved under accelerated approval based on tumor response rate and durability of response; continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Mercks clinical program in gastric cancer includes the first-line Phase 3 studies KEYNOTE-811, KEYNOTE-859 and LEAP-015, as well as KEYNOTE-585 in the neoadjuvant and adjuvant treatment setting.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,500 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDASevere and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

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Orchard Therapeutics and Pharming Group Announce Collaboration to Develop and Commercialize ex vivo autologous HSC Gene – GlobeNewswire

Tuesday, July 6th, 2021

Highlights the broader potential of Orchards ex vivo HSC gene therapy platform approach in new and larger indications

Reinforces Pharmings commitment to the HAE community and utilizes its relevant clinical expertise and global commercialization infrastructure

Companies to host joint investor call at 8:00 a.m. EDT / 2:00 p.m. CEST

BOSTON, LONDON and LEIDEN, The Netherlands, July 01, 2021 (GLOBE NEWSWIRE) -- Orchard Therapeutics(Nasdaq: ORTX), a global gene therapy leader, and Pharming Group N.V. (Euronext Amsterdam: PHARM/Nasdaq: PHAR), a global, commercial stage biopharmaceutical company, today announced a strategic collaboration to research, develop, manufacture and commercialize OTL-105, a newly disclosed investigational ex vivo autologous hematopoietic stem cell (HSC) gene therapy for the treatment of hereditary angioedema (HAE), a life-threatening rare disorder that causes recurring swelling attacks in the face, throat, extremities and abdomen.

OTL-105 is an investigational HSC gene therapy designed to increase C1 esterase inhibitor (C1-INH) in HAE patient serum to prevent hereditary angioedema attacks. OTL-105 inserts one or more functional copies of the SERPING1 gene into patients own HSCs ex vivo which are then transplanted back into the patient for potential durable C1-INH production. In preclinical studies, to date, OTL-105 demonstrated high levels of SERPING1 gene expression via lentiviral-mediated transduction in multiple cell lines and primary human CD34+ HSCs. Furthermore, the program achieved production of functional C1-INH protein, as measured by a clinically validated assay.

Under the terms of the collaboration, Pharming has been granted worldwide rights to OTL-105 and will be responsible for clinical development, regulatory filings, and commercialization of the investigational gene therapy, including associated costs. Orchard will lead the completion of IND-enabling activities and oversee manufacturing of OTL-105 during pre-clinical and clinical development, which will be funded by Pharming. In addition, both companies will explore the application of non-toxic conditioning regimen for use with OTL-105 administration.

Orchard will receive an upfront payment of $17.5 million comprising $10 million in cash and a $7.5 million equity investment from Pharming at a premium to Orchard's recent share price. Orchard is also eligible to receive up to $189.5 million in development, regulatory and sales milestones as well as mid-single to low double-digit royalty payments on future worldwide sales.

Given the combination of our expertise in HSC gene therapy with Pharmings long-standing legacy and experience, we have the potential to reinvent the treatment paradigm for HAE by providing people living with this life-threatening disorder a sustained therapy with a single administration, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard Therapeutics. This collaboration demonstrates the promise of the HSC gene therapy platform and how it can be applied to new therapeutic areas with larger patient populations. We believe the HSC gene therapy pipeline we are building could continue to be a source of future partnerships in areas where the biology supports our approach.

Pharming has been committed to the HAE community for more than two decades, said Sijmen de Vries M.D., MBA, chief executive officer of Pharming. We have partnered with Orchard Therapeutics, a leader in the development of autologous HSC gene therapy, to develop a potentially curative treatment for HAE. Based on Pharmings experience in HAE, we believe that HSC gene therapy has the potential for the highest probability of success. This confidence is based on the durability of effect and safety observed in approved treatments from Orchards HSC gene therapy portfolio and positive clinical data in several other programs. This a significant first step in developing a potentially transformative one-time treatment for HAE.

Great progress has been made in HAE treatment over the last 15 years.However, HAE remains a severe, debilitating disease with an ongoing burden of angioedema attacks or chronic medication use, said Dr. MarcRiedl, professor of medicine and clinical director of the U.S. Hereditary Angioedema Association Center at the University of California, San Diego.This promising work toward treatment with the potential for durable long-term clinical benefit is encouraging and signifies an ongoing commitment to the HAE community.I look forward to these efforts to identify and carefully advance a potential cure for HAE.

The HAE market is expected to generate ~$2 billion in sales in 2021, currently growing at 8% per annum. This represents a significant commercial opportunity for Pharming Group and Orchard Therapeutics.

Webcast Link:https://webcast.openbriefing.com/pharming-jul21/

Access code:470719

About HAE Hereditary angioedema (HAE) is a rare genetic disorder. The condition is caused by a deficiency of the C1 esterase inhibitor protein, which is normally present in blood and helps control inflammation (swelling) and parts of the immune system. Deficient C1 inhibitor does not adequately perform its regulatory function and, as a result, a biochemical imbalance can occur and produce unwanted peptides that induce the capillaries to release fluids into surrounding tissue, thereby causing swelling or edema.

HAE is characterized by spontaneous and recurrent episodes of swelling (edema attacks) of the skin in different parts of the body, as well as in the airways and internal organs. Edema of the skin usually affects the extremities, the face, and the genitals. Patients suffering from this kind of edema often withdraw from their social lives because of the disfiguration, discomfort and pain these symptoms may cause. Almost all HAE patients suffer from bouts of severe abdominal pain, nausea, vomiting and diarrhea caused by swelling of the intestinal wall.

Edema of the throat, nose or tongue is particularly dangerous and potentially life-threatening as it can lead to obstruction of the airway passages. Although there is currently no known cure for HAE, it is possible to treat the symptoms associated with angioedema attacks. HAE affects about 1 in 10,000 to 1 in 50,000 people worldwide. Experts believe a lot of patients are still seeking the right diagnosis: although HAE is (in principle) easy to diagnose, it is frequently identified very late or not discovered at all. The reason HAE is often misdiagnosed is because the symptoms are similar to those of many other common conditions such as allergies or appendicitis. By the time it is diagnosed correctly, the patient has often been through a long ordeal.

About Pharming Group N.V.Pharming Group N.V. is a global, commercial stage biopharmaceutical company developing innovative protein replacement therapies and precision medicines for the treatment of rare diseases and unmet medical needs.

The flagship of our portfolio is our recombinant human C1 esterase inhibitor (rhC1INH) franchise. C1INH is a naturally occurring protein that down regulates the complement and contact cascades in order to control inflammation in affected tissues.

Our lead product, RUCONEST, is the first and only plasma-free rhC1INH protein replacement therapy. It is approved for the treatment of acute hereditary angioedema (HAE) attacks. We are commercializing RUCONEST in the United States, the European Union and the United Kingdom through our own sales and marketing organization, and the rest of the world through our distribution network.

In addition, we are investigating the clinical efficacy of rhC1INH in the treatment of further indications, including pre-eclampsia, acute kidney injury, and severe pneumonia as a result of COVID-19 infections.

Furthermore, we are leveraging our transgenic manufacturing technology to develop next-generation protein replacement therapies, most notably for Pompe disease, which is currently in preclinical development.

About Orchard TherapeuticsOrchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by severe diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and theSan Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters in London and U.S. headquarters in Boston. For more information, please visit http://www.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About Orchard TherapeuticsInvestors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (Twitter andLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Orchard Therapeutics Forward-looking StatementsThis press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, the therapeutic potential of Orchards product candidates, including the product candidate or candidates referred to in this release, and the possibility of future milestone or royalty payments. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates, will be insufficient to support regulatory submissions or marketing approval in the US or EU, as applicable, or that long-term adverse safety findings may be discovered; the risk that any one or more of Orchards product candidates, including the product candidates referred to in this release, will not be approved, successfully developed or commercialized; the risk of cessation or delay of any of Orchards ongoing or planned clinical trials; the risk that Orchard may not successfully recruit or enroll a sufficient number of patients for its clinical trials; the delay of any of Orchards regulatory submissions; the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates or the receipt of restricted marketing approvals; the inability or risk of delays in Orchards ability to commercialize its product candidates, if approved, or Libmeldy in the EU; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; the risk that certain milestones may never be achieved or royalty payments may never be earned and paid; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards Quarterly Report on Form 10-Q for the quarter endedMarch 31, 2021, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Pharming Group N.V. Forward-looking Statements This press release contains forward-looking statements, including with respect to timing and progress of Pharmings preclinical studies and clinical trials of its product candidates, Pharmings clinical and commercial prospects, Pharmings ability to overcome the challenges posed by the COVID-19 pandemic to the conduct of its business, and Pharmings expectations regarding its projected working capital requirements and cash resources, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Pharmings clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in Pharmings 2020 Annual Report and the Annual Report on Form 20-F for the year ended December 31, 2020 filed with the U.S. Securities and Exchange Commission, the events and circumstances discussed in such forward-looking statements may not occur, and Pharmings actual results could differ materially and adversely from those anticipated or implied thereby. Any forward-looking statements speak only as of the date of this press release and are based on information available to Pharming as of the date of this release.

Inside InformationThis press release relates to the disclosure of information that qualifies, or may have qualified, as inside information within the meaning of Article 7(1) of the EU Market Abuse Regulation.

Orchard Therapeutics Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaBenjamin NavonDirector, Corporate Communications+1 857-248-9454Benjamin.Navon@orchard-tx.com

Pharming Group N.V. Contacts

CompanyPharming Group, Leiden, The NetherlandsSijmen de Vries, CEO+31 71 524 7400

InvestorsSusanne EmbletonInvestor Relations Manager+31 71 524 7400investor@pharming.com

Media FTI Consulting, London, UKVictoria Foster Mitchell/Alex Shaw +44 203 727 1000

LifeSpring Life Sciences Communication, Amsterdam, The NetherlandsLeon Melens+31 6 53 81 64 27pharming@lifespring.nl

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Merck (MRK) Granted Positive EU CHMP Opinion for KEYTRUDA (pembrolizumab) in Combination with Chemotherapy – StreetInsider.com

Thursday, May 27th, 2021

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Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

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New global guidelines for stem cell research aim to drive discussions, not lay down the law – The Conversation AU

Thursday, May 27th, 2021

The International Society for Stem Cell Research (ISSCR) today released updated guidelines for stem cell research and its translation to medicine.

Developed in response to recent scientific and clinical advances, the revised guidelines provide a series of detailed and practical recommendations that set out global standards for how these emerging technologies should be harnessed.

Stem cell research has huge potential it could help pave the way for new therapies for ailments ranging from Parkinsons disease to childhood kidney failure. But scientific advances in this field can present unique ethical and policy issues beyond that seen in other areas of medical research.

The science is advancing at breakneck pace. Just in the past couple of months, we have seen model human embryos grown from skin cells, and the creation of human-monkey embryos for use in research.

The ISSCR has long recognised the need to set clear ethical boundaries for stem cell research. Previous guidelines have provided advice on techniques such as the use of human embryos to create stem cells, and set the required standards when using these technologies to create new medicines.

They have also explicitly banned certain practices, such as reproductive cloning and the sale of unproven therapies that claim to be made of stem cells.

The 2021 guidelines an update on the previous version, released in 2016 aim to set standards for the many recent advances in stem cell and human embryo research. These include chimeric embryos containing cells from humans and other animals, organoids grown from stem cells to create tissue that resembles particular human organs, and models of human embryos arrangements of human cells that mimic the early stages of embryo development.

The guidelines contain a clear requirement for certain new stem cell research approaches only to be conducted after a specialised review process. This review should be independent of the researchers, and include community members as well as people with expertise in the relevant science, ethics and law.

This is beyond what is typically required by a university or research institute where medical research is conducted. Besides evaluating the merit of the proposed research, the new reviews should also consider whether there are alternative ways to do the research, the source of stem cells and how they were obtained, and the minimum time required to reach the research goals, particularly in relation to human embryo and related research.

Specialised review is not a new concept. The previous guidelines required it when researchers made stem cells from human embryos or sought to culture human embryos in the lab. But now researchers will now also be required to seek higher review when they create model embryos such as blastoids, or study the development of animal-human embryos in animal wombs.

Researchers developing new therapies for mitochondrial disease will also be required to seek higher-level review before attempting to transfer to the uterus of a woman human embryos in which affected mitochondria (a part of the cells energy-production apparatus) have been replaced.

Importantly, the revised guidelines also clearly rule out certain activities. These continue to include reproductive cloning and attempts to form a pregnancy in a woman from genetically edited human embryos or from model embryos made from stem cells. Prohibited activities also now include using eggs and sperm made from human stem cells for reproduction, or transferring a human-animal chimeric embryo into the uterus of a woman or an ape.

Read more: China's failed gene-edited baby experiment proves we're not ready for human embryo modification

The guidelines also call for a public conversation about whether we should allow limited lab research on human embryos beyond the existing limit of 14 days development. Historically, it has not been possible to support human embryonic development outside the body beyond this stage. However, recent advances in human embryo culture raise the possibility that this may now be technically feasible.

Extending the amount of time in culture - in terms of days - could potentially yield new treatments for developmental conditions or infertility, but will also raise concerns about whether possible benefits justify this research. Any decisions to overturn this long-held signpost would need to be carefully deliberated and take into consideration existing law, community values and discussion around what the new limit should be.

The revised guidelines also reinforce the need for informed consent for the collection of human material and participation in stem cell clinical trials, and reiterate that no new stem cell treatment should be made available before it is tested for safety and effectiveness in well-designed and publicly visible clinical trials. The ISSCR continues to condemn the commercial use of unproven stem cell treatments.

While stem cell science holds much promise, it is paramount that research is scientifically and ethically rigorous, with appropriate oversight, transparency and public accountability.

The fact these guidelines are driven by experts including stem cell scientists, doctors, ethicists, lawyers and industry representatives from across 14 countries indicates a deep sense of responsibility and integrity within the research community, and a desire to ensure science remains in step with community values.

However, these guidelines are recommendations, not laws.

Researchers will need to abide by their respective national or state regulations and ethical standards. Some countries already have regulatory frameworks that are consistent with the new recommendations. In other places there is no national guidance around laboratory and clinical stem cell research at all, or existing law touches on some but not all of the emerging applications of stem cell research.

Read more: As scientists move closer to making part human, part animal organisms, what are the concerns?

For example, in Australia there is already an established pathway for higher-level review of embryo models created from stem cells. However, the same legislation currently bans any attempt to use mitochondrial transfer techniques to create embryos for research or to achieve a pregnancy both of which are permissible under the new ISSCR guidelines.

Rather than attempting to impose a set of hard-and-fast rules on an ever-evolving research field, the new guidelines attempt to address emerging issues and drive important discussions at domestic level. Ultimately, it is the public and the regulators who will need to set the standards.

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New global guidelines for stem cell research aim to drive discussions, not lay down the law - The Conversation AU

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Merck Receives Positive EU CHMP Opinion for KEYTRUDA in Combination With Chemotherapy as First-Line Treatment for Certain Patients With Esophageal…

Thursday, May 27th, 2021

Opinion Supports Use of KEYTRUDA in Combination With Platinum- and Fluoropyrimidine-Based Chemotherapy in Patients Whose Tumors Express PD-L1 (CPS 10)

Recommendation Based on Significant Survival Benefit Demonstrated With KEYTRUDA Plus Chemotherapy Versus Chemotherapy in Phase 3 KEYNOTE-590 Trial

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of KEYTRUDA, Mercks anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] 10). The CHMPs recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2021.

Patients with metastatic esophageal cancer currently face five-year survival rates of just 5%, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Todays positive opinion for KEYTRUDA is an important step forward for patients in Europe with certain types of gastrointestinal cancers.

The positive CHMP opinion is based on results from the pivotal Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated significant improvements in overall survival and progression-free survival compared with 5-FU and cisplatin alone in patients regardless of histology or PD-L1 expression status. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p

Merck is studying KEYTRUDA across multiple settings and stages of gastrointestinal cancer including esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers through its broad clinical program.

About Esophageal Cancer

Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 604,000 new cases of esophageal cancer diagnosed and approximately 544,000 deaths resulting from the disease in 2020. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

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Merck Receives Positive EU CHMP Opinion for KEYTRUDA in Combination With Chemotherapy as First-Line Treatment for Certain Patients With Esophageal...

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Epigenetic therapies for heart failure | VHRM – Dove Medical Press

Thursday, May 27th, 2021

Introduction

Although novel drugs have successfully entered the clinical arena of heart failure with reduced ejection fraction (HFrEF), such as the PARADIGM-HF-derived angiotensin receptor neprilysin inhibitor (ARNI), disease-modifying therapies with a prognostic impact for patients affected by heart failure with preserved ejection fraction (HFpEF) are still lacking.15 HF is a complex and highly prevalent syndrome for which the heart undergoes a substantial structural remodeling in patients at risk for major cardiovascular diseases (CVDs) (Figure 1).16 Geneenvironment interactions can be mediated by specific patterns of epigenetic-sensitive changes (mainly DNA methylation and histone modifications) which may modulate the individual responsiveness to HF development.614 This complex molecular circuit seems to trigger early cardiomyocyte loss, cardiac-remodeling, and micro- and macrovascular damage contributing to the development of major CVDs which may lead to differential HF clinical phenotypes.614 Of note, the reversible nature of epigenetic-sensitive changes has been translated in the clinical management of specific hematological malignancies with the approval by the Food and Drug Administration (FDA) of some epidrugs, such as decitabine (Dacogen) and azacitidine (Vidaza), as DNA methylation inhibitors, as well as vorinostat (Zolinza), belinostat (Beleodaq), romidepsin (Istodax), and panobinostat (Farydak), as histone deacetylase inhibitors (HDACi).15 Epidrugs are now providing a novel vision for personalized therapy of HF and heart transplantation, opening up novel options for management of the affected patients.1518 At molecular level, we can classify the epidrugs in: direct epidrugs [eg, the bromodomain and extra-terminal (BET) protein inhibitor apabetalone]; and repurposed drugs with potential, indirect (non-classical) epigenetic-oriented interference by which they may exert cardioprotective functions [eg, hydralazine, metformin, statins, and sodium-glucose co-transporter-2 inhibitors (SGLT2i)] or nutraceutical compounds [eg, omega-3 polyunsaturated fatty acids (PUFAs)]. Encouraging results are coming from large randomized trials evaluating the putative beneficial effects of combining epidrugs with the conventional therapy in patients with HF.1422 Our goal is to update on the emerging epigenetic-based strategies which may be useful in the prevention and treatment of HFrEF and HFpEF (Figure 1).

Figure 1 The possible role of epitherapy in the current framework of HFrEF and HFpEF management. The unstable transition state from the ACC/AHA Stage A/B to Stage C/D-Acute/Hospitalized HF is the key point in the treatment of HFrEF and HFpEF. The epitherapy, mainly apabetalone, statins, metformin, SGLT2i, and PUFAs in addition to the standard of the care may improve personalized therapy of affected patients.

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; SGLT2i, sodium glucose co-transporter 2 inhibitors; PUFAs, polyunsaturated fatty acids.

The bromodomain and extra terminal domain (BET) proteins, including the ubiquitous BRD2, BRD3, BRD4, and the testis-restricted BRDT, are epigenetic readers (via bromodomains) existing in the form of nuclear multidomain docking platforms which control the cell-specific activation of gene expression profiles.23 Experimental data demonstrated that BETs regulate vascular cells, cardiac myocytes, and inflammatory cells,24 and their activity may be extended to the regulation of calcification, thrombosis, as well as lipid and lipoprotein metabolism, all of which participate in atherogenesis.2527 In particular, BRD4 facilitated the expression of multiple proinflammatory and proatherosclerotic targets involved in thrombosis, leukocyte adhesion, and endothelial barrier function, thus identifying BRD4 as a possible therapeutic target in CVD setting.24 The quinazolone (RVX-208), known as apabetalone, is a derivative of the plant polyphenol resveratrol. Apabetalone acts as a direct epidrug by selectively targeting the BET family member BRD4 to block its interaction with acetylated lysines located in histones.28 Apabetalone-BRD4 binding can impact cholesterol levels and inflammation; in fact, apabetalone stimulates ApoA-I gene expression and increases high-density lipoprotein (HDL).29,30 Besides, apabetalone may attenuate the development of cardiac hypertrophy31 and cardiac fibrosis,32 suggesting novel options for the management of HF.

Resverlogix developed apabetalone (RVX-208), a first-in-class, orally available, small molecule for the treatment of atherosclerosis and associated CVDs.20 BETonMACE (NCT02586155) is the first Phase 3 clinical trial evaluating the cardiovascular efficacy and safety of apabetalone.22 Recent results from the BETonMACE study have demonstrated that apabetalone is associated with a reduction in first HF hospitalization and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome as compared to controls (placebo-treated patients).22 Additionally, a significant increase in HDL and a decrease in alkaline phosphatase levels have been observed following 24 weeks of apabetalone treatment as compared to the placebo group.22 However, investigators were unable to make a distinction between HF in the setting of preserved or reduced ejection fraction. Thus, further clinical trials should be designed to evaluate the putative beneficial effects of apabetalone in HFrEF and HFpEF, separately.

Preclinical studies demonstrated that pharmacological HDACi,3336 BET inhibitors,31,37 and DNA methylation inhibitors38 can attenuate cardiac remodeling (cardiomyocyte hypertrophy and fibrosis). Although not originally developed as epidrugs, hydralazine (anti-hypertensive drug), metformin, and SGLT2i (anti-diabetic drugs), statins (anti-dyslipidemic drugs), and PUFAs (nutraceuticals) might have downstream epigenetic-oriented effects in cardiac cells. Hydralazine, for example, lowers blood pressure by a direct relaxation of vascular smooth muscle; additionally, it may reduce DNA methylation and improve cardiac function through increasing sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and modulating calcium homeostasis in cardiomyocytes.39 Statins are used as a first-line treatment to decrease serum cholesterol levels in dyslipidemic patients and as primary and secondary prophylaxis against atherosclerosis and associated CVDs.6 Many of their non-classical pleiotropic properties relevant for endothelial health are mediated by epigenetic mechanisms which improve blood flow, decrease LDL oxidation, enhance atherosclerotic plaque stability and decrease proliferation of vascular smooth muscle cells and platelet aggregation.6 Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients.10 Mechanistically, metformin may also have epigenetic-oriented effects through activating the AMP-activated protein kinase (AMPK) which, in turn, can phosphorylate and inhibit epigenetic enzymes such as histone acetyltransferases (HATs), class II HDAC, and DNA methyltransferases (DNMTs).40 Both metformin41,42 and statins43,44 may reduce cardiac fibrosis; however, whether their beneficial effects are mediated by epigenetic-oriented responses has yet to be demonstrated. Furthermore, SGLT2i are a new group of oral drugs used for treating type 2 diabetes and its cardiovascular/renal complications.45 Animal models have demonstrated that empagliflozin46,47 and dapagliflozin48 may improve hemodynamics in HF by increasing renal protection and cardiac fibrosis. Interestingly, inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by empagliflozin;49 this observation has provided insights about mechanisms by which SGLT2i can reduce cardiovascular mortality in man (EMPA-REG trial).50

An effective therapy for HFpEF has yet to be established. Hydralazine is frequently used in HFrEF, and represents a potential DNA methylation inhibitor.39 DNA methylation is the most studied direct epigenetic change with potential clinical implications in major CVDs and the development of HF.7,14 This epigenetic signature mainly involves methylation of CpG islands in the gene promoters leading to a specific long-term silencing of gene expression.7,14 A completed Phase 2 clinical trial (NCT01516346) evaluated the effect of prolonged therapy (24 weeks) with isosorbide dinitrate (ISDN) hydralazine on arterial wave reflections (primary endpoint) as well as left ventricular (LV) mass, fibrosis and diastolic function, and exercise capacity (6-minute walk test) in patients with HFpEF, New York Heart Association (NYHA) Class IIIV symptoms, and standard therapy as defined by ACEi, ARB, beta-blockers, or calcium channel blockers (CCBs).51 Results from this trial reported that ISDN, with or without hydralazine, had deleterious effects on reflection magnitude, LV remodeling, or submaximal exercise thus not supporting their routine use in patients with HFpEF.51

Metformin has been associated with a reduced mortality in patients with HFpEF, even if female gender was associated with worse outcomes.52 Recently, it has been observed that a long-term treatment with metformin can improve LV diastolic function and hypertrophy, decrease the incidence of new-onset HFpEF, and delay disease progression in patients with type 2 diabetes and hypertension.53 Besides, a prospective phase 2 clinical trial (NCT03629340) is testing the therapeutic efficacy of metformin in patients with pulmonary hypertension and HFpEF by evaluating exercise hemodynamics, functional capacity, skeletal muscle signaling, and insulin sensitivity. However, results have not been published. A recent study based on the JASPER registry, a multicenter, observational, prospective cohort of Japanese patients aged 20 years requiring hospitalization for acute HFpEF has reported that the use of statins could reduce mortality in affected patients without coronary heart disease.54 Furthermore, the use of statins was associated with improved clinical outcomes in patients with HFpEF but not in patients with HFrEF (or mid-range ejection fraction).55 A reduced rate of major adverse cardiac events, cardiovascular death and all-cause mortality was associated with SGLT2i treatment in both HFpEF and HFrEF patients as compared to placebo.56,57 However, the observed cardiovascular and renal benefits cannot be fully explained by improvement in risk factors (such as glycemia, blood pressure or dyslipidemias) suggesting that other molecular mechanisms may explain the cardiovascular benefits.56 Interestingly, the SGLT2i-related epigenetic interference may arise from their ability to increase the circulating and tissue levels of -hydroxybutyrate, a specific molecule able to generate a pattern of histone modifications (known as -hydroxybutyrylation) which are associated with the beneficial effects of fasting.58 Besides, the DELIVER (NCT03619213) multicenter, randomized, double-blind, placebo-controlled study of 6263 HFpEF patients will evaluate the effect of dapagliflozin 10 mg (1 per day) as compared to placebo in addition to the standard of care in order to reduce the composite of cardiovascular death or HF events. However, results have not yet been published.

The use of metformin has been generally considered a contraindication in HFrEF patients owing the potential risk of lactic acidosis; however, recent evidence has reported that metformin can provide beneficial effects in reducing the risk of incident HF and mortality in diabetic patients.5961 A completed, observational clinical trial (NCT03546062) has recently performed the evaluation of seriated cardiac biopsies from healthy implanted hearts in type 2 diabetes recipients during 12-month follow-up upon heart transplantation.21 Even if the intra-cardiomyocyte lipid accumulation in type 2 diabetes recipients may start in the early stages after heart transplantation, metformin therapy could reduce lipid accumulation independently of immunosuppressive therapy.21 The DANHEART trial (NCT03514108), a multicenter, randomized, double-blind, placebo-controlled study in 1500 patients with HFrEF will evaluate: 1) whether hydralazine-isosorbide dinitrate as compared to placebo may reduce the incidence of death and HF hospitalization, and 2) if metformin as compared to placebo may reduce the incidence of death, worsening of HF, acute myocardial infarction, and stroke in patients with diabetes or prediabetes. Two large randomized trials demonstrated that statins did not have beneficial effects in management of patients with HFrEF.62,63 Specifically, the CORONA phase 3 trial randomized more than 5000 patients with ischemic HFrEF to rosuvastatin as compared to placebo resulting in no benefits on the primary endpoints, as death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke.62 According to CORONA trial, the GISSI-HF study randomized almost 5000 patients with clinically apparent HF of any cause to rosuvastatin as compared to placebo and observed no benefits on the primary endpoints, as all-cause death or cardiovascular hospitalization.63 However, it is needed to highlight that both trials demonstrated that statins are safe in HF patients. In contrast with the previous evidence, the trial based on the Swedish Heart Failure Registry (21,864 patients with HFrEF, of whom 10,345 were treated with statins) reported an association between the use of statins and improved outcomes, as all-cause mortality, cardiovascular mortality, HF hospitalization, and combined all-cause mortality or cardiovascular hospitalization, especially in patients with ischemic HF.64 Thus, further randomized controlled trials focused on ischemic HF may be warranted. Omega-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are key players in modulating inflammatory process by limiting leucocyte chemotaxis, adhesion molecule expression, leucocyte-endothelium interaction as well as T cell reactivity.65 EPA and DHA are mainly gained from marine food consumption and large population-based studies have shown that Mediterranean diet with PUFA supplementation may aid to prevent CVDs owing to their ability in promoting the release of nitric oxide from endothelial cells and decreasing serum levels of triglycerides.66 Recent evidence has indicated that PUFAs can significantly affect the cellular epigenome mainly thought DNA methylation-sensitive mechanisms.67,68 The GISSI multicenter, double-blind trial enrolled 6975 HF patients (New York Heart Association class IIIV, irrespective of cause and LV ejection fraction) and randomized them to low dose (0.84 g per day) of PUFAs as compared to placebo. PUFAs supplementation reduced risk for total mortality and HF hospitalization when added to standard therapy.19 Furthermore, in the OMEGA-REMODEL trial, high-dose of PUFAs (3.4 g per day) for 6 months post-myocardial infarction reduced infarct size and non-infarct myocardial fibrosis as well as improved ventricular systolic function.69 Taken together, these results suggest that PUFAs may aid to prevent HFrEF. More recently, the MESA longitudinal trial including 6562 participants 45 to 84 years has demonstrated that higher plasma levels of EPA were significantly associated with reduced risk both in HFpEF and HFrEF.70

Although the possibility of improving the HF standard of care with epidrugs is still in its infancy, the BETonMACE study has provided promising results about the use of apabetalone in reducing hospitalization and cardiovascular death. Preclinical models of cardiac remodeling demonstrated that metformin, statins, SGLT2i, and PUFAs4148 can improve vascular health and cardiac fibrosis by modulating specific molecular pathways, and, in part, through downstream epigenetic interference, especially for hydralazine39 and empagliflozin (Figure 2).49 Of note, metformin and SGLT2i can impact on the epigenetic memory phenomenon. This latter suggests that an early glycemia normalization can arrest hyperglycemia-induced epigenetic processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids.71,72 In parallel, an increasing number of clinical trials is evaluating the putative beneficial repurposing of metformin, statins, SGLT2i, and PUFAs in patients with HFpEF and/or HFrEF;19,6264,69,7375 however, despite experimental evidence, none of these trials evaluated their potential epigenetic effects involved in improving the cardiac function. This gap should be overcome to improve personalized therapy of patients with HF. Thus, further randomized trials are needed to clarify whether apabetalone, as well as non-canonical repurposed epidrugs, will really be able to save failing hearts in different HF clinical phenotypes or prevent irreversible damages in high-risk patients. In this context, Network Medicine approaches may help to evaluate a possible repurposing of epidrugs in patients with major CVDs.15,76,77

Figure 2 Direct and indirect epigenetic drugs in preclinical models of HF. Cardiac remodeling includes different pathological phenotypes and each type of drug can selectively improve inflammation, cardiac fibrosis and hypertrophy, calcium homeostasis, and lipid metabolism.

Abbreviations: HF, heart failure; SGLT2i, sodium glucose co-transporter 2 inhibitors.

This work was supported by PRIN2017F8ZB89 from Italian Ministry of University and Research (MIUR) (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from Italian Ministry of Health (PI Prof. Napoli).

The authors report no conflicts of interest in this work.

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OPDIVO (nivolumab) in Combination with CABOMETYX (cabozantinib) Shows Sustained Survival and Response Rate Benefits as First-Line Treatment for…

Sunday, February 14th, 2021

PRINCETON, N.J., & ALAMEDA, Calif.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) and Exelixis, Inc. (NASDAQ: EXEL) today announced results from new analyses from the pivotal Phase 3 CheckMate -9ER trial, demonstrating clinically meaningful, sustained efficacy benefits as well as quality of life improvements with the combination of OPDIVO (nivolumab) and CABOMETYX (cabozantinib) compared to sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC). These data will be presented in two posters at the virtual American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium from February 11 to 13, 2021 and featured in the Poster Highlights Session on February 13, 2021 from 9:00 a.m. 9:45 a.m. EST.

Abstract #308: Nivolumab + cabozantinib (NIVO+CABO) vs. sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate -9ER (Motzer, et. al.)

With a median follow-up of two years (23.5 months), OPDIVO in combination with CABOMETYX continued to show superior progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation. No new safety signals were identified with extended follow-up. Across the full study population:

In an exploratory subgroup analysis of 75 patients with sarcomatoid features, the combination of OPDIVO and CABOMETYX showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64% vs. sunitinib (HR 0.36; 95% CI: 0.17 to 0.79) and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22.0%).

Abstract #285: Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: the CheckMate -9ER trial (Cella, et. al.)

In a separate analysis from the CheckMate -9ER trial conducted with 18.1 months of median follow-up, patients treated with the combination of OPDIVO and CABOMETYX reported statistically significant health-related quality of life benefits. Treatment with OPDIVO in combination with CABOMETYX was associated with a lower treatment burden, decreased risk of deterioration and a reduction of disease-related symptoms compared to sunitinib. These exploratory outcomes were measured using Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), a quality of life tool specific to kidney cancer, and EQ-5D-3L instruments.

There is a continued need for new therapies that show benefit across subgroups of patients with advanced renal cell carcinoma, said Robert Motzer, M.D., Kidney Cancer Section Head, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. In CheckMate -9ER, nivolumab in combination with cabozantinib doubled progression-free survival, increased overall survival and response rate and, in an exploratory analysis, showed impressive disease control, and these promising efficacy results were sustained with extended follow-up. Also of note, patients in this study reported significant quality of life improvements, which are important for patients undergoing treatment for this challenging disease.

These additional data from CheckMate -9ER provide strong evidence that OPDIVO in combination with CABOMETYX may help patients achieve and maintain control of their disease, said Dana Walker, M.D., M.S.C.E., vice president, development program lead, genitourinary cancers, Bristol Myers Squibb. This regimen brings together two proven agents in advanced renal cell carcinoma, and we believe it will play an important role alongside other first-line treatment options. We look forward to the potential to build on our heritage of transforming patient outcomes with OPDIVO-based combinations across a wide range of tumor types.

The overall survival benefit and quality-of-life measures reported in these findings continue to show improvement with the combination of CABOMETYX and OPDIVO after an extended follow-up of two years, said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. These new findings from CheckMate -9ER and the recent FDA approval of the combination regimen are extremely encouraging as we further explore the potential of CABOMETYX in combination with immunotherapies to help more patients with difficult-to-treat tumor types.

OPDIVO in combination with CABOMETYX was approved for the first-line treatment of advanced RCC by the U.S. Food and Drug Administration (FDA) in January 2021, and further applications are under review with health authorities globally.

Bristol Myers Squibb and Exelixis thank the patients and investigators involved in the CheckMate -9ER clinical trial.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized, multi-national Phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L11%) were randomized to receive OPDIVO plus CABOMETYX (n=323) vs. sunitinib (n=328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination vs. sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. The five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 13%.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision transforming patients lives through science. The goal of the companys cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patients life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About OPDIVO

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the bodys own immune system to help restore anti-tumor immune response. By harnessing the bodys own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivos leading global development program is based on Bristol Myers Squibbs scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Companys Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

OPDIVO INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 10% (5/49) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO monotherapy in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients. In patients receiving OPDIVO 1 mg/ kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushings syndrome.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg monotherapy, infusion-related reactions occurred in 2.9% (28/982) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in 2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, pneumonia, and anemia. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in 4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in 2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 227, the most common (20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigators choice. In Checkmate 275, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Checkmate 238, the most common adverse reactions (20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Attraction-3, the most common adverse reactions (20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%).

In a separate Phase 3 trial of YERVOY 3 mg/kg, the most common adverse reactions (5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 037previously treated metastatic melanoma; Checkmate 066previously untreated metastatic melanoma; Checkmate 067previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 227previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LApreviously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ERpreviously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025previously treated renal cell carcinoma; Checkmate 205/039classical Hodgkin lymphoma; Checkmate 141recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275urothelial carcinoma; Checkmate 142MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040hepatocellular carcinoma, as a single agent or in combination with YERVOY; Checkmate 238adjuvant treatment of melanoma; Attraction-3esophageal squamous cell carcinoma

CABOMETYX INDICATIONS

CABOMETYX(cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

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OPDIVO (nivolumab) in Combination with CABOMETYX (cabozantinib) Shows Sustained Survival and Response Rate Benefits as First-Line Treatment for...

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AlloVir Research Presented at the 2021 Transplantation & Cellular Therapy Meeting Digital Experience – Business Wire

Sunday, February 14th, 2021

CAMBRIDGE, Mass.--(BUSINESS WIRE)--AlloVir (Nasdaq: ALVR), a late clinical-stage cell therapy company, today announced results of a subgroup analysis from a Phase 2, proof-of-concept study (CHARMS) evaluating the companys lead product candidate, Viralym-M (ALVR105), an allogeneic, off-the-shelf, multi-virus specific investigational T-cell therapy (VST), in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients with virus-associated hemorrhagic cystitis (V-HC). These data are being presented in an oral presentation during the Transplantation & Cellular Therapy (TCT) Meeting of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR). Additionally, two separate oral presentations characterize the high economic and clinical burden of V-HC and double-stranded (ds) DNA viral infections in allo-HSCT recipients. Preclinical data was also presented in a poster presentation on ALVR109, AlloVirs virus-specific T-cell therapy targeting SARS-CoV-2, the virus responsible for COVID-19.

The data from the Phase 2 CHARMS study highlight Viralym-M's potential to treat and possibly prevent multiple viral infections and viral diseases. The findings presented at TCT show that this novel virus-specific T cell therapy has the potential to rapidly and effectively resolve macroscopic hematuria in allo-HSCT recipients with virus-associated hemorrhagic cystitis a disease that currently has no effective treatment options and causes significant morbidity and increased risk of mortality, said Agustin Melian, MD, Chief Medical Officer and Head of Global Medical Sciences of AlloVir. We have recently initiated our Phase 3, pivotal study of Viralym-M for the treatment of virus-associated hemorrhagic cystitis and look forward to advancing this therapy through development for patients in need.

Data of Viralym-M in fifty-eight allo-HSCT recipients with at least one treatment-refractory viral infection caused by BK virus (BKV), cytomegalovirus (CMV), adenovirus (AdV), Epstein Barr virus (EBV), human herpesvirus 6 (HHV-6), and/or JC virus (JCV) were evaluated in the CHARMS Phase 2 study. The subgroup analysis presented at TCT included 26 patients who received intravenous VST infusions for the treatment of V-HC due to infection with BKV (n=23), AdV (n=2) and BKV and AdV (n=1). Infusions were well tolerated with mild, grade 1, de novo skin rash from graft-versus-host disease (GVHD) occurring in 15% of patients (n=4). In the 20 patients with available V-HC grading, resolution of macroscopic hematuria was observed in 60% and 80% of patients at two- and six-weeks post-infusion, respectively. In comparison, resolution of macroscopic hematuria was observed in <10% and 30% of patients at weeks two and six, respectively, in a contemporary cohort of allo-HSCT recipients (n=33) with V-HC who were not treated with Viralym-M.

Health economic outcomes data was also presented in two separate oral presentations at the conference. The two presentations analyzed U.S. claims data to compare health care reimbursement, health resource utilization, and clinical outcomes in pediatric and adult allo-HSCT recipients with V-HC and those without V-HC, and allo-HSCT recipients with or without dsDNA infections, respectively. Both studies found that allo-HSCT recipients with V-HC and those with any dsDNA infection had higher reimbursement costs, increased hospital and ICU length of stay, and increased hospital readmission rates. The presence of V-HC or any dsDNA viral infection was associated with a higher risk of mortality.

In addition, a poster presentation at the conference demonstrated the in vitro effector and safety profile of ALVR109, an allogeneic, off-the-shelf investigational VST therapy designed to target SARS-CoV-2, the virus that causes the severe and life-threatening viral disease, COVID-19. These data suggest the potential for using these VSTs to treat COVID-19 in hospitalized high-risk patients to prevent the development of severe disease. A clinical trial evaluating these banked, off-the-shelf SARS-CoV-2 specific T cells has been initiated at the Center for Cell and Gene Therapy, Baylor College of Medicine (BCM), Texas Children's Hospital, and Houston Methodist Hospital.

Viral Infections in Immunocompromised Patients

In healthy individuals, virus-specific T cells (VSTs) from the bodys natural defense system provide protection against numerous disease-causing viruses. However, in patients with a weakened immune system these viruses may be uncontrolled. Viral diseases are common and can cause potentially devastating and life-threatening consequences in immunocompromised patients. For example, up to 90% of patients will reactivate at least one virus following an allogeneic stem cell transplant and two-thirds of these patients reactivate more than one virus, resulting in significant and prolonged morbidity, hospitalization, and premature death. Typically, when viruses infect immunocompromised patients, standard antiviral treatment does not address the underlying problem of a weakened immune system and therefore many patients suffer with life-threatening outcomes such as multi-organ damage and failure, and even death.

Viralym-M

Viralym-M (ALVR105) is an allogeneic, off-the-shelf, multi-virus specific investigational T-cell therapy targeting five devastating viral pathogens: BK virus, cytomegalovirus, adenovirus, Epstein-Barr virus, and human herpesvirus 6. Viralym-M has the potential to transform care for transplant recipients as well as individuals who are at high risk for opportunistic viral infections by reducing or preventing disease morbidity and dramatically improving patient outcomes. Three pivotal and proof-of-concept clinical (POC) trials are ongoing and actively recruiting patients in indications such as treatment of virus-associated hemorrhagic cystitis and multi-virus prevention following allo-HSCT, and preemptive treatment of BK viremia in adult kidney transplant recipients. Additional pivotal and POC trials are expected to initiate for the treatment of CMV and the treatment of AdV in allo-HSCT recipients and in CMV for solid organ transplant recipients, respectively. For more information on the ongoing clinical trials visit clinicaltrials.gov.

Viralym-M has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA), as well as PRIority MEdicines (PRIME) and Orphan Drug Designations (ODD) from the European Medicines Agency.

About AlloVir

AlloVir is a leading late clinical-stage cell therapy company with a focus on restoring natural immunity against life-threatening viral diseases in pediatric and adult patients with weakened immune systems. The companys innovative and proprietary technology platforms leverage off-the-shelf, allogeneic, multi-virus specific T-cells targeting devastating viruses for patients with T-cell deficiencies who are at risk from the life-threatening consequences of viral diseases. AlloVirs technology and manufacturing process enables the potential for the treatment and prevention of a spectrum of devastating viruses with each single allogeneic cell therapy. The company is advancing multiple mid- and late-stage clinical trials across its product portfolio. For more information visit http://www.allovir.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding AlloVirs development and regulatory status of our product candidates, the planned conduct of its preclinical studies and clinical trials and its prospects for success in those studies and trials, and its strategy, business plans and focus. The words may, will, could, would, should, expect, plan, anticipate, intend, believe, estimate, predict, project, potential, continue, target and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on managements current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, those related to AlloVirs financial results, the timing for the initiation and successful completion of AlloVirs clinical trials of its product candidates, whether and when, if at all, AlloVirs product candidates will receive approval from the U.S. Food and Drug Administration, or FDA, or other foreign regulatory authorities, competition from other biopharmaceutical companies, the impact of the COVID-19 pandemic on AlloVirs product development plans, supply chain, and business operations and other risks identified in AlloVirs SEC filings. AlloVir cautions you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. AlloVir disclaims any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. Any forward-looking statements contained in this press release represent AlloVirs views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date.

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Opdivo in Combination with Cabometyx Shows Sustained Survival and Response Rate Benefits as First-Line Treatment for Patients with Advanced RCC -…

Sunday, February 14th, 2021

PRINCETON, N.J., & ALAMEDA, Calif.(BUSINESS WIRE)Bristol Myers Squibb (NYSE: BMY) and Exelixis, Inc.(NASDAQ: EXEL) today announced results from new analyses from the pivotal Phase 3 CheckMate -9ER trial, demonstrating clinically meaningful, sustained efficacy benefits as well as quality of life improvements with the combination of OPDIVO (nivolumab) and CABOMETYX (cabozantinib) compared to sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC). These data will be presented in two posters at the virtual American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium from February 11 to 13, 2021 and featured in the Poster Highlights Session on February 13, 2021 from 9:00 a.m. 9:45 a.m. EST.

Abstract #308: Nivolumab + cabozantinib (NIVO+CABO) vs. sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate -9ER (Motzer, et. al.)

With a median follow-up of two years (23.5 months), OPDIVO in combination with CABOMETYX continued to show superior progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation. No new safety signals were identified with extended follow-up. Across the full study population:

In an exploratory subgroup analysis of 75 patients with sarcomatoid features, the combination of OPDIVO and CABOMETYX showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64% vs. sunitinib (HR 0.36; 95% CI: 0.17 to 0.79) and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22.0%).

Abstract #285: Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: the CheckMate -9ER trial (Cella, et. al.)

In a separate analysis from the CheckMate -9ER trial conducted with 18.1 months of median follow-up, patients treated with the combination of OPDIVO and CABOMETYX reported statistically significant health-related quality of life benefits. Treatment with OPDIVO in combination with CABOMETYX was associated with a lower treatment burden, decreased risk of deterioration and a reduction of disease-related symptoms compared to sunitinib. These exploratory outcomes were measured using Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), a quality of life tool specific to kidney cancer, and EQ-5D-3L instruments.

There is a continued need for new therapies that show benefit across subgroups of patients with advanced renal cell carcinoma, said Robert Motzer, M.D., Kidney Cancer Section Head, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. In CheckMate -9ER, nivolumab in combination with cabozantinib doubled progression-free survival, increased overall survival and response rate and, in an exploratory analysis, showed impressive disease control, and these promising efficacy results were sustained with extended follow-up. Also of note, patients in this study reported significant quality of life improvements, which are important for patients undergoing treatment for this challenging disease.

These additional data from CheckMate -9ER provide strong evidence that OPDIVO in combination with CABOMETYXmay help patients achieve and maintain control of their disease, said Dana Walker, M.D., M.S.C.E., vice president, development program lead, genitourinary cancers, Bristol Myers Squibb. This regimen brings together two proven agents in advanced renal cell carcinoma, and we believe it will play an important role alongside other first-line treatment options. We look forward to the potential to build on our heritage of transforming patient outcomes with OPDIVO-based combinations across a wide range of tumor types.

The overall survival benefit and quality-of-life measures reported in these findings continue to show improvement with the combination of CABOMETYX and OPDIVO after an extended follow-up of two years, said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. These new findings from CheckMate -9ER and the recent FDA approval of the combination regimen are extremely encouraging as we further explore the potential of CABOMETYX in combination with immunotherapies to help more patients with difficult-to-treat tumor types.

OPDIVO in combination with CABOMETYX was approved for the first-line treatment of advanced RCC by the U.S. Food and Drug Administration (FDA) in January 2021, and further applications are under review with health authorities globally.

Bristol Myers Squibb and Exelixis thank the patients and investigators involved in the CheckMate -9ER clinical trial.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized, multi-national Phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L11%) were randomized to receive OPDIVO plus CABOMETYX (n=323) vs. sunitinib (n=328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination vs. sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. The five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 13%.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision transforming patients lives through science. The goal of the companys cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patients life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

Photo courtesy of Bristol Myers Squibb

About OPDIVO

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the bodys own immune system to help restore anti-tumor immune response. By harnessing the bodys own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivos leading global development program is based on Bristol Myers Squibbs scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivotrials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Companys Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

OPDIVO INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 10% (5/49) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO monotherapy in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients. In patients receiving OPDIVO 1 mg/ kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushings syndrome.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune):conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg monotherapy, infusion-related reactions occurred in 2.9% (28/982) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in 2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, pneumonia, and anemia. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in 4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in 2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 227, the most common (20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigators choice. In Checkmate 275, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Checkmate 238, the most common adverse reactions (20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Attraction-3, the most common adverse reactions (20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%).

In a separate Phase 3 trial of YERVOY 3 mg/kg, the most common adverse reactions (5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 037previously treated metastatic melanoma; Checkmate 066previously untreated metastatic melanoma; Checkmate 067previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 227previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LApreviously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ERpreviously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025previously treated renal cell carcinoma; Checkmate 205/039classical Hodgkin lymphoma; Checkmate 141recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275urothelial carcinoma; Checkmate 142MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040hepatocellular carcinoma, as a single agent or in combination with YERVOY; Checkmate 238adjuvant treatment of melanoma; Attraction-3esophageal squamous cell carcinoma

CABOMETYX INDICATIONS

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Opdivo in Combination with Cabometyx Shows Sustained Survival and Response Rate Benefits as First-Line Treatment for Patients with Advanced RCC -...

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Astellas and Seagen Announce Presentation of Results from PADCEV (enfortumab vedotin-ejfv) Pivotal Trial in Patients with Previously Treated Advanced…

Sunday, February 14th, 2021

TOKYO and BOTHELL, Wash., Feb. 12, 2021 /PRNewswire/ --Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN) today announced results from the second cohort (cohort 2) of patients in the pivotal phase 2 single-arm EV-201 trial. In the trial, 52 percent of patients who received PADCEV (enfortumab vedotin-ejfv) had an objective response (95 percent Confidence Interval [CI]: 40.8, 62.4) and the median duration of response was 10.9 months (95 percent CI: 5.8, NR). Twenty percent of patients had a complete response, the absence of detectable cancer, after PADCEV treatment, and 31 percent had a partial response. Adverse events were consistent with those observed in previous trial data, with the most common all-grade treatment-related adverse events (AEs) being alopecia (51 percent), peripheral sensory neuropathy (47 percent), and fatigue (34 percent).

Cohort 2 of the EV-201 trial evaluated PADCEV in patients with locally advanced or metastatic urothelial cancer who had been previously treated with a PD-1/L1 inhibitor, had not received a platinum-containing chemotherapy in this setting, and were ineligible for cisplatin. Urothelial cancer is the most common type of bladder cancer and can also be found in the renal pelvis, ureter and urethra.1

Thefindings were presented today in an oral presentation as part of the virtual scientific program of the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) (Abstract 394).

"Roughly half of all patients with locally advanced or metastatic urothelial cancer have comorbidities that make them ineligible for cisplatin-based chemotherapy and after progression on first-line immunotherapy, there are few effective treatment options," said Arjun Balar, M.D., Associate Professor of Medicine, Director Genitourinary Medical Oncology Program, NYU Laura and Isaac Perlmutter Cancer Center, NYU Langone Health and an investigator for the trial. "Results from EV-201 cohort 2 indicate that enfortumab vedotin may be an important therapeutic option for these patients."

"Fifty-two percent of patients in this study cohort responded to PADCEV including some patients who showed no detectable cancer following treatment an important result for people with this difficult-to-treat form of urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas.

"We're pleased that PADCEV provided meaningful clinical benefit to a group of patients who historically have very few options and may choose not to pursue further treatment for the disease," said Roger Dansey, M.D., Chief Medical Officer, Seagen.

The results are expected to be submitted to the U.S. Food and Drug Administration by the end of March as part of a supplemental biologics licensing application. EV-201 results will also be included in submissions to some global health authorities.

EV-201 Cohort 2 Trial ResultsIn cohort 2 of the dual-cohort trial, 52 percent of patients who received PADCEV had an objective response (46/89); (95 percent CI: 40.8, 62.4) per blinded independent central review (the primary endpoint), with 20percent of patients (18/89) experiencing a complete response and 31 percent of patients experiencing a partial response (28/89).

In the trial's secondary endpoints, duration of response lasted a median of 10.9 months (95 percent CI: 5.8, NR).Patients lived a median of 5.8 months without cancer progression (progression-free survival) (95 percent CI: 5.0, 8.3), and had a median overall survival of 14.7 months(95 percent CI: 10.5,18.2).

Grade 3 or greater treatment-related AEs of interest included skin reactions (17 percent), peripheral neuropathy (8 percent) and hyperglycemia (6 percent). Four deaths were reported as treatment-related by investigators in patients age 75 years and older with multiple comorbidities.

About Urothelial CancerUrothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.1 Globally, approximately 549,000 new cases of bladder cancer and 200,000 deaths are reported annually.2

About the EV-201 TrialThe EV-201 trial (NCT03219333) is a single-arm, pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (cohort 2). The trial enrolled 128 patients in cohort 1 and 91 patients in cohort 2 at multiple centers internationally.

The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability.

About PADCEV (enfortumab vedotin-ejfv)PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA's Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.3

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.3,4 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).4 PADCEV is co-developed by Astellas and Seagen.

PADCEV Important Safety Information Warnings and Precautions

Adverse ReactionsSerious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab AbnormalitiesIn one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website athttps://www.astellas.com/en.

About Seagen Seagen Inc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people's lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on our marketed products and robust pipeline, visit http://www.seagen.com and follow @SeagenGlobal on Twitter.

About the Astellas and Seagen CollaborationAstellas and Seagen are co-developing enfortumab vedotin under a collaboration that was entered into in 2007 and expanded in 2009.

Astellas Cautionary NotesIn this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

Seagen Forward Looking StatementsCertain statements made in this press release are forward looking, such as those, among others, relating to the submission of data from cohort 2 of the EV-201 trial for presentation at an upcoming scientific congress; intended regulatory actions, including plans to submit a supplemental biologics licensing application to the FDA and to make submissions to global health authorities; and the therapeutic potential of PADCEV, including its efficacy, safety and therapeutic uses. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the possibilities that we may experience delays in the submission of results to the FDA; that the results from cohort 2 of the EV-201 trial may not be support any approvals by regulatory authorities; that, even if PADCEV receives an additional approval in the U.S. or an approval in any global registrations, the product labeling may not be as broad or desirable as anticipated; that ongoing and subsequent clinical trials may fail to establish sufficient efficacy; that adverse events or safety signals may occur; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seagen is contained under the caption "Risk Factors" included in the company's Annual Report on Form 10-K for the year ended December 31, 2020 filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

References

1

American Society of Clinical Oncology. Bladder cancer: introduction (5-2019). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed January 27, 2021.

2

Cancer today: data visualization tools for exploring the global cancer burden in 2020. https://gco.iarc.fr/today/home. Accessed January 27, 2021.

3

PADCEV [package insert] Northbrook, IL: Astellas Pharma Inc.

4

Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.

SOURCE Astellas Pharma Inc.

http://www.us.astellas.com

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Astellas and Seagen Announce Presentation of Results from PADCEV (enfortumab vedotin-ejfv) Pivotal Trial in Patients with Previously Treated Advanced...

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[Full text] Loganin Attenuates Septic Acute Renal Injury with the Participation of | DDDT – Dove Medical Press

Sunday, February 14th, 2021

Introduction

Sepsis, a destructive inflammatory response syndrome in clinical practice, is principally caused by multi-factors, such as toxins, pathogenic bacteria, and their metabolic products entering in the blood stream.1,2 As a terrible generalized hyperinflammatory condition, sepsis patients suffer a variety of tissue injuries and organ dysfunctions involving in lung, kidney, and heart.35 Despite many efforts have been made to reduce mortality and improve the cure rate of sepsis worldwide, sepsis remains a terrible disease that seriously threatens the patients. Only 30% septic patients survive according to statistics, besides, at least 6 million patients die from septic infection annually according to the statistics of the World Health Organization (WHO).6,7 Among the complications of sepsis, acute kidney injury (AKI) is the most common and serious with high mortality. It is considered that over 60% septic cases occur with AKI and approximately 50% AKI cases are associated with sepsis.8,9 Dreadfully, although the standard treatments are used, the mortality of severe AKI is as high as 45 to 70%.10 Hence, it is extremely urgent to study the accurate mechanisms and develop effective methods to alleviate sepsis-related AKI.

Several studies have revealed the mechanisms related to AKI are controversial, uncontrolled inflammatory response, severe oxidative stress, maladaptive apoptosis, and aberrant endoplasmic reticulum stress are all involved in the pathological process of AKI.11 As known, except for inflammation, oxidative stress is frequently prescribed for AKI pathogenesis. Oxidative stress referring to a state of imbalance between oxidation and anti-oxidation is a negative effect produced by free radicals, which is considered to be an important factor leading to multiple diseases, including retinopathy.12 Under various pathologic conditions, the strong correlation between oxidative stress injury and nuclear factor E2-related factor 2 (Nrf2) has been previously proved.1315 The preceding study has pointed out that Nrf2/HO-1 pathway is one of the most recognized signaling closely associated with oxidative and anti-oxidative balance.16,17 Under normal circumstances, the cap n collar subfamily of basic region-leucine zipper transcription factor Nrf2 is restricted in the cytoplasm by binding to its ligand Kelch-like ECH associating protein 1 (Keap1).18 Once exposed to oxidative stress stimulation, Nrf2-Keap1 complexes can be dissociated, the detached Nrf2 translocates into the nucleus to promote heme-oxygenase 1 (HO-1) expression, which involves in the balance of molecules associated with oxidative stress, such as superoxide dismutase (SOD), malonaldehyde (MDA), reactive oxygen species (ROS), and glutathione peroxidase (GSH-Px).19,20 Previously, regulating Nrf2 and its downstream genes could decrease inflammatory factor release, reduce oxidative stress, and maintain anti-apoptotic and survival abilities in the injured kidney.21 Therefore, restraining oxidative stress through activating Nrf2 pathway might be a possible therapeutic strategy targeting sepsis-related AKI.

The evolving evidence indicates that ROS accumulation resulting from abnormal oxidative stress promotes macromolecule peroxidation, and thereby causing cytochrome c-mediated mitochondrial apoptosis.22 Oxidative-stress-related excessive ROS generation contributes to cardiolipin oxidation, and thereby resulting in cytochrome c binding reduction.23 The free cytochrome c in the mitochondria migrates from inter-membrane side to the cytoplasm and touches off apoptotic cascade at the molecular level.24 Therefore, reducing oxidative stress and thus mitochondrial apoptosis induced by oxidative stress may be a potential therapeutic strategy for septic AKI.

Loganin (iridoid glycoside) is the main active ingredient of Corni fructus, which is the fruit of Cornus officinalis Sieb. and has been used to nourish the liver and kidney in the East for fairly long time.25 Loganin has been reported to possess the property of anti-inflammation, antioxidant, anti-diabetes, neuroprotection, and sedation.2630 Liu et al reported that Loganin alleviated diabetic nephropathy by down-regulating MDA level while up-regulating SOD activity in serum and kidney tissues, indicating the antioxidant capacity of Loganin in renal injury models.29 Moreover, Loganin could also play a hepatoprotective role in type 2 diabetic db/db mice by suppressing inflammatory reaction, oxidative stress, and apoptosis, which are the pathogenesis of septic AKI.28 However, whether Loganin can serve as a potential treatment for septic AKI is still unknown. Hence, the following study was conducted to investigate the effects of Loganin on septic AKI and preliminarily explore the related mechanism.

Cecal ligation and puncture (CLP) method was used to induce sepsis in mice. Male C57BL/6 mice at the age of 8 weeks (License number: SCXK (Liaoning, China) 20150001) were obtained from Changsheng biotechnology Co., Ltd. and kept in a standard laboratory environment (12-hour day/night cycle, 4555% humidity, 22 1C). After the adaption, the mice were randomly divided into the following five groups: Sham; CLP; III CLP+L-Loganin (20 mg/kg); CLP+M-Loganin (40 mg/kg); CLP+H-Loganin (80 mg/kg). After anesthesia, the abdomen of mice was open to expose the cecum. The cecal puncture point was the midpoint between the end of the cecum and the ligation point. For the mice in sham group, the cecum was found and returned into the abdominal. After the CLP operation, the mice were given Loganin (20, 40, 80 mg/kg) or equal volume of vehicle by gavage for once. A part of the mice were euthanized under deep anesthesia 24 h after the CLP operation to collect serum and renal cortex for follow-up experiments. The remaining mice were used to calculate the survival rate. All the animal treatment was performed in accordance with the Guide for Care and Use of Laboratory Animals (Eighth Edition) published by the Institute of Laboratory Animal Resources Commission on Life Sciences. All laboratory procedures were approved by The First Affiliated Hospital of Harbin Medical University (No.SYDW2019-229).

The collected serum was used to determine the levels of creatinine and blood urea nitrogen in accordance with the manufacturers instruction (Jiancheng Bioengineering Institute, China).

The fixed kidney tissues were embedded in paraffin, sliced into sections at 5 mm thick, subjected to hematoxylin solution (Solarbio, China), and counterstained with eosin (Sangon, China) in accordance with the manufacturer's instruction. The kidney pathological alterations were observed under light microscopy at 200 X magnification and scored to evaluate the degree of renal injury.

Simply, the above-mentioned kidney sections were blocked in goat serum at room temperature for 15 min, incubated in the primary antibody (Rabbit anti-neutrophil gelatinase-associated lipocalin (NGAL), dilution: 1:50, Affinity, China) at 4C overnight, and treated with HRP IgG antibody (dilution: 1:500, Thermo Fisher, USA) at room temperature for 1 hTo visualize renal NGAL expression, diaminobenzidine slide (Solarbio, China) and hematoxylin (Solarbio, China) were applied according to the manufacturers instruction. Finally, the expression of target protein was observed under light microscopy at 400 X magnification.

Briefly, cell apoptosis in the aforementioned kidney section was detected by TUNEL assay by using the In Situ Cell Death Detection Kit (Roche, Switzerland). After all the procedure required by the manufacturer's instruction, apoptosis was observed under light microscopy at 400 X magnification.

Human kidney proximal tubular (HK2) cells were obtained from Procell Life Science & Technology Co., Ltd. (Wuhan, China) and cultured in DMEM medium (Gibco, USA) in a humidified 5% CO2 incubator at 37C. After adhering to the plates, HK2 cells were exposed to 100 ng/mL lipopolysaccharides (LPS) with or without Loganin (5, 10, 20 M) for 48 h. The treated HK2 cells were collected for the future experiments.

To inhibit the function of AKT or Nrf2, HK2 cells were grown in 10 M LY294002 (a broad-spectrum inhibitor of PI3K) or 10 M ML385 (a specific Nrf2 inhibitor) for 48 h in the presence of 100ng/mL LPS and 20 M Loganin.

Oxidative stress markers, including SOD and GSH-Px activity as well as MDA production in the kidney tissues or HK2 cells, were, respectively, measured by corresponding assay kits (Nanjing Jiancheng Biological Engineering Institute, China). The microplate reader (BioTek, USA) was used to read the optical density (OD) value at 570 nm. ROS production in the kidney tissues or HK2 cells was measured by a ROS assay kit (Nanjing Jiancheng Biological Engineering Institute, China) and flow cytometry (NovoCyte, Aceabio, USA) was used for its quantitative analysis.

Mitochondrial membrane potential detection kit obtained from Beyotime Institute of Biotechnology (Shanghai, China) was used to detect the changes in mitochondrial membrane potential of kidney tissue homogenates or HK2 cells. All the procedures were according to the manufacturers instructions and flow cytometry (NovoCyte, Aceabio, USA) was used for the quantitative analysis.

Fluo-4 AM fluorescent probe was used to detect intracellular calcium mobilization. Briefly, kidney tissue homogenates or HK2 cells were incubated in 4 M Fluo-4 AM (Beyotime Institute of Biotechnology, China) at 37C for 30 min. After washing by PBS for three times, flow cytometry (NovoCyte, Aceabio, USA) was used for quantitative analysis.

Kidney tissues and treated HK2 cells were used to extract total, cytoplasmic, or nuclear protein, and the protein concentration was quantified by the BCA kit (Solarbio, China). The isolated protein was separated by sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE), transferred onto polyvinylidene difluoride (PVDF) membranes and blocked by 5% skimmed milk. Next, the PVDF membranes were subjected to the primary antibodies and horseradish peroxidase (HRP) labelled secondary antibody. Finally, chemiluminescence (ECL) kit was used to visualize the protein, which integrated intensity was calculated by Gel-Pro-Analyzer. The protein levels were presented as relative expression, which was calculated by comparing with the sham or control group. The primary antibodies were as follows: Rabbit anti-cytochrome c; anti-Bax; anti-Bcl-2; anti-AKT, anti-p-AKT (Ser473); anti-Nrf2; anti-HO-1 (dilution: 1:1000, Abclonal, China); anti-cleaved caspase-3 (dilution: 1:1000, Affinity, China).

Data were represented as means standard derivations (SD). The data from three or more groups were analyzed by one-way ANOVA followed by Tukeys multiple comparison tests. P value less than 0.05 was considered statistically significant.

First of all, we detected the survival rate in septic mice with Loganin administration. As shown in Figure 1A, the survival rate was observably elevated in the Loganin-treated septic mice when compared with the model ones (20, 40, 80 mg/kg). The concentrations of serum creatinine and blood urea nitrogen (Figure 1B and C) as well as the expressions of acute kidney injury marker NGAL (Figure 1E) were down-regulated with Loganin treatment (20, 40, 80 mg/kg, p < 0.05). Besides, compared with the septic group, the renal injury score calculated by HE staining was also decreased with Loganin treatment (20, 40, 80 mg/kg, Figure 1D and F, p < 0.05). The above results indicated that Loganin not only possessed the feature of down-regulating mortality but also could relieve AKI in septic mice.

Figure 1 Effects of Loganin on the survival rate, renal function and renal pathological changes in septic mice. (A) The survival rate in septic mice after Loganin treatment. The levels of serum (B) creatinine and (C) blood urea nitrogen in septic mice after Loganin treatment. (D) HE staining (at 200magnification) and (E) immunohistochemistry targeting NGAL (at 400magnification) in kidney tissue of septic mice after Loganin treatment. (F) HE staining score. Data were represented as mean SD at least six independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. ###p < 0.001 vs the sham group and **p < 0.01, ***p < 0.001 vs the CLP group.

Since oxidative stress is considered to be one of the principal elements mediating AKI, we measured the changes in oxidative stress status of kidney tissues after Loganin treatment. As exhibited in Figure 2AD, the activities of SOD and GSH-Px were up-regulated, while the productions of MDA and ROS were down-regulated in the kidney tissue of septic mice after Loganin treatment (20, 40, 80 mg/kg, p < 0.05), indicating Loganin prevented oxidative stress damage. To investigate whether Loganin was involved in mitochondrial dysfunction associated with renal impairment, we detected mitochondrial function in the kidney tissue of septic mice after Loganin treatment. As described in Figure 2E and F, the mitochondrial membrane potential loss and calcium overload were obvious in the kidney tissues after CLP procedure, which could be remitted by Loganin treatment (20, 40, 80 mg/kg, p < 0.05). With the restoration of mitochondrial function after Loganin treatment, the release of cytochrome c from mitochondria to cytoplasm was also decreased (20, 40, 80 mg/kg, Figure 2G and H, p < 0.05). Afterwards, the possible molecular mechanism related oxidative stress status was preliminarily studied. As shown in Figure 2IK, the nuclear translocation of Nrf2 was accelerated in Loganin-treated group (20, 40, 80 mg/kg, p < 0.05). Accompanied by Nrf2 nuclear translocation, HO-1 expression was also increased in kidney tissue of septic mice (20, 40, 80 mg/kg, p < 0.05). The above results indicated that Loganin reduced oxidative stress injury and promoted mitochondrial function recovery in kidney tissue of septic mice, which might be regulated by Nfr2/HO-1 signaling pathway.

Figure 2 Effects of Loganin on oxidative stress and mitochondrial function in kidney tissue of septic mice. (A) SOD activity in kidney tissue of septic mice after Loganin treatment. (B) MDA levels in kidney tissue of septic mice after Loganin treatment. (C) GSH-Px activity in kidney tissue of septic mice after Loganin treatment. (D) ROS production in kidney tissue of septic mice after Loganin treatment. (E) Flow cytometry was used to analyze JC-1 staining in kidney tissue of septic mice after Loganin treatment. (F) Flow cytometry was used to analyze calcium overload in kidney tissue of septic mice after Loganin treatment. Representative Western blot for (G) mitochondrial cytochrome c, (H) cytoplasmic cytochrome c (I) nuclear Nrf2, (J) cytoplasmic Nrf2 and (K) HO-1 in kidney tissues of septic mice after Loganin treatment. Data were represented as mean SD at least six independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. #p< 0.05, ###p < 0.001 vs the sham group and *p< 0.05 **p < 0.01, ***p < 0.001 vs the CLP group.

Subsequently, apoptosis in kidney tissues was also studied in our work. As suggested by TUNEL staining of the kidney tissue, apoptosis was distinctly increased after CLP procedure, which could be inhibited by Loganin administration (Figure 3A, 20, 40, 80 mg/kg). Consistent with TUNEL staining results, the levels of cleaved caspase-3 and Bax were decreased, whereas Bcl-2 levels were increased in the kidney of septic mice treated with Loganin (Figure 3BD, 20, 40, 80 mg/kg, p < 0.05). Simultaneously, AKT phosphorylation was down-regulated by CLP procedure compared with the sham operation, which was restored by Loganin administration (Figure 3E, 20, 40, 80 mg/kg, p < 0.05). The above results indicated that Loganin inhibited apoptosis in kidney tissue of septic mice, which might be regulated by AKT signaling pathway.

Figure 3 Effects of Loganin on apoptosis in kidney tissue of septic mice. (A) TUNEL staining in kidney tissue of septic mice. Representative Western blot for (B) cleaved caspase-3, (C) Bax, (D) Bcl-2 and (E) p-AKT in kidney tissue of septic mice after Loganin treatment. Data were represented as mean SD at least six independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. ###p < 0.001 vs the sham group and ***p < 0.001 vs the CLP group.

Since the in vivo experiments suggested Loganin could alleviate oxidative stress injury and promoted mitochondrial function recovery in septic kidney tissues, we should prove the beneficial effects of Loganin in vitro. As described in Figure 4AD, SOD and GSH-Px activities were decreased, while MDA and ROS productions were increased in LPS-incubated HK2 cells (p < 0.05). The incubation of Loganin could eliminate this phenomenon (5, 10, 20 M, p < 0.05). In addition, the loss of mitochondrial membrane potential and the overload of calcium, accompanied by cytochrome c release to cytoplasm, were almost reversed by Loganin incubation (Figure 4EJ, 5, 10, 20 M, p < 0.05). Similar to the in vivo results, the abnormal activation of Nrf2/HO-1 signaling pathway was also reversed with Loganin treatment (Figure 4KM, 20 M, p < 0.05), indicating Loganin mitigated oxidative stress and facilitated mitochondrial function recovery possibly via activating Nrf2/HO-1 signaling pathway in LPS-stimulated HK2 cells.

Figure 4 Effects of Loganin on oxidative stress and mitochondrial function in LPS-treated HK2 cells. (A) SOD activity in LPS-stimulated HK2 cells after Loganin treatment. (B) MDA levels in LPS-stimulated HK2 cells after Loganin treatment. (C) GSH-Px activity in LPS-stimulated HK2 cells after Loganin treatment. (D) ROS production in LPS-stimulated HK2 cells after Loganin treatment. (E) and (G) Flow cytometry was used to analyze JC-1 staining in LPS-stimulated HK2 cells after Loganin treatment. (F) and (H) Flow cytometry was used to analyze calcium overload in LPS-stimulated HK2 cells after Loganin treatment. Representative Western blot for (I) mitochondrial cytochrome c, (J) cytoplasmic cytochrome c, (K) nuclear Nrf2, (L) cytoplasmic Nrf2 and (M) HO-1 in LPS-stimulated HK2 cells after Loganin treatment. Data were represented as mean SD at least three independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. ##p < 0.01, ###p < 0.001 vs the control group and *p< 0.05 **p < 0.01, ***p < 0.001 vs the LPS group.

As shown in Figure 5A, the apoptosis rate of LPS-treated HK2 cells was distinctly increased compared with the control (p < 0.05), which could be lessened by Loganin incubation (5, 10, 20 M, p < 0.05). The incubation of Loganin inhibited caspase-3 splitting and Bax expression, whereas elevated Bcl-2 levels in LPS-stimulated HK2 cells (Figure 5BD, 5, 10, 20 M, p < 0.05). In addition, the aberrant phosphorylation of AKT was also reversed by Loganin treatment in LPS-stimulated HK2 cells (Figure 5E, 20 M, p < 0.05), which was consistent with the results of in vivo experiments, indicating Loganin inhibited LPS-induced HK2 cell apoptosis potentially by regulating AKT signaling pathway.

Figure 5 Effects of Loganin on apoptosis in LPS-treated HK2 cells. (A) Flow cytometry was used to analyze apoptosis in LPS-stimulated HK2 cells after Loganin treatment. Representative Western blot for (B) cleaved caspase-3, (C) Bax, (D) Bcl-2 and (E) p-AKT in LPS-stimulated HK2 cells after Loganin treatment. Data were represented as mean SD at least three independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. #p< 0.05, ##p < 0.01, ###p < 0.001 vs the control group and *p< 0.05 **p < 0.01, ***p < 0.001 vs the LPS group.

The aforementioned data suggested both Nrf2/HO-1 and AKT pathway might involve in the protective effects of Loganin on septic AKI. Finally, antagonist targeting the activity of Nrf2 and AKT, ML385 and LY294002 was used to verify the regulating effects of Loganin on Nrf2/HO-1 and AKT signaling pathway in LPS-induced HK2 cells. As shown in Figure 6AD, the antioxidant properties of Loganin were diminished by ML385 or LY294002 application in LPS-treated HK2 cells as indicated by SOD and GSH-Px activities as well as MDA and ROS productions (p < 0.05). Besides, the protective effects of mitochondrial function of Loganin were offset by Nrf2 or AKT suppression (Figure 6EH and J, p < 0.05). Similarly, as indicated by flow cytometry results, its antiapoptotic effects were also weakened by ML385 or LY294002 (Figure 6I, p < 0.05). The above results proved that the protective effects of Loganin were mediated by regulating Nrf2/HO-1 and AKT signaling pathway, but the direct target of Loganin was left to be explored in the future.

Figure 6 Verifying the effects of Loganin on AKT and Nrf2/HO-1 signaling. (A) SOD activity in LPS-stimulated HK2 cells after Loganin treatment. (B) MDA levels in LPS-stimulated HK2 cells after Loganin treatment. (C) GSH-Px activity in LPS-stimulated HK2 cells after Loganin treatment. (D) ROS production in LPS-stimulated HK2 cells after Loganin treatment. (E) and (G) Flow cytometry was used to analyze JC-1 staining in LPS-stimulated HK2 cells after Loganin treatment. (F) and (H) Flow cytometry was used to analyze calcium overload in LPS-stimulated HK2 cells after Loganin treatment. (I) Flow cytometry was used to analyze apoptosis in LPS-stimulated HK2 cells after Loganin treatment. Representative Western blot for (J) mitochondrial cytochrome c and cytoplasmic cytochrome c in LPS-stimulated HK2 cells after Loganin treatment. Data were represented as mean SD at least three independent experiments and analyzed by one-way analysis of variance (ANOVA) followed by Tukeys multiple comparison test. *p< 0.05 **p < 0.01, ***p < 0.001 vs the indicated group.

Sepsis is a complex inflammatory condition that responded to infection. The complications of sepsis are varied. Acute lung injury (ALI) is the first to appear, whereas AKI is the most serious one resulting in a mortality of 4570% in septic patients.10 In the present work, we aimed to study whether Loganin possessed the nephroprotective effect in septic mice and investigated the underlying mechanisms. Firstly, we found Loganin administration improved the survival rate in septic mice. Meanwhile, AKI was also relieved Loganin administration reflected by reduced oxidative stress, restored mitochondrial function, and inhibited apoptosis in the kidney tissue of septic mice. Besides, Loganin treatment promoted Nrf2 nuclear translocation, activated its downstream molecules, and simultaneously facilitated AKT phosphorylation in the kidney of septic mice and LPS-treated HK2 cells. Meanwhile, the beneficial effects of Loganin could be crippled by Nrf2 antagonist ML385 or PI3K inhibitor LY294002, indicating Nrf2/HO-1 and AKT signaling pathway activation is essential for the nephroprotective effects of Loganin in septic models. Above all, the present work suggested that Loganin treatment acquired protective effects in septic AKI through reducing oxidative stress and apoptosis via regulating Nrf2/HO-1 and AKT signaling pathway.

The sepsis model was established by using the CLP method, which was supposed to be the gold in vivo model for the experimental sepsis.31 It is well accepted that CLP method can simulate clinical symptoms of sepsis more practically than endotoxin or bacteria injection method.32 Hence, CLP method was adopted in our work to evaluate the therapeutic effect of Loganin on septic AKI and its underlying mechanisms. In the present study, the degree of kidney injury was analyzed after CLP procedure in mice. Consistent with previous research,33 we found the levels of serum creatinine, blood urea nitrogen, and AKI marker NGAL expression were significantly increased, indicating the septic AKI models were successfully imitated. As the exhibited results, the survival rate in septic mice with Loganin treatment was distinctly increased, indicating the potential protection of Loganin in sepsis. Afterwards, the reduction in serum creatinine concentration, blood urea nitrogen level, and renal NGAL expression was observed in septic mice with Loganin treatment, suggesting the palliative effects of Loganin on sepsis-related AKI. The in vivo data preliminarily confirmed the renal protective effects of Loganin in septic mice.

It is well understood that excessive oxidative stress is appeared to participate in the process of kidney injury resulting from multiple factors, including diabetes and sepsis.34,35 The influence of abnormal oxidative stress in the kidney tissue of CLP-treated mice should not be belittled. The previous studies have reported that Loganin possesses the ability to restore the balance of oxidative stress in diabetic nephropathy animal models by down-regulating MDA level while up-regulating SOD activity.29 Besides, Loganin also could remit inflammatory reaction, oxidative stress, and apoptosis in the livers of type 2 diabetic db/db mice models.28 Based on these backgrounds, we preliminarily inferred that Loganin might play the protective role of renal injury in septic mice by alleviating oxidative stress and experiments were carried out. In our study, we found that the CLP procedure induced SOD and GSH-Px activity decline while MDA and ROS production rise in the kidney tissue, which could be restored by the single gavage of Loganin. Similar to previous studies, the results reminded that the anti-oxidant effect of Loganin might be the basis of its renal protection.36,37 The evidence presented supported the strong relationship between mitochondrial dysfunction and abundant oxidative stress.38 In the work, we found the mitochondrial membrane potential loss and calcium overload were obvious in the kidney tissue after CLP procedure, indicating mitochondrial dysfunction occurred in the septic kidney. Not surprisingly, improved mitochondrial function reflected by elevated mitochondrial membrane potential and decreased calcium overload in the septic kidney was concurrently remitted by Loganin. The above results indicated that the anti-oxidation and mitochondrial function protection might be the basis for nephroprotective effects of Loganin.

Except for providing energy for cells, mitochondria are also involved in differentiation information transmission and apoptosis.39 Given that apoptosis, an important factor contributing to AKI progression, is worthy to be studied. Under the pathological conditions, cytochrome c in the inter-membrane space of mitochondria was released to cytoplasm, recruited apoptosome formation, and thereby inducing pathological apoptosis.40 Our data showed CLP surgery caused cytochrome c migration from mitochondrial inter-membrane space to the cytoplasm, which could be reversed by Loganin treatment. To evaluate apoptosis occurrence in the kidney, TUNEL staining and apoptosis-related protein expressions (cleaved caspase-3, Bax, and Bcl-2) were detected. Fortunately, apoptosis could be inhibited by Loganin treatment in vivo and in vitro in a dose-dependent form, indicating the anti-apoptosis effects of Loganin.

Several lines of evidence showed that Nrf2 is a redox-sensitive transcription factor modulating the transcription of oxidative stress-associated genes.41 Meanwhile, the salutary effects of Loganin in type 2 diabetic db/db might be mediated by Nrf2 introduction to the nuclei.28 Therefore, we speculated that Loganin might also alleviate septic AKI by activating Nrf2-related signalling pathway. Fortunately, we found that Loganin administration promoted Nrf2 nuclear translocation and HO-1 activation. Next, the in vitro studies were implemented to confirm whether Nrf2/HO-1 signaling was involved in the beneficial effect of Loganin in LPS-treated HK2 cells. Similar to the experimental results in vivo, Loganin alleviated oxidative stress injury, restored mitochondrial function, and inhibited apoptosis in LPS-stimulated HK2 cells, which could be diminished by the specific Nrf2 inhibitor ML385. Although it has not been confirmed that Nrf2 is a direct target of Loganin, our experimental results show that Nrf2/HO-1 signaling pathway is closely related to its protective effect. The key point regulating apoptosis, AKT phosphorylation, was also measured in our work. Analogously, Loganin increased the phosphorylation of AKT in the injured kidney and LPS-stimulated HK2 cells. Besides, the salutary effects also diminished in vitro by LY294002, the broad-spectrum inhibitor of PI3K, indicating AKT pathway is associated with the property of Loganin. According to the validating results of in vitro experiments, our study suggested that Loganin alleviated septic AKI through regulating oxidative stress injury, mitochondrial function, and apoptosis in tubular epithelial cells, which might attribute to the involvement of AKT and Nrf2/HO-1 signaling. However, the direct target of Loganin remained to be explored, which was the focus of our future work.

Above all, our work suggested that Loganin possessed the property to remit AKI in septic mice by regulation of oxidative stress mitochondrial function and apoptosis tubular epithelial cells via AKT and Nrf2/HO-1 signaling, which might provide a new therapeutic strategy for septic AKI.

AKI, acute kidney injury; CLP, cecal ligation and puncture; GSH-Px, glutathione peroxidase; LPS, lipopolysaccharides; HO-1, heme-oxygenase 1; Keap1, Kelch-like ECH associating protein 1; MDA, malonaldehyde; Nrf2, nuclear factor E2-related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase.

This research was supported by grants from the National Natural Science Foundation of China (No. 81571871 and 81770276) and Nn10 program of Harbin Medical University Cancer Hospital.

The authors declared no conflicts of interest for this work.

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4. Navegantes-Lima KC, Monteiro VVS, de Frana Gaspar SL, et al. Agaricus brasiliensis Mushroom Protects Against Sepsis by Alleviating Oxidative and Inflammatory Response. Front Immunol. 2020;11:1238.

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7. Nwafor D, Brown C. A novel role for tissue-nonspecific alkaline phosphatase at the blood-brain barrier during sepsis. Neural Regen Res. 2021;16:99.

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12. Opatrilova R, Kubatka P, Caprnda M, et al. Nitric oxide in the pathophysiology of retinopathy: evidences from preclinical and clinical researches. Acta Ophthalmol. 2018;96(3):222231. doi:10.1111/aos.13384

13. Fei L, Jingyuan X, Fangte L, et al. Preconditioning with rHMGB1 ameliorates lung ischemia-reperfusion injury by inhibiting alveolar macrophage pyroptosis via the Keap1/Nrf2/HO-1 signaling pathway. J Transl Med. 2020;18(1):301. doi:10.1186/s12967-020-02467-w

14. Garrido-Pascual P, Alonso-Varona A, Castro B, Burn M, Palomares T. H2O2-preconditioned human adipose-derived stem cells (HC016) increase their resistance to oxidative stress by overexpressing Nrf2 and bioenergetic adaptation. Stem Cell Res Ther. 2020;11(1):335. doi:10.1186/s13287-020-01851-z

15. Yifan Z, Benxiang N, Zheng X, et al. Ceftriaxone Calcium Crystals Induce Acute Kidney Injury by NLRP3-Mediated Inflammation and Oxidative Stress Injury. Oxid Med Cell Longev. 2020;2020:6428498. doi:10.1155/2020/6428498

16. Luo J, Li X, Li X, et al. Selenium-Rich Yeast protects against aluminum-induced peroxidation of lipide and inflammation in mice liver. BioMetals. 2018;31(6):10511059. doi:10.1007/s10534-018-0150-2

17. Diao C, Chen Z, Qiu T, et al. Inhibition of PRMT5 Attenuates Oxidative Stress-Induced Pyroptosis via Activation of the Nrf2/HO-1 Signal Pathway in a Mouse Model of Renal Ischemia-Reperfusion Injury. Oxid Med Cell Longev. 2019;2019:2345658. doi:10.1155/2019/2345658

18. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89116. doi:10.1146/annurev.pharmtox.46.120604.141046

19. Zhou X, Liu Z, Ying K, et al. WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling. Oxid Med Cell Longev. 2020;2020:7950457. doi:10.1155/2020/7950457

20. Irazabal MV, Torres VE. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells. 2020;9(6):1342. doi:10.3390/cells9061342

21. Zhang X, Zhu Y, Zhou Y, Fei B. Activation of Nrf2 Signaling by Apelin Attenuates Renal Ischemia Reperfusion Injury in Diabetic Rats. Diabetes Metab Syn Obesity. 2020;13:21692177. doi:10.2147/DMSO.S246743

22. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12(5):913922. doi:10.1007/s10495-007-0756-2

23. Dodd-O JM, Welsh LE, Salazar JD, et al. Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury. Am J Physiol. 2004;287(2):H92736.

24. Ruffolo SC, Breckenridge DG, Nguyen M, et al. BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell Death Differ. 2000;7(11):11011108. doi:10.1038/sj.cdd.4400739

25. Lee KY, Sung SH, Kim SH, Jang YP, Oh TH, Kim YC. Cognitive-enhancing activity of loganin isolated from Cornus officinalis in scopolamine-induced amnesic mice. Arch Pharm Res. 2009;32(5):677683. doi:10.1007/s12272-009-1505-6

26. Shi R, Han Y, Yan Y, et al. Loganin exerts sedative and hypnotic effects via modulation of the serotonergic system and GABAergic neurons. Fron Pharmacol. 2019;10:409. doi:10.3389/fphar.2019.00409

27. Li Y, Li Z, Shi L, et al. Loganin inhibits the inflammatory response in mouse 3T3L1 adipocytes and mouse model. Int Immunopharmacol. 2016;36:173179. doi:10.1016/j.intimp.2016.04.026

28. Park CH, Tanaka T, Kim JH, et al. Hepato-protective effects of loganin, iridoid glycoside from Corni Fructus, against hyperglycemia-activated signaling pathway in liver of type 2 diabetic db/db mice. Toxicology. 2011;290(1):1421. doi:10.1016/j.tox.2011.08.004

29. Liu K, Xu H, Lv G, et al. Loganin attenuates diabetic nephropathy in C57BL/6J mice with diabetes induced by streptozotocin and fed with diets containing high level of advanced glycation end products. Life Sci. 2015;123:7885. doi:10.1016/j.lfs.2014.12.028

30. Kim H, Youn K, Ahn M-R, et al. Neuroprotective effect of loganin against A 2535 -induced injury via the NF-B-dependent signaling pathway in PC12 cells. Food Funct. 2015;6(4):11081116. doi:10.1039/C5FO00055F

31. Dejager L, Pinheiro I, Dejonckheere E, Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol. 2011;19(4):198208. doi:10.1016/j.tim.2011.01.001

32. Doi K, Leelahavanichkul A, Yuen PST, Star RA. Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest. 2009;119(10):28682878. doi:10.1172/JCI39421

33. Sung P-H, Lo Chang C, Tsai T-H, et al. Apoptotic adipose-derived mesenchymal stem cell therapy protects against lung and kidney injury in sepsis syndrome caused by cecal ligation puncture in rats. Stem Cell Res Therapy. 2013;4(6):155. doi:10.1186/scrt385

34. Kim JY, Leem J, Hong HL. Protective effects of spa0355, a thiourea analogue, against lipopolysaccharide-induced acute kidney injury in mice. Antioxidants. 2020;9:113.

35. Chen X, Liu W, Xiao J, et al. FOXO3a accumulation and activation accelerate oxidative stress-induced podocyte injury. FASEB J. 2020;34(10):1330013316. doi:10.1096/fj.202000783R.

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41. Feng X, Guan W, Zhao Y, et al. Dexmedetomidine ameliorates lipopolysaccharide-induced acute kidney injury in rats by inhibiting inflammation and oxidative stress via the GSK-3/Nrf2 signaling pathway. J Cell Physiol. 2019;234:1899419009.

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[Full text] Loganin Attenuates Septic Acute Renal Injury with the Participation of | DDDT - Dove Medical Press

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Joint inflammation: Causes, treatment, and symptoms – Medical News Today

Sunday, February 14th, 2021

Joint inflammation can lead to swollen, painful joints. Depending on the cause, it can affect one particular joint or be more widespread, affecting multiple joints throughout the body.

Inflammation is the bodys normal immune response to an injury, infection, or irritant. Allergies, wounds, and diseases can all cause inflammation. The most common causes of joint inflammation are injuries and inflammatory arthritis.

Pain and inflammation resulting from injuries usually resolve, but inflammatory arthritis is a chronic condition that may get worse with time. Keep reading to learn more.

Joint inflammation occurs when the immune system or damaged tissue releases chemicals that cause swelling and other symptoms in a joint. It can affect just one joint, such as when a person sustains an injury. However, certain medical conditions can lead to multiple instances of joint inflammation throughout the body.

When a joint is inflamed, the blood vessels around it dilate to allow more blood to reach it. White blood cells, which play a crucial role in the bodys immune response, rush to the inflamed site, where they work to fight any infection or irritant.

This response leads to inflammation in this area. The joint may feel hot or painful, and the inflammation may intensify the pain of an underlying injury or infection.

In the short term, inflammation helps the body fight off dangerous invaders. However, chronic inflammation can damage the joint.

The most common causes of joint inflammation are:

An injury to a joint usually causes localized inflammation. However, it can sometimes cause inflammation in several joints if they are very close together. For example, if a person injures their foot, they might have joint inflammation in several toes.

Swelling is the bodys natural response to an injury. Inflammation helps the body deliver nutrients and white blood cells to an injured joint to fight off infection and promote healing.

However, inflammation is painful, and intense swelling may actually slow healing. Anyone who experiences inflammation that is serious enough to interfere with everyday functioning should see a doctor.

Arthritis is a group of conditions that affect joint health. Inflammatory forms of arthritis cause inflammation in the joints. Most types of inflammatory arthritis are chronic, progressive conditions. They may begin in one joint but eventually progress to other joints.

Some examples of inflammatory arthritis include:

Many types of inflammatory arthritis are autoimmune diseases, which means that they appear when the bodys immune system mistakenly attacks healthy tissue.

However, some infections can also cause inflammatory arthritis. Septic arthritis happens when a joint becomes infected. Sometimes, an infection in another area of the body travels through the bloodstream to a joint.

This type of inflammation is not chronic and usually gets better with treatment. Without quick treatment, though, there is a risk of permanent damage to the joints and bones.

Learn more about inflammatory arthritis here.

Some symptoms of joint inflammation include:

When the symptoms appear following an injury, inflammation is usually just a short-term response to the injury.

People who notice ongoing inflammation or pain may have arthritis. Joint pain that occurs with a fever or following an infection may signal a joint infection that requires immediate medical treatment.

The right treatment for inflammation depends on the cause. Some minor injuries will improve on their own with rest and time. More serious injuries may require medical treatment or even surgery.

People with a bacterial infection often need antibiotics. In severe cases, they may need to stay in the hospital.

For serious injuries and chronic inflammation, these medical treatments may help:

Several home remedies can help with most types of inflammation, regardless of the cause:

A person should contact a doctor or healthcare provider if:

It is necessary to go to the emergency room or call 911 if:

Inflammation comes in many forms, and it can affect a single joint or many joints throughout the body.

Short-term joint inflammation from an injury usually goes away on its own.

While chronic inflammation can be difficult to treat and may get worse with time, various medications can help. A person can contact a doctor for help managing all forms of inflammation.

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[Full text] Encephalopathy Induced by Preventive Administration of Acyclovir in a | IJGM – Dove Medical Press

Sunday, February 14th, 2021

Introduction

Acyclovir (ACV) neurotoxicity is a neuropsychiatric condition induced by the administration of the anti-herpetic drugs ACV and valacyclovir (VACV).1 VACV is the prodrug of ACV. Usually, various neuropsychiatric symptoms, such as disturbance of consciousness, tremor, and myoclonus, occur within 2 days after initiating the therapy.13 Hallucinations are also common.13 It is presumed that elevated blood levels of ACV and its metabolite, 9-carboxymethoxymethylguanine (CMMG), are involved in the development of ACV-induced encephalopathy4 and that age and renal dysfunction are risk factors.5

Bortezomib/dexamethasone (BD) therapy is one of the standard regimens for patients with symptomatic multiple myeloma who have severe renal impairment.6 In bortezomib-containing regimens, low-dose oral ACV is recommended for herpes zoster prophylaxis.7,8

We present a case of encephalopathy caused by the administration of VACV for herpes zoster prophylaxis in a patient with renal dysfunction due to multiple myeloma.

Renal dysfunction was diagnosed in a 70-year-old man who visited our hospital for a medical checkup. His serum creatinine level and creatinine clearance rate were 8.78 mg/dL (normal range: 0.531.02 mg/dL) and 8 mL/min (normal range: 80180 mL/min), respectively. He was diagnosed with BenceJones protein -type multiple myeloma based on the presence of 40% plasma cells in his bone marrow (10% or more of plasma cells is considered definitive of the disease) and BenceJones proteinuria (M proteinuria of 4.8 g/day). Additionally, the diagnosis of symptomatic multiple myeloma (International Staging System stage 3) was based on the presence of renal dysfunction. Renal biopsy revealed cast nephropathy known as myeloma kidney, in which large amounts of BenceJones proteins formed casts that blocked the tubules (Figure 1). BD therapy was initiated with concurrent VACV for herpes zoster prophylaxis. We administered a reduced dose VACV of 500 mg three times a week because of the patients renal impairment, based on the drug information on VACV provided in the UpToDate database.9 His renal function was monitored twice per week during therapy. Six weeks later, during his second course of BD therapy, the patient was hospitalized because of impaired consciousness. He displayed no other symptoms during hospitalization.

Figure 1 Histology of kidney tissue showing myeloma cast nephropathy. (A) Hematoxylin and eosin stain (magnification 200). (B) Periodic acid-Schiff stain (magnification 400).

On admission, his vital signs were as follows: Glasgow Coma Scale score, E2, V4, M4; body temperature, 36.5C; blood pressure, 145/79 mmHg; pulse rate, 73 beats/min; respiratory rate, 15 breaths/min; and SpO2, 96%. His vital signs were normal, and there were no remarkable neurological abnormalities except for disturbance of consciousness. Table 1 summarizes the results of patients blood test on admission. The results, including renal function, were unchanged. Brain magnetic resonance imaging and cerebrospinal fluid analysiscell counts 1/L, protein 40 mg/dL, glucose 98 mg/dL, reference blood glucose level 125 mg/dLrevealed no abnormalities. There was no new electrolyte, endocrine hormone abnormality, or suggestion of epilepsy. Therefore, we suspected drug-induced disturbance of consciousness and suspended the BD and VACV therapy. Three days after discontinuing the drugs, his level of consciousness returned to normal, and the BD therapy was restarted after 20 days of drug interruption. The Naranjo score10 for estimating the probability of adverse drug reactions was 7 points. In this scoring system, 9 points indicate high probability for adverse reactions and 58 points indicate probability for adverse reactions.10 In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. Though his blood level of ACV could not be measured, the clinical diagnosis was ACV neurotoxicity based on his response to the suspension of the therapy, the high Naranjo score, and the lack of other contributing factors. We theorized that ACV blood levels gradually increased over the long-term administration of oral VACV owing to renal dysfunction. Figure 2 illustrates his clinical course.

Table 1 Results of the Patients Admission Blood Tests

Figure 2 Clinical course of the patient after starting bortezomib/dexamethasone therapy. BD therapy: Bortezomib was administered at a dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 with dexamethasone (20 mg) administered on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12. The 21-day regimen administered in 2 cycles was defined as 1 course.

The patient underwent 9 cycles of BD therapy and achieved complete remission. We administered 250 mg of famciclovir for herpes zoster prophylaxis, three times a week, between cycles 4 to 9. One year after the end of treatment, he remained in remission. His creatinine level recovered and remained stable at 45 mg/dL in response to the treatment. He did not exhibit any sequelae of ACV encephalopathy.

We presented a case of ACV-induced encephalopathy caused by the administration of VACV for herpes zoster during the treatment of multiple myeloma in a man with renal dysfunction. To the best of our knowledge, this is the first report of ACV neurotoxicity in a patient taking low-dose VACV for herpes zoster prophylaxis. This case illustrates that ACV or VACV should be used with caution in patients with myeloma-associated renal dysfunction, even if used in low doses for herpes zoster prophylaxis.

In all Japan, the laboratories do not have facilities to measure ACV/CMMG levels. However, we diagnosed ACV-induced encephalopathy based on his clinical course, the high Naranjo score, the lack of other contributing factors. ACV or VACV can cause renal tubular obstruction secondary to crystal-induced nephropathy, and direct action of the ACV aldehyde can cause acute kidney injury; these can lead to increased blood concentrations of ACV and CMMG and cause encephalopathy.2,11 In this case, our patient exhibited BenceJones proteinuria. Increased excretion of BenceJones proteins may have damaged the tubular epithelium or formed casts that blocked the renal tubules, leading to myeloma cast nephropathy. It is the most common cause of myeloma-associated renal injury and may cause renal dysfunction.12,13 Though the renal dysfunction in our patient was stable at a low level, we theorized that long-term preventive oral VACV therapy gradually led to increased plasma concentrations of ACV and CMMG, resulting in encephalopathy.

In this case, the VACV prophylaxis resulted in ACV-induced encephalopathy, even though we administered it at a dose lower than the recommended dose for patients with renal dysfunction. ACV-induced encephalopathy has been observed in patients administered with extremely high doses (10 mg/kg every hour) of the drug or in cases of renal failure without dose adjustment.4 It has often been reported in elderly people and patients with impaired renal function,5 but it has occurred in patients without renal dysfunction and young patients.14 In all cases, ACV-induced encephalopathy developed owing to the ACV or VACV treatment for herpes simplex or zoster virus. There were no reports that ACV-induced encephalopathy developed with prophylactic administration. Myeloma kidney with BenceJones proteinuria causes kidney renal tubular damage, which is disproportionate to the degree of renal impairment suggested by the creatinine level. Thus, it is presumed that it inhibits the excretion of drugs, including ACV, in renal tubules, resulting in an elevated blood concentration. It is difficult to measure ACV and CMMG blood levels. Therefore, even with the recommended level of ACV or VACV prophylaxis for renal impairment, it is not possible to predict ACV neurotoxicity, such as impaired consciousness and impaired renal function.

In conclusion, among patients with multiple myeloma with BenceJones proteinuria, the renal tubules are easily damaged, and the plasma concentration of ACV is likely to increase and induce ACV neurotoxicity. Careful monitoring of the level of consciousness is necessary during preventive ACV therapy in patients with renal dysfunction.

ACV, acyclovir; BD, bortezomib/dexamethasone; CMMG, 9-carboxymethoxymethylguanine; VACV, valacyclovir.

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

All authors contributed to the conception, study design, execution, acquisition of data, analysis and interpretation, drafting and revising the article, and critically reviewing the article; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work.

There is no funding to report.

The authors declare that they have no conflicts of interest.

1. Rashiq S, Briewa L, Mooney M, Giancarlo T, Khatib R, Wilson FM. Distinguishing acyclovir neurotoxicity from encephalomyelitis. J Intern Med. 1993;234:507511. doi:10.1111/j.1365-2796.1993.tb00785.x

2. Asahi T, Tsutsui M, Wakasugi M, et al. Valacyclovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol. 2009;16:457460. doi:10.1111/j.1468-1331.2008.02527.x

3. Adair JC, Gold M, Bond RE. Acyclovir neurotoxicity: clinical experience and review of the literature. South Med J. 1994;87:12271231. doi:10.1097/00007611-199412000-00006

4. Chowdhury MA, Derar N, Hasan S, Hinch B, Ratnam S, Assaly R. Acyclovir-induced neurotoxicity: a case report and review of literature. Am J Ther. 2016;23:e941e943. doi:10.1097/MJT.0000000000000093

5. Das V, Peraldi MN, Legendre C. Adverse neuropsychiatric effects of cytomegalovirus prophylaxis with valaciclovir in renal transplant recipients. Nephrol Dial Transplant. 2006;21:13951401. doi:10.1093/ndt/gfk031

6. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 Phase III trial. J Clin Oncol. 2010;28:46214629. doi:10.1200/JCO.2009.27.9158

7. Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26:47844790. doi:10.1200/JCO.2007.14.9641

8. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906917. doi:10.1056/NEJMoa0801479

9. UpToDate. Valaciclovir: drug information. Available from: https://www.uptodate.com/contents/valacyclovir-drug-information?search=valacyclovir&topicRef=8337&source=see_link#F50991799. Accessed January 17, 2021.

10. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239245. doi:10.1038/clpt.1981.154

11. Sacchetti D, Alawadhi A, Albakour M, Rapose A. Herpes zoster encephalopathy or acyclovir neurotoxicity: a management dilemma. BMJ Case Rep. 2014;2014:bcr2013201941. doi:10.1136/bcr-2013-201941

12. Hutchison CA, Batuman V, Behrens J, et al. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol. 2011;8:4351. doi:10.1038/nrneph.2011.168

13. Leung N, Rajkumar SV. Renal manifestations of plasma cell disorders. Am J Kidney Dis. 2007;50:155165. doi:10.1053/j.ajkd.2007.05.007

14. Izumo A, Sakai K, Tamura Y. Acyclovir-induced neurotoxicity in an elderly patient: report of a case. J Japan Soc Emerg Med. 2017;20:763768.

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Creative Medical Technology Holdings Identifies and Files Patent on Novel Mechanism of ImmCelz Therapeutic Activity – PRNewswire

Wednesday, February 3rd, 2021

PHOENIX, Feb. 1, 2021 /PRNewswire/ --(OTC CELZ) Creative Medical Technology Holdings, Inc. announced today new data demonstrating that administration of ImmCelz to animals with a variety of conditions results is a significant surge of the protein hepatocyte growth factor (HGF-1). When scientists blocked the effects of HGF in ImmCelz treated animals, the therapeutic effects where significantly inhibited. The data suggests one of the molecular mechanisms of action of ImmCelz is mediated by production of this therapeutic molecule.

"One of the drawbacks of many cellular therapies is their complicated, and many times ill-defined mechanisms of action." Said Dr. Amit Patel, co-founder of the company and co-inventor of the patent application. "I am proud of our scientific team for focusing not only on the exploration of therapeutic benefits of ImmCelz in a wide variety of diseases, but also on homing in on mechanisms of action. We have previously reported ImmCelz induces T regulatory cells and endogenous neurogenesis.1 The current data suggests that HGF-1 may be acting upstream of these effects."

To date the Company has reported therapeutic activity of ImmCelz in models of rheumatoid arthritis,2 stroke,3 type 1 diabetes,4 kidney failure5 and liver failure.6 The data disclosed today are supported by independent studies which have shown HGF-1 is capable of inducing T regulatory cells7,8 and stimulating neurogenesis.9,10

"Cellular immunotherapy has commanded extremely lucrative valuations for companies in early stages of clinical trials." Said Timothy Warbington, President and CEO of Creative Medical Technology Holdings. "We believe for regenerative immunotherapy products such as ImmCelz to attract similar valuations, understanding of biological mechanisms of action is important. I commend our scientific collaborators for their work that resulted in this current patent filing."

About Creative Medical Technology HoldingsCreative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in regenerative medicine/stem cell technology in the fields of immunotherapy, urology, neurology and orthopedics and is listed on the OTC under the ticker symbol CELZ. For further information about the company, please visitwww.creativemedicaltechnology.com.

Forward Looking StatementsOTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website atwww.sec.gov.

Creativemedicaltechnology.comwww.StemSpine.com http://www.Caverstem.com http://www.Femcelz.com ImmCelz.com

1 Creative Medical Technology Holdings Identifies Mechanism of Action of ImmCelz Stroke Regenerative Activity (prnewswire.com)2 Creative Medical Technology Holdings Reports Positive Preclinical Data on ImmCelz Immunotherapy Product in Rheumatoid Arthritis Model | BioSpace3 Creative Medical Technology Holdings Identifies Mechanism of Action of ImmCelz Stroke Regenerative Activity (prnewswire.com)4 Creative Medical Technology Holdings Announces Positive Data and Patent Filing Using ImmCelz to Treat Type 1 Diabetes (prnewswire.com)5 Creative Medical Technology Holdings Files Patent based on Positive Data on Renal Failure using ImmCelz Regenerative Immunotherapy (prnewswire.com)6 Creative Medical Technology Holdings Announces Reversion of Liver Failure Using ImmCelz Personalized Cellular Immunotherapy in Preclinical Model | Nasdaq7 https://pubmed.ncbi.nlm.nih.gov/22158517/ 8 https://pubmed.ncbi.nlm.nih.gov/20332205/ 9 https://pubmed.ncbi.nlm.nih.gov/21683144/ 10 https://pubmed.ncbi.nlm.nih.gov/20963849/

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How Coronavirus Damages Lung Cells Within Mere Hours And What Drugs Could Halt COVID-19 Infection – SciTechDaily

Wednesday, February 3rd, 2021

Human lung cells (blue) infected with SARS-CoV-2 (red). Courtesy of Hekman, et al. Credit: Courtesy of Hekman, et al.

Multipronged BU research team finds 18 FDA-approved drugs that could halt coronavirus infection earlier.

What if scientists knew exactly what impact the SARS-CoV-2 virus had inside our lung cells, within the first few hours of being infected? Could they use that information to find drugs that would disrupt the virus replication process before it ever gets fully underway? The discovery that several existing FDA-approved drugsincluding some originally designed to fight cancercan stop coronavirus in its tracks indicates the answer is a resounding yes.

A team of Boston University researchershailing from BUs National Emerging Infectious Diseases Laboratories (NEIDL), the Center for Regenerative Medicine (CReM) at BUs Medical Campus, and BUs Center for Network Systems Biology (CNSB)embarked on a months-long, collaborative and interdisciplinary quest, combining multiple areas of expertise in virology, stem cellderived lung tissue engineering, and deep molecular sequencing to begin answering those questions. They simultaneously infected tens of thousands of human lung cells with the SARS-CoV-2 virus, and then tracked precisely what happens in all of those cells during the first few moments after infection. As if that was not complicated enough, the team had to cool their entire high-containment research facility inside the NEIDL to a brisk 61 degrees Fahrenheit.

The result of that challenging and massive undertaking? The BU team has revealed the most comprehensive map to date of all the molecular activities that are triggered inside lung cells at the onset of coronavirus infection. They also discovered there are at least 18 existing, FDA-approved drugs that could potentially be repurposed to combat COVID-19 infections shortly after a person becomes infected. Experimentally, five of those drugs reduced coronavirus spread in human lung cells by more than 90 percent. Their findings were recently published in Molecular Cell.

Now, academic and industry collaborators from around the world are in contact with the team about next steps to move their findings from bench to bedside, the researchers say. (Although COVID-19 vaccines are starting to be rolled out, its expected to take the better part of a year for enough people to be vaccinated to create herd immunity. And there are no guarantees that the current vaccine formulations will be as effective against future SARS-CoV-2 strains that could emerge over time.) More effective and well-timed therapeutic interventions could help reduce the overall number of deaths related to COVID-19 infections.

What makes this research unusual is that we looked at very early time points [of infection], at just one hour after the virus infects lung cells. It was scary to see that the virus already starts to damage the cells so early during infection, says Elke Mhlberger, one of the studys senior investigators and a virologist at BUs NEIDL. She typically works with some of the worlds most lethal viruses like Ebola and Marburg.

The most striking aspect is how many molecular pathways are impacted by the virus, says Andrew Emili, another of the studys senior investigators, and the director of BUs CNSB, which specializes in proteomics and deep sequencing of molecular interactions. The virus does wholesale remodeling of the lung cellsits amazing the degree to which the virus commandeers the cells it infects.

Viruses cant replicate themselves because they lack the molecular machinery for manufacturing proteinsthats why they rely on infecting cells to hijack the cells internal machinery and use it to spread their own genetic material. When SARS-CoV-2 takes over, it completely changes the cells metabolic processes, Emili says, and even damages the cells nuclear membranes within three to six hours after infection, which the team found surprising. In contrast, cells infected with the deadly Ebola virus dont show any obvious structural changes at these early time points of infection, and even at late stages of infection, the nuclear membrane is still intact, Mhlberger says.

The nuclear membrane surrounds the nucleus, which holds the majority of a cells genetic information and controls and regulates normal cellular functions. With the cell nucleus compromised by SARS-CoV-2, things rapidly take a bad turn for the entire cell. Under siege, the cellswhich normally play a role in maintaining the essential gas exchange of oxygen and carbon dioxide that occurs when we breathedie. As the cells die, they also emit distress signals that boost inflammation, triggering a cascade of biological activity that speeds up cell death and can eventually lead to pneumonia, acute respiratory distress, and lung failure.

I couldnt have predicted a lot of these pathways, most of them were news to me, says Andrew Wilson, one of the studys senior authors, a CReM scientist, and a pulmonologist at Boston Medical Center (BMC), BUs teaching hospital. At BMC, Bostons safety net hospital, Wilson has been on the front lines of the COVID-19 pandemic since March 2020, trying to treat and save the sickest patients in the hospitals ICU. Thats why our [experimental] model is so valuable.

Science is the answerif we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us. Darrell Kotton

The team leveraged the CReMs organoid expertise to grow human lung air sac cells, the type of cell that lines the inside of lungs. Air sac cells are usually difficult to grow and maintain in traditional culture and difficult to extract directly from patients for research purposes. Thats why much coronavirus research to date by other labs has relied on the use of more readily available cell types, like kidney cells from monkeys. The problem with that is kidney cells from monkeys dont react the same way to coronavirus infection as lung cells from humans do, making them a poor model for studying the viruswhatever is learned from them doesnt easily translate into clinically relevant findings for treating human patients.

Our organoids, developed by our CReM faculty, are engineered from stem cellstheyre not identical to the living, breathing cells inside our bodies, but they are the closest thing to it, says Darrell Kotton, one of the studys senior authors. He is a director of the CReM and a pulmonologist at BMC, where he has worked alongside Wilson in the ICU treating COVID-19 patients. The two of them often collaborated with Mhlberger, Emili, and other members of their research team via Zoom calls that they managed to join during brief moments of calm in the ICU.

In another recent study using the CReMs engineered human lung cells, the research team confirmed that existing drugs remdesivir and camostat are effective in combating the virus, though neither is a perfect fix for controlling the inflammation that COVID-19 causes. Remdesivir, a broad-use antiviral, has already been used clinically in coronavirus patients. But based on the new studys findings that the virus does serious damage to cells within hours, setting off inflammation, the researchers say theres likely not much that antiviral drugs like remdesivir can do once an infection has advanced to the point where someone would need to be put on a ventilator in the ICU. [Giving remdesivir] cant save lives if the disease has already progressed, Emili says.

Seeing how masterfully SARS-CoV-2 commandeers human cells and subverts them to do the manufacturing work of replicating the viral genome, it reminded the researchers of another deadly invader.

I was surprised that there are so many similarities between cancer cells and SARS-CoV-2-infected cells, Mhlberger says. The team screened a number of cancer drugs as part of their study and found that several of them are able to block SARS-CoV-2 from multiplying. Like viruses, cancer cells want to replicate their own genomes, dividing over and over again. To do that, they need to produce a lot of pyrimidine, a basic building block for genetic material. Interrupting the production of pyrimidineusing a cancer drug designed for that purposealso blocks the SARS-CoV-2 genome from being built. But Mhlberger cautions that cancer drugs typically have a lot of side effects. Do we really want to use that heavy stuff against a virus? she says. More studies will be needed to weigh the pros and cons of such an approach.

The findings of their latest study took the four senior investigators and scientists, postdoctoral fellows, and graduate students from their laboratories almost four months, working nearly around the clock, to complete the research. Of critical importance to the teams leaders was making sure that the experimental setup had rock-solid foundations in mimicking whats actually happening when the SARS-CoV-2 virus infects people.

Science is the answerif we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us, Kotton says. Objective scientific data gives us hints at what to do and has lessons to teach us. It can reveal a path out of this pandemic.

Hes particularly excited about the outreach the team has received from collaborators around the world. People with expertise in supercomputers and machine learning are excited about using those tools and the datasets from our publication to identify the most promising drug targets [for treating COVID-19], he says.

Kotton says the theme thats become obvious among COVID-19 clinicians and scientists is understanding that timing is key. Once a patient is on a ventilator in the ICU, we feel limited in what we can do for their body, he says. Timing is everything, its crucial to identify early windows of opportunity for intervention. You can keep guessing and hope we get luckyor you [do the research] to actually understand the infection from its inception, and take the guesswork out of drug development.

Reference: Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2 by Ryan M. Hekman, Adam J. Hume, Raghuveera Kumar Goel, Kristine M. Abo, Jessie Huang, Benjamin C. Blum, Rhiannon B. Werder, Ellen L. Suder, Indranil Paul, Sadhna Phanse, Ahmed Youssef, Konstantinos D. Alysandratos, Dzmitry Padhorny, Sandeep Ojha, Alexandra Mora-Martin, Dmitry Kretov, Peter E.A. Ash, Mamta Verma, Jian Zhao, J.J. Patten, Carlos Villacorta-Martin, Dante Bolzan, Carlos Perea-Resa, Esther Bullitt, Anne Hinds, Andrew Tilston-Lunel, Xaralabos Varelas, Shaghayegh Farhangmehr Ulrich Braunschweig, Julian H. Kwan, Mark McComb, Avik Basu, Mohsan Saeed, Valentina Perissi, Eric J. Burks, Matthew D. Layne, John H. Connor, Robert Davey, Ji-Xin Cheng, Benjamin L. Wolozin, Benjamin J. Blencowe, Stefan Wuchty, Shawn M. Lyons, Dima Kozakov, Daniel Cifuentes, Michael Blower, Darrell N. Kotton, Andrew A. Wilson, Elke Mhlberger and Andrew Emili, 18 November 2020, Molecular Cell.DOI: 10.1016/j.molcel.2020.11.028

This research was funded by the National Institutes of Health, the Australian National Health and Medical Research Council, the Pulmonary Fibrosis Foundation, the Massachusetts Consortium on Pathogen Readiness, the C3.ai Digital Transformation Institute, the Canadian Institutes of Health Research, and Fast Grants.

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Mini kidneys bioprinted in the lab – Lab + Life Scientist

Friday, December 4th, 2020

Researchers from the Murdoch Childrens Research Institute (MCRI) and biotech company Organovo have used cutting-edge technology to bioprint miniature human kidneys in the lab, paving the way for new treatments for kidney failure and possibly lab-grown transplants. Their study has been published in the journal Nature Materials.

Like squeezing toothpaste out of a tube, extrusion-based 3D bioprinting uses a bioink made from a stem cell paste, squeezed out through a computer-guided pipette to create artificial living tissue in a dish. According to MCRI Professor Melissa Little, a world leader in modelling the human kidney, this new bioprinting method is faster and more reliable than previous methods, allowing the whole process to be scaled up. 3D bioprinting could now create about 200 mini kidneys in 10 minutes without compromising quality.

From larger than a grain of rice to the size of a fingernail, bioprinted mini kidneys fully resemble a regular-sized kidney, including the tiny tubes and blood vessels that form the organs filtering structures called nephrons. Prof Little said the mini organs will be used to screen drugs to find new treatments for kidney disease or to test if a new drug was likely to injure the kidney.

Drug-induced injury to the kidney is a major side effect and difficult to predict using animal studies; bioprinting human kidneys are a practical approach to testing for toxicity before use, she said.

In the study, researchers tested the toxicity of aminoglycosides a class of antibiotics that commonly damage the kidney. Prof Little said, We found increased death of particular types of cells in the kidneys treated with aminoglycosides.

By generating stem cells from a patient with a genetic kidney disease, and then growing mini kidneys from them, also paves the way for tailoring treatment plans specific to each patient, which could be extended to a range of kidney diseases.

Prof Little said the study also showed that 3D bioprinting of stem cells can produce large enough sheets of kidney tissue needed for transplants. She noted, 3D bioprinting can generate larger amounts of kidney tissue but with precise manipulation of biophysical properties, including cell number and conformation, improving the outcome.

Prof Little said prior to this study the possibility of using mini kidneys to generate transplantable tissue was too far away to contemplate, but that may no longer be the case.

The pathway to renal replacement therapy using stem cell-derived kidney tissue will need a massive increase in the number of nephron structures present in the tissue to be transplanted, she said.

By using extrusion bioprinting, we improved the final nephron count, which will ultimately determine whether we can transplant these tissues into people.

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Telix Pharmaceuticals Limited Acquires TheraPharm GmbH, Broadening Reach to Hematologic Cancers and Transplant Medicine – BioSpace

Friday, December 4th, 2020

MELBOURNE, Australia and BAAR, Switzerland, Nov. 29, 2020 (GLOBE NEWSWIRE) -- Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) announces it has entered into an agreement with Scintec Diagnostics GmbH (Scintec) to acquire TheraPharm GmbH (TheraPharm), a Swiss-German biotechnology company developing innovative diagnostic and therapeutic solutions in the field of hematology.

The acquisition of TheraPharm provides Telix with access to a portfolio of patents, technologies, production systems, clinical data and know-how in relation to the use of Molecularly Targeted Radiation (MTR) in hematology and immunology. TheraPharm is developing antibody MTR technology against CD66, a cell surface target highly expressed by neutrophils (a type of white blood cell) and tumor-infiltrating lymphocytes. As such, the technology has potentially very broad applications in the diagnosis and treatment of hematologic diseases (e.g. blood cancers), lymphoproliferative disorders and immune-mediated diseases (e.g. lupus, and multiple sclerosis). Of particular interest is the demonstrated use of the technology to safely and effectively perform bone marrow conditioning (BMC) prior to bone marrow stem cell transplant.

Telix CEO, Dr. Christian Behrenbruch stated, Telix is committed to extending and improving the lives of patients with serious diseases. As such, the acquisition of TheraPharm and its MTR assets are uniquely aligned to Telixs mission and technical strengths in antibody engineering and radiochemistry. TheraPharms technology has a significant role to play in BMC and stem cell transplantation across a broad range of blood cancers and rare diseases. The current approach to BMC employs highly toxic drugs that have a poor morbidity and mortality profile, and for which many patients are ineligible. MTR offers an excellent safety profile that may greatly expand the number of patients able to undergo life prolonging stem cell transplantation while greatly reducing the hospitalisation burden and cost associated with such procedures.

TheraPharm co-founder and Managing Director, Dr. Klaus Bosslet added, Over the past 5 years, TheraPharm, in collaboration with Dr. Kim Orchard from the University of Southampton (UK), has made excellent progress developing 90Y-besilesomab for the treatment of hematologic cancers and several related conditions including multiple myeloma, leukemia and amyloidosis. This unique asset is a logical addition to Telixs portfolio, offering a potentially rapid development path to a first commercial indication for the treatment of patients with SALA, while at the same time having potentially broad applications for stem cell transplantation in patients with more common cancers of the blood, including multiple myeloma and leukemia. We look forward to joining the Telix team in order to expedite the development of products for this under-served field.

Full transaction details, including financial terms, can be found via the Telix website and ASX portal here.

About Hematopoietic Stem Cell Transplant (HSCT)

Bone marrow conditioning (BMC) followed by hematopoietic stem cell transplantation (HSCT) is presently performed to treat patients with hematologic malignancies (blood cancers), with the objective of extending patient survival or achieving cure. HSCT is also performed for a broad range of non-cancer conditions. HSCT is preferentially performed in countries of high income (Europe >30,000, Americas >20,000, worldwide >65,000 p.a., respectively) and is growing at around 5% annually.

About Systemic Amyloid Light-Chain Amyloidosis (SALA)

SALA is a rare, but serious protein deposition disease, caused by a protein known as amyloid that is produced by abnormal plasma cells residing in the bone marrow. As amyloid accumulates in the organs of the body, organ function will eventually deteriorate, ultimately causing organ failure. SALA has an estimated prevalence of 30,000 and 45,000 in United States and Europe, respectively and while a rare disease, SALA portends a very poor prognosis, with a median survival from diagnosis of ~11 months if untreated.

The current standard of care comprises of induction therapy (typically cyclophosphamide, bortezomib, dexamethasone) plus high dose melphalan BMC, followed by HSCT. This approach is typically only accessible to a small proportion of patients (<20%) who are able to tolerate induction therapy and melphalan BMC.

About Telix Pharmaceuticals Limited

Telix is a clinical-stage biopharmaceutical company focused on the development of diagnostic and therapeutic products using Molecularly Targeted Radiation (MTR). Telix is headquartered in Melbourne, Australia with international operations in Belgium, Japan and the United States. Telix is developing a portfolio of clinical-stage oncology products that address significant unmet medical needs in prostate, kidney and brain cancer. Telix is listed on the Australian Securities Exchange (ASX: TLX). For more information visit http://www.telixpharma.com.

AboutTheraPharm GmbH

TheraPharm is a biotechnology company specialised in the research, development and manufacturing of monoclonal antibodies for targeted radiation of hematopoietic malignant and non-malignant diseases, lymphoproliferative diseases, conditioning for allogeneic stem cells as well as in diagnostics of inflammatory diseases and bone marrow metastases.

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News briefing: Four biotechs announce IPO terms, setting the pace to round out a busy year; FDA sets PDUFA date for Kadmon’s graft-versus-host drug -…

Friday, December 4th, 2020

Four more biotechs set the terms for their IPOs, lining up yet another busy week on Wall Street.

Silverback Therapeutics, which initially filed for a $100 million raise, is now shooting for $125 million from 7 million shares at a range of $17 to $19. About $70 million is tagged for the companys lead Phase I/Ib antibody-drug conjugate, SBT6050, for advanced or metastatic HER2-expressing solid tumors. Interim data from the Phase I dose-escalation cohorts are expected in the second half of 2021. Another $55 million is set aside for Silverbacks two other candidates, which have yet to reach the clinic.

Kinnate Biopharma is looking for a $170 million raise, and set a $16 to $18 range for its 10 million share offering. About $105 is earmarked for its RAF inhibitors, including its lead preclinical candidate KIN002787 for patients with lung cancer, melanoma and other solid tumors. An IND is coming in the first half of 2021, the company says. Back in August, it hooked a $98 million Series C.

Seer also set its shares at a $16 to $18 range. The company, which is working on next-gen proteome analysis tests, is offering 8.8 million shares, going for a $150 raise. About $65.0 million would go to its Proteograph Product Suite, which already has one collaborator and could have a second by the end of the year.

Sigilon Therapeutics is seeking $101 million from 5.6 million shares at a $17 to $19 range. Between $30 to $35 million will be set aside for its lead candidate, SIG-001, which is in a Phase I/II trial to prevent bleeding episodes in patients with hemophilia A. Another $30 to $35 million would fund a scale-up of the companys GMP manufacturing processes SIG-001 and SIG-005, its preclinical candidate for patients with mucopolysaccharidosis type 1, or MPS-1.

More than 72 biotech and biopharma companies and counting have hit Nasdaq so far this year, and head of healthcare listings Jordan Saxe predicted rounding out the year with just under $14 billion in proceeds.

Kadmons chronic graft-versus-host drug belumosudil is in the FDAs hands.

The agency accepted the biotechs NDA under its real-time oncology review (RTOR) pilot program, and set the PDUFA date for May 30, 2021. The submission was based on positive results from a pivotal, open-label trial dubbed ROCKstar, which enrolled 132 patients who had received at least two prior lines of therapy.

Belumosudil is designed to tamp down the inflammatory response seen after hematopoietic stem cell transplant by blocking Rho-associated coiled-coil kinase 2 (ROCK2). Instead of a comparator arm, Kadmon set the bar at a 30% overall response rate, based on conversations with the FDA. Patients were given 200 mg of the drug either once or twice daily. At six months after the completion of enrollment, Kadmon saw an ORR of 73% and 75% in the respective arms.

Thats it for data, until the full report is read out at ASH in December. The companys stock $KDMN was up 6.68% on Monday, at $4.39 per share.Kadmon was founded by Sam Waksal, the biotech exec who was sentenced to prison for his insider trading conviction involving Martha Stewart.

Hookipa Pharma said no one from a small group of Phase II participants treated with its prophylactic cytomegalovirus vaccine came down with the disease, according to interim results.

The analysis was based on 41 participants 8 of whom received 3 doses, 19 of whom received 2 doses, and 14 of whom received a placebo. Compared to the placebo, researchers saw a 48% reduction in CMV viremia, and a 42% reduction in the use of antiviral therapy. There were no cases of CMV disease in the treatment arm, compared to 2 in the placebo group.

While these interim data are from a small group of patients, they offer early insight into the potential of a three-dose schedule of HB-101 to help protect kidney transplant recipients against CMV disease, CEO Joern Aldag said in a statement.

The candidate is going head-to-head with Modernas mRNA-1647, which produced positive results from a proof-of-concept study back in January. Researchers said they saw an increasing level of neutralizing antibody titers in those who had received a third vaccination.

This could really be a company builder, CEO Stphane Bancel said at the time, adding that the candidate could turn into a $2 billion to $5 billion annual franchise.

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News briefing: Four biotechs announce IPO terms, setting the pace to round out a busy year; FDA sets PDUFA date for Kadmon's graft-versus-host drug -...

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Government of Canada and JDRF Canada announce new research funding to accelerate stem cell-based therapies for type 1 diabetes – Philippine Canadian…

Friday, December 4th, 2020

There are more than 300,000 Canadians living with type 1 diabetes (T1D), an autoimmune disease with no known cause or cure, resulting in the dysfunction, damage or loss of pancreatic beta cells that produce insulin in our bodies. People with T1D must treat themselves with insulin several times per day to keep their blood glucose levels normal, and despite their best efforts, they often experience serious, and even life-threatening, complications.

To mark the end of Diabetes Awareness Month, Sonia Sidhu, Member of Parliament for Brampton South, on behalf of the Honourable Patty Hajdu, Minister of Health, announced an investment of $6 million through the CIHR-JDRF Partnership to Defeat Diabetes for two Canadian research teams to accelerate the development of stem cell-based therapies for the treatment of T1D.

Stem cells show great promise as a source of insulin-producing cells that could be transplanted to provide a new source of insulin, to replace dysfunctional, damagedor lost pancreatic beta cells. Canada has a remarkable legacy in leading discoveries in this area. Stem cells were discovered in Toronto in 1961, and in 2000, a team in Edmonton were the first to pioneer transplantation of pancreatic islets (the part of the pancreas that contains insulin-producing cells). These achievements represent important steps toward a treatment that will allow people with T1D to live healthy lives without daily insulin injections.

The research teams are led by Dr. Maria Cristina Nostro at the University Health Network and the University of Toronto and Dr. Francis Lynn at the BC Childrens Hospital Research Institute and the University of British Columbia. The teams will build on Canadas demonstrated research excellence and leadership in clinical islet transplantation, stem cell biology, diabetes, immunology and genetic engineering to accelerate stem cell-based therapies for T1D. They will work in collaboration with other Canadian researchers to tackle some of the biggest scientific challenges that impede our progress in this area and move us closer to a future where people with T1D will no longer rely on insulin therapy.

This funding was provided by the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD), and JDRF Canada, through the CIHR-JDRF Partnership to Defeat Diabetes established in 2017. Each partner will invest $3 million over five years. This investment is part of a large research initiative,100 Years of Insulin: Accelerating Canadian Discoveries to Defeat Diabetes, funded by CIHR and partners. This initiative commemorates the 100th anniversary of the discovery of insulin to be marked in 2021a discovery that changed the lives of millions of Canadians and people around the world and won researchers Sir Frederick Banting and John Macleod the Nobel Prize in Physiology or Medicine.

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Merck Announces KEYNOTE-598 Trial Evaluating KEYTRUDA in Combination With Ipilimumab Versus KEYTRUDA Monotherapy in Certain Patients With Metastatic…

Wednesday, November 11th, 2020

Merck Announces KEYNOTE-598 Trial Evaluating KEYTRUDA (pembrolizumab) in Combination With Ipilimumab Versus KEYTRUDA Monotherapy in Certain Patients With Metastatic Non-Small Cell Lung Cancer To Stop for Futility and Patients to Discontinue Ipilimumab

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that it will be stopping KEYNOTE-598, a Phase 3 trial investigating KEYTRUDA, Mercks anti-PD-1 therapy, in combination with ipilimumab (Yervoy ), compared with KEYTRUDA monotherapy, for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (tumor proportion score [TPS] 50%) with no EGFR or ALK genomic tumor aberrations. Merck is discontinuing the study following the recommendation of an independent Data Monitoring Committee (DMC), which determined the benefit/risk profile of the combination did not support continuing the trial. At an interim analysis, the combination of KEYTRUDA and ipilimumab showed no incremental benefit in overall survival (OS) or progression-free survival (PFS), the studys dual primary endpoints, compared with KEYTRUDA alone and crossed futility boundaries. No new safety signals for KEYTRUDA monotherapy were observed, however the combination of KEYTRUDA and ipilimumab was associated with a higher incidence of grade 3-5 adverse events (AEs), serious AEs, and AEs leading to discontinuation or death, compared with KEYTRUDA monotherapy. Merck will inform study investigators of the recommendation from the DMC and the DMC is advising that patients in the study discontinue treatment with ipilimumab/placebo. Data from this study will be submitted for presentation at an upcoming scientific congress and communicated to regulatory agencies.

We conducted KEYNOTE-598 in order to explicitly explore whether combining our anti-PD-1 therapy, KEYTRUDA, with ipilimumab provided additional benefits beyond treatment with KEYTRUDA alone in the metastatic non-small cell lung cancer setting, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. It is very clear that in this study, the addition of ipilimumab did not add clinical benefit but did add toxicity. KEYTRUDA monotherapy remains a standard of care for the treatment of certain patients with metastatic non-small cell lung cancer whose tumors express PD-L1.

While the combination of an anti-PD-1 therapy plus ipilimumab has been approved in certain indications, studies supporting these approvals have, for the most part, not compared the combination directly with anti-PD-1 monotherapy. Bristol Myers Squibb has reported topline results of CheckMate-915, a Phase 3 study in adjuvant melanoma that directly compared treatment with ipilimumab in combination with an anti-PD-1 therapy versus the anti-PD-1 therapy alone. In two separate news releases issued over the last year, the company announced the study did not meet its co-primary endpoints in the all-comer population or in patients whose tumors expressed PD-L1

Merck has an extensive clinical development program in lung cancer and is advancing multiple registration-enabling studies with KEYTRUDA in combination with other treatments and as monotherapy. The lung program is evaluating KEYTRUDA across all stages of disease and lines of therapy in over 200 trials with more than 10,000 patients.

About KEYNOTE-598

KEYNOTE-598 (ClinicalTrials.gov, NCT03302234 ) is a randomized, double-blind, Phase 3 trial investigating KEYTRUDA in combination with ipilimumab compared to KEYTRUDA monotherapy for the first-line treatment of patients with metastatic NSCLC whose tumors express PDL1 (TPS 50%) with no EGFR or ALK genomic tumor aberrations. The dual primary endpoints are OS and PFS. Secondary endpoints include objective response rate, duration of response and safety. The study enrolled 568 patients who were randomized (1:1) to receive:

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10% to 15% of all lung cancers. Before 2014, the five-year survival rate for patients diagnosed in the U.S. with NSCLC and SCLC was estimated to be 5% and 6%, respectively.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients. Pneumonitis occurred in 8% (31/389) of patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and post-marketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risk of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients; those 1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression. The most common adverse reactions (20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, and cough (20% each).

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Merck Announces KEYNOTE-598 Trial Evaluating KEYTRUDA in Combination With Ipilimumab Versus KEYTRUDA Monotherapy in Certain Patients With Metastatic...

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