StemCell Therapy

Millions of Americans have chronic kidney disease. Hundreds of thousands will progress to end stage kidney disease requiring either dialysis or kidney transplant. But research is underway to keep people from reaching that point.

Our goal is to take a look at how we can repair the diabetic kidney in terms of delaying the rate of progression of kidney failure, says LaTonya Hickson, M.D., a Mayo Clinic nephrologist.

Dr. Hickson is part of the research team looking at using stem cells to help regenerate failing kidneys.

We take these cells from our abdominal fat and we can inject them back into the body for them to do good, says Dr. Hickson. They basically tell the kidney or other organ systems that are impaired to wake up and get back to work and help heal that organ system.

While theres a lot more research ahead, Dr. Hickson is excited about the possibilities.

Listen to the Mayo Clinic Radio Health Minute and learn more about stem cells and chronic kidney disease in the video below:

Tags: chronic kidney disease, Dr. LaTonya Hickson, Mayo Clinic Center for Regenerative Medicine, Medical Research, Research, stem cells

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Stem Cells and Chronic Kidney Disease | Mayo Clinic Center ...

Current treatment options often fail due to the progression of renal disease. The pathology involves tubulointerstitial fibrosis, oxidative damage, glomerular fibrosis, and microvascular rarefaction. The kidneys have intrinsic regenerative capacity, which allows them to recover after minimal injury. The regenerative potential of these organs is limited, however.

Stem cell infusions are now being used to treat kidney failure with positive outcomes. Mesenchymal stem cells (MSCs) produce cytokines and growth factors that support hematopoiesis. These cells can transform into renal epithelial cells, functional mesangial cells, and tubular cells. Research shows that each stem cell viability is 95%, and injections work 99% of the time. MSCs have ability to reduce inflammatory response, reduce apoptosis, and increase renal function recovery.

Most chronic kidney disease patients are treated with stem cells and show improvement in the following areas:

Research:

Stem cells at R3 Stem Cell are harvested in a very safe process from consenting donors after a scheduled c-section. No babies or mother are harmed during the process. These cells possess unique immunomodulatory properties that relieve inflammation, and they can facilitate renal tissue repair. Several clinical studies have proved that stem cells are safe and effective for treating renal failure. Some research suggests that stem cells can change into ectodermal and endodermal lineages, and secrete growth factors, cytokines, and chemokines.

In a recent clinical study, researchers found that stem cells possessed a high potential for angiogenesis (vessel re-growth). In addition, investigators noted local tissue turnover and repair of kidney damage after stem cell therapy. The cells were also noted to go to the site of kidney injury. The stem cells are known to release dozens of active biological factors that act on local cell dynamics, reduce inflammation, lessen fibrosis, and recruit resident progenitor cells.

A phase 1 research study involved stem cell infusions given one week after kidney transplant surgery. The researchers found that they decreased graft rejection, and both patients had excellent kidney function at the 1-year follow-up evaluation. The patients also recovered faster from surgery, had less complications, and few adverse effects. Another similar study involving five people with renal failure involved administration of stem cell injections. Six months after transplant, a noted immunomodulatory effect was noted.

Another clinical study showed feasibility and safety of stem cell infusion for the treatment of renal disease. The study involved several cohort patients, as well as a control group. The stem cells were infused through the renal artery. At the 1-year follow-up, researchers noted a beneficial effect and reduced dosage requirement of immunosuppressive drugs. These clinical trials prove effectiveness and safety of stem cell therapy for renal diseases. Notable findings include improved resolution of tubular atrophy and interstitial fibrosis, as well as decreased risk of infection, positive effects of infusion, and lower incidence of acute rejection.

References:

Peired AJ, Sisti A, & Romagnani P (2016). Mesenchymal Stem Cell-Based Therapy for Kidney Disease: A Review of Clinical Evidence. Stem Cells Int, 4798639.

Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility.Clin J Am Soc Nephrol.2011;6:412422

Reinders ME, de Fijter JW, Roelofs H, Bajema IM, de Vries DK, Schaapherder AF, et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study.Stem Cells Transl Med.

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Kidney Failure | Stem Cell Treatment in Tijuana Mexico

NEW YORK, April 08, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB) today announced that its allogeneic mesenchymal stem cell (MSC) product candidate remestemcel-L will be formally evaluated in a randomized, placebo-controlled trial in 240 patients with acute respiratory distress syndrome (ARDS) caused by coronavirus infection (COVID-19). This multi-center Phase 2/3 trial will be conducted as a public-private partnership in a collaboration with the Cardiothoracic Surgical Trials Network (CTSN), which was established by the United States National Institutes of Healths National Heart, Lung and Blood Institute (NHLBI) as a flexible platform for conducting collaborative trials. Mesoblast holds an Investigational New Drug (IND) Application from the United States Food and Drug Administration (FDA) for use of remestemcel-L in the treatment of patients with COVID-19 ARDS, and will provide investigational product for the trial.

Mesoblast Chief Executive Dr Silviu Itescu stated: This significant public-private partnership is a prime example of how the combined resources of industry and government can be leveraged to evaluate in a most efficient and rigorous manner the potential of innovative therapies to make a meaningful difference to patient outcomes.

CTSN Chairman Dr A. Marc Gillinov said: We are excited to work with Mesoblast to make a real impact on the high mortality associated with COVID-19. Thisrandomized controlled trialis in line with our mandate torigorously evaluate novel therapies forpublic health imperatives.

Professor and System Chair of Population Health Science and Policy and the Edmond A. Guggenheim Professor of Health Policy at the Icahn School of Medicine at Mount Sinai, Dr Annetine Gelijns, said: The COVID-19 pandemic has resulted in very large numbers of people suffering with ARDS requiring ventilation in hospital intensive care units, with dismal outcomes, placing an enormous burden on the United States health system.We are committed to evaluating whether Mesoblasts mesenchymal stem cell product candidate for ARDS has the potential to make an impact on this unprecedented health crisis.

ARDS occurs due to an excessive immune response against the COVID-19 virus in the lungs, with the inflammatory cytokines produced by the immune cells (cytokine storm) destroying the lung tissue. These inflammatory cytokines also can cause damage to other organs such as liver, kidney, and heart.

Remestemcel-L is being developed for various inflammatory conditions, and is believed to counteract the inflammatory processes implicated in these diseases by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.The safety and therapeutic effects of remestemcel-L intravenous infusions have been evaluated in over 1,100 patients in various clinical trials.

Remestemcel-L was successful in a Phase 3 trial for steroid-refractory acute graft versus host disease (aGVHD) in children, a potentially fatal inflammatory condition due to a similar cytokine storm process as is seen in COVID-19 ARDS.Additionally, a post-hoc analysis of a randomized, placebo-controlled study in 60 patients with chronic obstructive pulmonary disease demonstrated that remestemcel-L significantly improved respiratory function in patients with the same elevated inflammatory biomarkers that are also observed in patients with COVID-19 ARDS. Together, these outcomes provide the rationale for evaluating remestemcel-L in patients with COVID-19 ARDS.

Mesoblast Chief Medical Officer Dr Fred Grossman said: The mortality rate in moderate to severe ARDS due to COVID-19 can be as high as 80%. Remestemcel-L has demonstrated safety, efficacy and significant survival benefit in aGVHD where inflammation is at the core, similar to ARDS from COVID-19. The mechanism of action of remestemcel-L demonstrated in aGVHD supports the evaluation of remestemcel-L to safely tame a similar cytokine storm in the lungs that leads to the high mortality in patients with COVID-19.

About MesoblastMesoblast Limited (Nasdaq: MESO; ASX: MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. Mesoblasts proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

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Mesoblasts Biologics License Application to seek approval of its product candidate RYONCIL (remestemcel-L) for steroid-refractory acute graft versus host disease (acute GVHD) has been accepted for priority review by the United States Food and Drug Administration (FDA). Remestemcel-L is also being developed for other rare diseases. Mesoblast is completing Phase 3 trials for its product candidates for advanced heart failure and chronic low back pain. If approved, RYONCIL is expected to be launched in the United States in 2020 for pediatric steroid-refractory acute GVHD. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has a strong and extensive global intellectual property (IP) portfolio with protection extending through to at least 2040 in all major markets. This IP position is expected to provide the Company with substantial commercial advantages as it develops its product candidates for these conditions.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

Forward-Looking StatementsThis announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of Mesoblast and its collaborators clinical studies; Mesoblast and its collaborators ability to advance product candidates into, enroll and successfully complete, clinical studies; the timing or likelihood of regulatory filings and approvals; and the pricing and reimbursement of Mesoblasts product candidates, if approved; the potential benefits of strategic collaboration agreements and Mesoblasts ability to maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

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MESOBLAST PARTNERS WITH THE CARDIOTHORACIC SURGICAL TRIALS NETWORK ESTABLISHED BY THE U.S. NATIONAL INSTITUTES OF HEALTHS NATIONAL HEART, LUNG AND...

Supplemental Biologics License Application (sBLA) Accepted for KEYTRUDA Monotherapy in Patients Whose Tumors Are Tumor Mutational Burden-High (TMB-H) Who Have Progressed Following Prior Treatment

Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has accepted and granted priority review for a new supplemental Biologics License Application (sBLA) for KEYTRUDA, Merck's anti-PD-1 therapy. The application seeks accelerated approval of KEYTRUDA monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with tissue tumor mutational burden-high (TMB-H) 10 mutations/megabase, as determined by an FDA-approved test, who have progressed following prior treatment and who have no satisfactory alternative treatment options. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 16, 2020.

"From the start, biomarker research has been a critical aspect of our clinical program evaluating KEYTRUDA monotherapy," said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. "TMB has been an area of scientific interest to help identify patients most likely to benefit from KEYTRUDA. We look forward to working with the FDA throughout the review process to help bring KEYTRUDA monotherapy to patients with cancer in the second-line or higher treatment setting, where options remain limited."

The application was based in part on results from the Phase 2 KEYNOTE-158 trial, which also supported Merck's 2017 FDA approval for KEYTRUDA as the first cancer treatment based on a biomarker, regardless of cancer type, in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. MSI-H is on the highest end of the TMB spectrum. Data from KEYNOTE-158 on the TMB-H patient population were presented at the European Society for Medical Oncology (ESMO) 2019 Congress.

About KEYNOTE-158

KEYNOTE-158 (NCT02628067) is a multicenter, multi-cohort, non-randomized, open-label trial evaluating KEYTRUDA (200 mg every three weeks) in patients with solid tumors. Tissue TMB status was determined using the Foundation Medicine, Inc. FoundationOneCDx assay. Tumor response was assessed every nine weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent, central, blinded radiographic review. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body's 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 industry's 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 patient's 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 and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines 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 the confirmatory trials.

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. 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. 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 (MSI-H) 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.

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).

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.

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 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

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 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

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 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

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 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

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 postmarketing 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)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

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-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those 2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

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Merck Receives Priority Review from FDA for Second Application for KEYTRUDA (pembrolizumab) Based on Biomarker, Regardless of Tumor Type - Benzinga

Imagine generating a vaccine for the novel coronavirus from your immune system.

The virus that causes COVID-19 has swept the globe with about 1.3 million infections and 70,000 deaths through Sunday evening.Development of a widely available vaccine can take a year or more while a virus continues its rampage.

Key to the race to develop a vaccine for the new coronavirus is a technology that uses the virus' genetic code to essentially persuade your body to make its own vaccine.

This techniqueis faster than egg-based manufacturing, which produces the majority of annual flu vaccines and led to delays in distributing a vaccine forH1N1 during the 2009 pandemic.

And it's enablingapossible vaccine for the new coronavirus to be developed in record time.

Coronavirus updates: Get the latest in USA TODAY's live blog

Its quicker to get started, said Clem Lewin, who is working onvaccine candidates for the manufacturer Sanofi Pasteur. All you need is the blueprint for the protein."

Testing still will take time. Scientists must determine whether any of several vaccine candidates fight the virus effectively. If so, they need to determine the proper dose. This tinkering is what could take a year or more.

When the first potential vaccine from the manufacturer Moderna was injected into people on March 16, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said he believed the coronavirus vaccine was being developed at a record pace. It took 63 days to go from identifying a viruss genetic sequence to testing a vaccine in people.

Scrambling egg-based production

Several manufacturers pursuing a vaccine for the latest coronavirus have been aided by a technological innovation.

The method that Moderna, Sanofi and others are pursuing is different from traditional vaccinations, in which a weakened or dead version of the virus is introduced into the body, triggering itto createantibodies that would attack the live virus should the person be exposed to it.

In the new approach, pieces of messenger RNA that hold the chemical template of a spike protein from the SARS-CoV-2 virus are injected into a human, said Mark Slifka, a professor of viral immunology at Oregon Health and Science University in Portland, Oregon.

The spikes are what the virus uses to attach to a human cell the first step in sickening someone.

In response to the injection of those molecules, the cells in the body produce the spike protein encoded by that mRNA. That triggers the body tomountan immune response to that viral protein, just as in traditional vaccines.

Essentially, the patient makes their own vaccine, says the narrator of a Moderna video about the vaccine.This cuts out the middleman.

Fauci said volunteers would be given two injections of the potential coronavirus vaccine, the second after 28 days. The doses are 25 milligrams, 100 milligrams and 250 milligrams, he said.

The individuals will be followed for one year both for safety and whether it induces the kind of response that we predict would be protective, Fauci said.

Moderna, the manufacturer conducting the initial tests, projected the first commercially available vaccine in 12 to 18 months. A corporate filing March 23 said CEO Stephane Banceltold Goldman Sachs it is possible that under emergency use, a vaccine could be available to some people, possibly including healthcare professionals, in the fall of 2020.

Why change the menu from reliable eggs?

Most flu vaccines are produced from fertilized chicken eggs, a decades-old process that takes four to five months.The mRNA process ismuch faster.

Delays in producing an H1N1 vaccine spurred health officials to urge development of other technologies, according to a Government Accountability Office report.

Its a state-of-the-art technology for the 1950s, Luciana Borio, then director for medical and biodefense preparedness at the National Security Council, said at a 2018 conference on the 100th anniversary of the Spanish flu pandemic.

A New England Journal of Medicine review of the response to H1N1 found that 78 million doses of the vaccine were eventually produced for 70 countries worldwide, but only after two waves of the illness worldwide.

The most serious operational shortcoming ...was the failure to distribute enough influenza vaccine in a timely way, the report said. The cause: distribution problems, "a shortfall in global vaccine-production capacity and technical delays due to reliance on viral egg cultures for production.

Developing a vaccine is laborious, said Harvey Fineberg, a former president of the U.S. Institute of Medicine and former dean of the public-health faculty at Harvard University.

One step is confirmingthat a possible vaccine doesn't causebad reactions in patients. Then scientists examine how much vaccine is required for an antibody response. And they must verify the vaccine actually protects against infection, which is why it's ideal to test during an outbreak.

All those steps come after scientists identifythe genetic sequence to target for a vaccine.

Its like saying,'Ive got my architectural plans my house must be ready to move into,' Fineberg said. There are a lot of things you need to do between now and being ready to open the door.

Manufacturers work with government

The manufacturers pursuing coronavirus vaccines are working closely withthe Centers for Disease Control and Prevention, the Food and Drug Administration, the National Institute of Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Agency.

Moderna is working on 13 potential vaccines. Sanofi is working on two candidates:an mRNA candidate with the company Translate Bio and another option in collaboration with the Biomedical Advanced Research and Development Agency.

Other companies are pursuing other technologies. GlaxoSmithKline is working with China-based Clover Biopharmaceuticals through a different process to produce a cell-based vaccine.

Johnson & Johnson, which is working on several possible vaccines,announced last week it wouldinvest$1 billion for vaccine research, development and testing. The company said it could produce 1 billion doses of a vaccine when the time comes.

Sen. Chris Coons, D-Del., said $3.5 billion in the coronavirus spending packagewill help develop manufacturing technologies to ensure a robust, agile, U.S.-based supply chain of vaccines, therapeutics, and active pharmaceutical ingredients.

The biggest challenge we face in the United States is not developing a vaccine, tricky as that step is, Coons said in a statement. Its that we lack the domestic manufacturing capacity to quickly produce a vaccine once its proven and deliver it to the American people.

Lewin of Sanofi said the global health emergency spurred manufacturers to try different technologies.

We and all the other manufacturers are working as quickly as possible to accelerate these programs while ensuring the vaccine is safe and effective, Lewin said. It isnt business as usual for anybody.

What about changes to flu vaccines?

The technology used todevelop a coronavirus vaccine wont affect the annual flu vaccine because they are different viruses requiring different approaches. But evenbefore the pandemic,steps were underwayto hasten changes to the flu vaccine.

President Donald Trump signed an executive orderin September calling onmanufacturers to move away from egg-based vaccines because of critical shortcomings, including the months they take to produce. The order anticipated a pandemic more lethalthanthe 1918 Spanish flu, which killed 675,000 Americans.

William Schaffner, professor of infectious diseases at Vanderbilt University, said one reason tochange vaccine productionis that growing the vaccine in eggs allows mutationsthat make it less effective.

People were working on this already, Schaffner said. That sort of commitment, a presidential commitment, plus the moneys that go with it, really put the pedal to the metal for future research.

Egg-based vaccine manufacturing has been reliable. Developing another process would require a multimillion-dollar investment in an industry with small profit margins, Schaffner said.

Moving away from egg-based production is not like flipping a switch, he said. Im sure all the manufacturers are all thinking about this, but how and how quickly they do it is another matter.

Other options include cell-based and recombinant processes. A cell-based vaccine is grown in a mammal's cells, such as kidney cells from monkeys or dogs, rather than in a hen's eggs. A recombinant vaccine is created synthetically from the DNA, or genetic instructions, of a protein from the flu virus. The DNA is then combined with a baculovirus, which infects invertebrates.

Other changes could address vaccine delivery, perhaps moving from injections to pills or skin patches, Schaffner said.

A loftier goal is to develop what is called a universal vaccine, which could last five years at a time. Such a vaccine could be administered any time of year during a doctor's visit, rather than just in the fall.

Doing that would require changing how the vaccine attacks the flu virus, whichis shaped like a sphere with lollipops protruding from it. Vaccines so far have targeted the candy at the end ofthe lollipop, which changes every year.

A vaccine that targetsthe stem of the lollipop could offer protection for years, Shaffner said. If you get vaccinated, youre vaccinated against a whole series of different influenza viruses,Schaffner said.

The coronavirus pandemic has come during a severe flu season. This years vaccine is about as effective as usual, according to a Centers for Disease Control and Prevention study of cases through Feb. 8. The study found the severity for people up to 49 years old including hospitalizations was worse than other recent seasons, including the severe year of 2017-2018.

Current influenza vaccines are providing substantial public health benefits,"said the study in CDCs Morbidity and Mortality Weekly Report."However more effective vaccines are needed."

Contributing:Elizabeth Weise

Read the rest here:
A coronavirus vaccine is being developed in record time. But dont expect that technology to speed up flu vaccines yet. - Columbia Daily Herald

This research was partly funded by the Federal Canadian government, to support the development, testing and implementation of ways to manage the pandemic. Rumours have been circulating social media platforms at the speed of light, discussing the imminence or the impossibility of a real cure. Here, we discuss the ongoing research of a trial drug that is biologically capable of preventing fatalities from Coronavirus.

The answer is by closing the door that COVID-19 uses to enter the cells of your body.The door is the ACE2 protein on the surface of the cell membrane.

SARS-CoV-2 is the virus that causes COVID-19, which is commonly known as Coronavirus. During the last major outbreak of SARS, a similar viral respiratory illness that caused global devastation in 2003, it was Dr. Penninger and his colleagues who discovered that the ACE2 protein was the key receptor for SARS. In further research, he discovered that this protein was linked to a resultant cardiovascular disease and lung failure.

The ACE2 protein is where the spike glycoprotein of SARS-CoV-2 enters the human cell, like a door being broken down. The world is looking for a cure but there is no clinically proven antiviral treatment right now, or any treatment focusing on protecting the ACE2 receptor. This means that late-stage COVID-19 can be a fatal situation for those who are already experiencing other immune or lung issues.

The NHS defines antiviral treatment as: a type of medication used specifically for treating viral infections. They act by killing or preventing the growth of viruses.

The researchers here are not proposing a treatment that could kill the virus they are exploring the potential of highly calculated self-defence, on a microscopic level. What if those cellular doors were never broken down by the invading COVID-19 forces, because they were hidden or protected?

Dr. Josef Penninger, the UBC scientist leading this study, said:

There is hope for this horrible pandemic.

The study found that in cell cultures, hrsACE2 inhibited the early stages of COVID-19 load by a factor of 1000-5000. The researchers grew organs of blood vessels and kidneys from stem cells, to quickly test their ideas on a functioning human being.

Nria Montserrat, ICREA professor at the Institute for Bioengineering of Catalonia in Spain, said:

In these moments in which time is short, human organoids save the time that we would spend to test a new drug in the human setting.

The researchers showed that in these organs, the virus can directly infect and duplicate itself in the tissues of the blood vessel and kidney. This gave them valuable insight into how COVID-19 cases that are severe present with multi-organ failure, with evidence of cardiovascular damage.

It was found that clinical grade hrsACE2 reduced the infection in these engineered organs.

Dr. Art Slutsky, a scientist at the Keenan Research Centre for Biomedical Science of St. Michaels Hospital and professor at the University of Toronto, said:

Our new study provides very much needed direct evidence that a drug called APN01 (human recombinant soluble angiotensin-converting enzyme 2 hrsACE2) soon to be tested in clinical trials by the European biotech company Apeiron Biologics, is useful as an antiviral therapy for COVID-19.

Apeiron Biologics write that they are currently planning a clinical pilot study in China with COVID-19 infected patients, whilst evaluating options for further clinical development. APN01 was previously being used for Acute Lung Injury and Pulmonal Arterial Hypertension, for which the company currently have APN01 in Phase-2 clinical development. It is possible, given the existing Phase-2 level of development, that the next clinical trial for COVID-19 could automatically go to Phase-3. The length of Phase-3 clinical trials in Canada are usually one to three years, which involves around 1000-3000 patients. After that, the regulatory review can take anything between six months to two years.

However, given the global urgency, funding from Canadian government and clinical trials being held in China, it is highly likely that development of APN01 will be fast-tracked. We reached out for comment to the biotech company about possible timelines but have received no response at the time of publishing.

Penninger, professor in UBCs faculty of medicine, director of the Life Sciences Institute and the Canada 150 Research Chair in Functional Genetics at UBC said:

This work stems from an amazing collaboration among academic researchers and companies, including Dr. Ryan Conders gastrointestinal group at STEMCELL Technologies in Vancouver, Nuria Montserrat in Spain, Drs. Haibo Zhang and Art Slutsky from Toronto and especially Ali Mirazimis infectious biology team in Sweden, who have been working tirelessly day and night for weeks to better understand the pathology of this disease and to provide breakthrough therapeutic options.

The virus causing COVID-19 is a close sibling to the first SARS virus.

Our previous work has helped to rapidly identify ACE2 as the entry gate for SARS-CoV-2, which explains a lot about the disease. Now we know that a soluble form of ACE2 that catches the virus away, could be indeed a very rational therapy that specifically targets the gate the virus must take to infect us. There is hope for this horrible pandemic.

The findings of the study have been published in Cell.

Editor's Recommended Articles

Read more:
Researchers test drug that stops early stages of COVID-19 - Open Access Government

Ever since the novel coronavirus, or COVID-19, was first reported in China's Wuhan city, the virus has spread to more than 196 countries and territories around the world with393,284 confirmed cases and17,161 deaths so far. In India, the maximum number of cases has been reported in the state of Maharashtra.The number of coronavirus cases in the country has risen to 519, with 10 deaths.

It is the need of the hour to find a solution for coronavirus.

Clinical trials in China are already testing the efficacy of stem cell therapies for COVID-19. Arecent clinical trialwith seven COVID-19 patients showed that a stem cell product improved patient outcome. According to research published in the peer-reviewed journalAging and Disease,mesenchymal stem cell (MSC) therapy could be effective in treating COVID-19.

Coronaviruses (CoV) belong to a large family of viruses leading to respiratory illnesses, such as common coldto more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute RespiratorySyndrome (SARS-CoV).

Earlier this year, a new strain of coronavirus was discovered, which was not previously identified in humanbeings, also known as the novel coronavirus (nCov). The symptoms of the infection are respiratory issues, fever, cough, shortness of breath, and breathingdifficulties. More severe cases of COVID-19 can cause pneumonia, severe acute respiratory syndrome, and kidneyfailure.

In recent years, scientific research hasshown that MSCs have properties that maymake them very useful to repair damaged tissues in the patients respiratory system and promotefaster healing and recovery.Umbilical cord tissueis particularly rich inthese cells, which is why many parents arechoosing to store them at birth.

MSCs can reduce the overproduction of immune cells caused by a reaction to the virus and reduce excessive levels of inflammatory substances, thus regulating the immune system.

Currently, many vaccines or drugs are being tested to deal with coronavirus. There is widespread fear and phobia among the population. Why not use your own defence system rather than searching for drugs to tackle the virus?

MSCs are multi-potent cells that have been widely used for tissue regeneration and immunomodulation, and can be a potential solution. The infusion of autologous and allogenic MSCs has been proven safe and effective in tissue repair and disease modulation. MSCs have anti-inflammatory, antimicrobial properties; therefore, they have the potential to control inflammatory conditions, possibly viral diseases, and may reduce mortality.

Another interesting therapeutic avenue is immunotherapy. Natural killer (NK) cells, a component of our innate immune system, play an important role in tackling malignancies as well as virally infected cells. These cells serve to contain viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells that can clear the infection. Thus, NK cell therapy can be safe and effective in the management of COVID-19.

We need to ensure control of person-to-person transmission of the infection. Therefore, stringent isolation/quarantine measures are important until complete recovery of an infected individual.

(Disclaimer: The views and opinions expressed in this article are those of the author and do not necessarily reflect the views of YourStory.)

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Can cell-based therapy be helpful in tackling coronavirus? - YourStory

Astronauts are growing the beginnings of new organs on board the International Space Station.

The experiment is an attempt to grow human tissue by sending adult human stem cells into space, and allowing them to grow in space.

Eventually, it is hoped, the stem cells will develop into bone, cartilage and other organs. If that is successful, the discoveries could be used to try and grow organs for transplant, the scientists involved say.

The experiment uses weightlessness as a tool, according to Cara Thiel, one of the two researchers from the University of Zurich. The lack of gravity on board the ISS will be used to encourage the stem cells to grow into tissue in three dimensions, rather than the single-layer structures that form on Earth.

It is being conducted by the astronauts on board the ISS using a mobile mini-laboratory that was sent on a SpaceX rocket last week. The experiment will last for a month, during which scientists will watch to see how the stem cells grow.

If it is successful, they hope to switch from a small laboratory to bigger production. From there, they could use the process to generate tissue for transplants by taking cells from patients, or generating organ-like material, either ensuring that it works for a specific patients or reducing the number of animals used in experiments.

On Earth, tissue grows in monolayer cultures: generating flat, 2D tissue. But investigations both in space and Earth suggest that in microgravity, cells exhibit spatially unrestricted growth and assemble into complex 3D aggregates, said Oliver Ullrich, who is also leading the research.

Previous research has involved simulated ad real experiments, mostly using tumour cells, and placing real human stem cells into microgravity simulators. But for the next stage of the research there is no alternative to the ISS, he says, as 3D tissue formation of this kind requires several days or even weeks in microgravity.

After the month-long experiment, the scientists will get the samples back and expect to see successful formation of organoids smaller, more simple versions of organs inside the test tubes.

Scientists are still not sure why the conditions of the ISS lead to the assembly of complex 3D tissue structures. Scientists are still continuing to research how the gravitational force and the molecular machinery in the cell interact to create new and different kinds of tissue on Earth and in space.

Read the original here:
Made-in-space organs could soon be reality - ETHealthworld.com

If you're confused, think about HIV/AIDS. Human-immunodeficiency virus infects people. If left untreated, HIV can lead to autoimmune deficiency syndrome, or AIDS. Some people might get infected with SARS-CoV-2 and not get sick at all. Others will come down with symptoms of the disease Covid-19. (Yeah, it sounds like the name of a robot raven to us, too.)

The first cases were identified at the tail end of 2019 in Wuhan, the capital city of Chinas Hubei province, when hospitals started seeing patients with severe pneumonia. Like the viruses that cause MERS and SARS, the new coronavirus appears to have originated in bats, but its not clear how the virus jumped from bats to humans or where the first infections occurred. Often, pathogens journey through an intermediary animal reservoirbats infect the animals, and humans come into contact with some product from that animal. That could be milk or undercooked meat, or even mucus, urine, or feces. For example, MERS moved to humans through camels, and SARS came through civet cats sold at a live animal market in Guangzhou, China.

Scientists dont know why some coronaviruses have made that jump while others havent. It may be that the viruses havent made it to animals that humans interact with, or that the viruses dont have the right spike proteins, so they cant attach to our cells. Its also possible that these jumps happen more often than anyone realizes, but they go unnoticed because they dont cause serious reactions.

Coronaviruses are divided into four groups called genera: alpha, beta, gamma, and delta. These little invaders are zoonotic, meaning they can spread between animals and humans; gamma and delta coronaviruses mostly infect birds, while alpha and beta mostly reside in mammals.

Researchers first isolated human coronaviruses in the 1960s, and for a long time they were considered pretty mild. Mostly, if you got a coronavirus, youd end up with a cold. But the most famous coronaviruses are the ones that jumped from animals to humans.

Coronaviruses are made up of one strip of RNA, and that genetic material is surrounded by a membrane studded with little spike proteins. (Under a microscope, those proteins stick up in a ring around the top of the virus, giving it its namecorona is Latin for crown.) When the virus gets into the body, those spike proteins attach to host cells, and the virus injects that RNA into the cells nucleus, hijacking the replication machinery there to make more virus. Infection ensues.

The severity of that infection depends on a couple of factors. One is what part of the body the virus tends to latch onto. Less serious types of coronavirus, like the ones that cause the common cold, tend to attach to cells higher up in the respiratory tractplaces like your nose or throat. But their more gnarly relatives attach in the lungs and bronchial tubes, causing more serious infections. The MERS virus, for example, binds to a protein found in the lower respiratory tract and the gastrointestinal tract, so that, in addition to causing respiratory problems, the virus often causes kidney failure.

The other thing that contributes to the severity of the infection is the proteins the virus produces. Different genes mean different proteins; more virulent coronaviruses may have spike proteins that are better at latching onto human cells. Some coronaviruses produce proteins that can fend off the immune system, and when patients have to mount even larger immune responses, they get sicker.

This story was last updated on 3/3/20 2:15pm ET

What can we tell you? No, really, what do you want one of our in-house experts to tell you? Email the Know-It-Alls.

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What Is the Coronavirus? - WIRED

Whenever Harry Wuest has a doctors appointment in northern Atlantas hospital cluster dubbed Pill Hill, he makes sure to stop by the office of Dr. Douglas Doug Murphy for a quick chat.

And Murphy, unless hes tied up in the operating room, always takes a few minutes to say hello to his former patient. Remember when ... ? is how the conversation typically starts, and its always tinged with laughter, often joyful, sometimes bittersweet.

Its a reunion of two men who shaped a piece of Georgias medical history.

Almost 35 years ago, Murphy opened the chest of Wuest and sewed in a new heart, giving him a second shot at life. Wuest was the third heart transplant patient at Emory University Hospital.

Tall, lanky, with short curly hair and a quiet demeanor, Wuest is the longest-surviving heart transplant recipient in Georgia and one of the longest-surviving in the world. The 75-year-old accountant still plays golf twice a week and only recently went from working full-time to part-time. My heart is doing just fine, he says.

Murphy is now the chief of cardiothoracic surgery at Emory Saint Josephs Hospital and still in the operating room almost every day. He has moved on to become the worlds leading expert in robotically assisted heart surgery.

Harry Wuest is originally from Long Island, New York. After a stint in the Air Force, he moved to Florida to work and go to school. He wanted to become a physical education teacher. Then, in 1973, he fell ill. It started with some pain on his left side. He didnt think much of it, but when he got increasingly winded and fatigued, he went to see a doctor.

Several months and numerous specialists later, he received the diagnosis: Cardiomyopathy, a disease of the heart muscle that can make the heart become enlarged, thick and rigid, preventing it from pumping enough blood through the body.

They didnt know how I got it, says Wuest, sitting back in a brown leather armchair in the dark, wood-paneled living room of his Stone Mountain home. Maybe it was a virus. And back then, there wasnt much they could do to treat it, except bed rest.

For the next 12 years, Wuest lived life as best as he could. He got a degree in accounting from the University of Central Florida and worked for a real estate developer. There were good days, but there were more bad days. He was often too weak to do anything, and his heart was getting bigger and bigger.

Emorys first transplant surgeon

The first successful human-to-human heart transplant was performed in Cape Town, South Africa, in 1967 a medical breakthrough that catapulted the surgeon, Dr. Christiaan Barnard, onto the cover of Life magazine and to overnight celebrity status.

This highly publicized event was followed by a brief surge in the procedure around the world, but overall, heart transplants had a rocky start. Most patients died shortly after the surgery, mainly due to organ rejection. Back then, immunosuppressive drugs, which can counteract rejection, were still in their infancy. Many hospitals stopped doing heart transplants in the 1970s.

That changed with the discovery of a highly effective immunosuppressive agent. Cyclosporine got FDA approval in 1983 and altered the world of organ transplants.

It was shortly thereafter when Emory University Hospital decided to launch a heart transplant program, but none of the senior surgeons wanted to do it. Even with the new drug, it was a risky surgery, and mortality was still high.

Its an all-or-nothing operation, Murphy says, as he sits down in his small office overlooking the grayish hospital compound. Hes wearing light blue scrubs from an early morning surgery. At 70, he still has boyish looks, with a lean build and an air of laid-back confidence. If you have a number of bad outcomes initially, it can be detrimental to your career as a surgeon, he says.

But Murphy didnt really have a choice. He remembers that during a meeting of Emorys cardiac surgeons in 1984, he was paged to check on a patient. When he returned, the physicians congratulated him on being appointed the head of the new heart transplant program. He was the youngest in the group and had been recruited from Harvards Massachusetts General Hospital just three years before.

Yeah, thats how I became Emorys first transplant surgeon, says Murphy.

He flew to California to shadow his colleagues at Stanford University Hospital, where most heart transplants were performed at the time. Back home at Emory, he put together a team and rigorously rehearsed the operation. The first transplant patient arrived in April 1985. The surgery was successful, as was the second operation less than a month later.

Around the same time, Harry Wuest wound up in a hospital in Orlando. He needed a transplant, but none of the medical centers in Florida offered the procedure. One of his doctors recommended Emory, and Wuest agreed. I knew I was dying. I could feel it. He was flown to Atlanta by air ambulance and spent several weeks in Emorys cardiac care unit until the evening of May 23, when Murphy walked into his room and said, Weve got a heart.

I could finally breathe again

The heart, as the patient later learned, came from a 19-year-old sophomore at Georgia Tech who had been killed in a car crash.

Organ transplants are a meticulously choreographed endeavor, where timing, coordination and logistics are key. While Murphy and his eight-member team were preparing for the surgery, Wuest was getting ready to say farewell to his family his wife and three teenage sons, and to thank the staff in the cardiac ward.

I was afraid, he recalls, especially of the anesthesia. It scared the heck out of me. He pauses during the reminiscence, choking briefly. I didnt know if I was going to wake up again.

The surgery took six hours. Transplants usually happen at night because the procurement team, the surgeons who retrieve different organs from the donor, only start working when regularly scheduled patients are out of the operating room.

Despite the cultural mystique surrounding the heart as the seat of life, Murphy says that during a transplant surgery, its not like the big spirit comes down to the operating room. Its very technical. As the team follows a precise routine, emotions are kept outside the door. We dont have time for that. Emotions come later.

Waking up from the anesthesia, Wuests first coherent memory was of Murphy entering the room and saying to a nurse, Lets turn on the TV, so Harry can watch some sports.

Wuest spent the next nine days in the ICU, and three more weeks in the hospital ward. In the beginning, he could barely stand up or walk, because he had been bedridden weeks before the surgery and had lost a lot of muscle. But his strength came back quickly. I could finally breathe again, he says. Before the surgery, he felt like he was sucking in air through a tiny straw. I cannot tell you what an amazing feeling that was to suddenly breathe so easily.

Joane Goodroe was the head nurse at Emorys cardiovascular post-op floor back then. When she first met Wuest before the surgery, she recalls him lying in bed and being very, very sick. When she and the other nurses finally saw him stand up and move around, he was a whole different person.

In the early days of Emorys heart transplant program, physicians, nurses and patients were a particularly close-knit group, remembers Goodroe, whos been a nurse for 42 years and now runs a health care consulting firm. There were a lot of firsts for all of us, and we all learned from each other, she said.

Wuest developed friendships with four other early transplant patients at Emory, and he has outlived them all.

When he left the hospital, equipped with a new heart and a fresh hunger for life, Wuest made some radical changes. He decided not to return to Florida but stay in Atlanta. Thats where he felt he got the best care, and where he had found a personal support network. And he got a divorce. Four months after the operation, he went back to working full-time: first in temporary jobs and eventually for a property management company.

After having been sick for 12 years, I was just so excited to be able to work for eight hours a day, he recalls. That was a big, big deal for me.

At 50, he went back to school to get his CPA license. He also found new love.

Martha was a head nurse in the open-heart unit and later ran the cardiac registry at Saint Josephs Hospital. Thats where Wuest received his follow-up care and where they met in 1987. Wuest says for him it was love at first sight, but it took another five years until she finally agreed to go out with him. Six months later, they were married.

Harry Wuest and his wife, Martha. She was a head nurse in the open-heart unit and later ran the cardiac registry at Saint Josephs Hospital. Thats where Wuest received his follow-up care and where they met in 1987. Wuest says for him it was love at first sight, but it took another five years until she finally agreed to go out with him. Six months later, they were married.

Having worked in the transplant office, I saw the good and the bad, Martha Wuest says. A petite woman with short, perfectly groomed silver hair, she sits up very straight on the couch, her small hands folded in her lap. Not every transplant patient did as well as Harry. And I had a lot of fear in the beginning. Now he may well outlive her, she says with a smile and a wink.

Wuests surgeon, meanwhile, went on to fight his own battles. Two and a half years into the program, Murphy was still the only transplant surgeon at Emory and on call to operate whenever a heart became available. Frustrated and exhausted, he quit his position at Emory and signed up with Saint Josephs (which at the time was not part of the Emory system) and started a heart transplant program there.

At St. Josephs, Murphy continued transplanting hearts until 2005. In total, he did more than 200 such surgeries.

Being a heart transplant surgeon is a grueling profession, he says, and very much a younger surgeons subspecialty.

He then shifted his focus and became a pioneer in robotically assisted heart surgery. He has done more than 3,000 operations with the robot, mostly mitral valve repairs and replacements more than any other cardiac surgeon in the world.

Heart transplants "remain the gold standard"

Since Murphy sewed a new heart into Wuest 35 years ago, there has been major progress in the field of heart transplants, but it has been uneven.

There is improved medication to prevent rejection of the donor heart, as well as new methods of preserving and transporting donor hearts.

Yet patients requiring late-stage heart failure therapy, including transplantation, still exceed the number of donor hearts available. In 2019, 3,551 hearts were transplanted in the United States, according to the national Organ Procurement and Transplantation Network. But 700,000 people suffer from advanced heart failure, says the American Heart Association.

New technologies and continued research are providing hope to many of these patients. There has been significant progress in the development of partial artificial hearts, known as Left Ventricular Assist Devices, or LVADs. They can be used as bridge devices, to keep patients alive until donor hearts are available, or as destination therapy, maintaining patients for the remainder of their lives.

Also, total artificial hearts have come a long way since the first artificial pump was implanted in a patient in 1969. The technology is promising, says Dr. Mani Daneshmand, the director of Emorys Heart & Lung Transplantation Program. But its not perfect.

Long-term research continues into xenotransplantation, which involves transplanting animal cells, tissues and organs into human recipients.

Regenerative stem cell therapy is an experimental concept where stem cell injections stimulate the heart to replace the rigid scar tissue with tissue that resumes contraction, allowing for the damaged heart to heal itself after a heart attack or other cardiac disease. Certain stem cell therapies have shown to reverse the damage to the heart by 30 to 50 percent, says Dr. Joshua Hare, a heart transplant surgeon and the director of the Interdisciplinary Stem Cell Institute at the University of Miamis Miller School of Medicine.

All of these ideas have potential, says Daneshmand. But none of them are ready to replace a human donor heart. A heart transplant remains the gold standard, because you cant accommodate the same success with a machine right now, he says.

Efforts around expanding the donor pool are really the best way to address this problem, while we wait for technology to catch up, he adds.

Besides Emory, other health care systems in Georgia that currently have a heart transplant program are Piedmont Healthcare, Childrens Healthcare of Atlanta and Augusta University Health.

Organ rejection remains a major issue, and long-term survival rates have not improved dramatically over the past 35 years. The 10-year survival is currently around 55 percent of patients, which makes long-term survivors like Harry Wuest rare in the world of heart transplants.

The United Network of Organ Sharing, or UNOS, which allocates donor hearts in the United States, doesnt have comprehensive data prior to 1987. An informal survey of the 20 highest-volume hospitals for heart transplants in the 1980s found only a scattering of long-term survivors.

In for the long haul

Being one of the longest-living heart transplant recipients is something that Wuest sees as a responsibility to other transplant patients, but also to the donors family, which hes never met. If you as a transplant recipient reject that heart, thats like a second loss for that family.

Part of this responsibility is living a full and active life. Both he and Martha have three children from their previous marriages and combined they have 15 grandchildren. Most of their families live in Florida, so they travel back and forth frequently. Wuest still works as a CPA during tax season, and he does advocacy for the Georgia Transplant Foundation. In addition to golf, he enjoys lifting weights and riding his bike.

Hes had some health scares over the years. In 2013, he was diagnosed with stage 1 kidney cancer, which is in remission. Also, he crossed paths with his former surgeon, and not just socially. In 2014, Murphy replaced a damaged tricuspid valve in Wuests new heart. That operation went well, too.

Murphy says there are several reasons why Wuest has survived so long. Obviously, his new heart was a very good match. But a patient can have the best heart and the best care and the best medicines and still die a few months or years after the transplantation, the surgeon says. Attitude plays a key role.

Wuest was psychologically stable and never suffered from depression or anxiety, Murphy says. Hes a numbers guy. He knew the transplant was his only chance, and he was set to pursue it.

Wuest attributes his longevity to a good strong heart from his donor; good genetics; great doctors and nurses; and a life that he loves. Im just happy to be here, he says.

Quoting his former surgeon and friend, he adds: Doug always said, Having a transplant is like running a marathon. And Im in for the long haul.

See the article here:
34 years with a new heart and counting - MDJOnline.com

The novel coronavirus has claimed around 1,770 lives and affected almost 70,000 people with no possible cure in sight. Scientists all over the world are working hard to find treatment. More than 80 clinical trials have been launched to find the treatment for the deadly virus. While trying everything from stem cell therapy to HIV drugs, China has resorted to giving a 3,000-year-old traditional remedy a trial, to treat the patients. The new health commission head in Hubei, Wang Hesheng said that their efforts have shown some good results and the Traditional Chinese Medicine experts have been sent to Hubei for research and treatment. The treatment in Wuhan hospital combines Traditional Chinese Medicine, commonly known as TCM and western medicines. This combination is given to more than half of the confirmed cases in Hubei.

The reports of treatments and vaccine of those infected with the virus have caused ripples of excitement in people who are looking at it as a sign of hope!

What is Traditional Chinese Medicine?Traditional Chinese Medicine ranges back to thousands of years. TCM practitioners use various mind and body practices (acupuncture, tai chi, Chinese herbal products) to address several health issues.

Coronavirus in IndiaTill now there have three positive cases of novel Coronavirus in Kerela, India. The good news is that out of these three, two patients have already been discharged after showing negative results for the test of the virus.

Common symptoms of novel coronavirusThe initial symptoms of novel coronavirus are very similar to that of normal cold and flu. Common symptoms include:

- Fever

- Cough

- Shortness of breath

Read the rest here:
Coronavirus: Doctors try 3,000-year-old Traditional Chinese Medicine (TCM) to treat the virus - Times of India

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the pivotal Phase 3 KEYNOTE-355 trial investigating KEYTRUDA, Mercks anti-PD-1 therapy, in combination with chemotherapy met one of its dual primary endpoints of progression-free survival (PFS) in patients with metastatic triple-negative breast cancer (mTNBC) whose tumors expressed PD-L1 (Combined Positive Score [CPS] 10). Based on an interim analysis conducted by an independent Data Monitoring Committee (DMC), first-line treatment with KEYTRUDA in combination with chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) demonstrated a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy alone in these patients. Based on the recommendation of the DMC, the trial will continue without changes to evaluate the other dual primary endpoint of overall survival (OS). The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies; no new safety signals were identified.

Triple-negative breast cancer is an aggressive malignancy. It is very encouraging that KEYTRUDA in combination with chemotherapy has now demonstrated positive results as both a first-line treatment in the metastatic setting with this trial, and as neoadjuvant therapy in the KEYNOTE-522 trial, said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. We look forward to sharing these findings with the medical community at an upcoming congress and discussing them with the FDA and other regulatory authorities.

The KEYTRUDA breast cancer clinical development program encompasses several internal and external collaborative studies. In addition to KEYNOTE-355, in TNBC these include the ongoing registration-enabling studies KEYNOTE-242 and KEYNOTE-522.

About KEYNOTE-355

KEYNOTE-355 is a randomized, two-part, Phase 3 trial (ClinicalTrials.gov, NCT02819518) evaluating KEYTRUDA in combination with one of three different chemotherapies (investigators choice of either nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) compared with placebo plus one of the three chemotherapy regimens for the treatment of locally recurrent inoperable or mTNBC that has not been previously treated with chemotherapy in the metastatic setting. Part 1 of the study was open-label and evaluated the safety and tolerability of KEYTRUDA in combination with either nab-paclitaxel, paclitaxel or gemcitabine/carboplatin in 30 patients. Part 2 of KEYNOTE-355 was double-blinded, with dual primary endpoints of OS and PFS in all participants and in participants whose tumors expressed PD-L1 (CPS 1 and CPS 10). The secondary endpoints include objective response rate (ORR), duration of response (DOR), disease control rate (DCR) and safety.

Part 2 of KEYNOTE-355 enrolled 847 patients who were randomized to receive KEYTRUDA (200 mg intravenously [IV] on day 1 of each 21-day cycle) plus nab-paclitaxel (100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle), paclitaxel (90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle) or gemcitabine/carboplatin (1,000 mg/m2 [gemcitabine] and Area Under the Curve [AUC] 2 [carboplatin] on days 1 and 8 of each 21-day cycle); or placebo (normal saline on day 1 of each 21-day cycle) plus nab-paclitaxel (100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle), paclitaxel (90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle) or gemcitabine/carboplatin (1,000 mg/m2 [gemcitabine] and AUC 2 [carboplatin] on days 1 and 8 of each 21-day cycle).

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some breast cancers may test positive for estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. As a result, TNBC does not respond to therapies targeting these markers, making it more difficult to treat. Approximately 15-20% of patients with breast cancer are diagnosed with TNBC.

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 1,000 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

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 and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines 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 the confirmatory trials.

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. 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. 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 (MSI-H) 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.

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).

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.

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 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

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 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

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 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

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 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

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 postmarketing 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)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

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-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those 2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Original post:
Merck's KEYTRUDA (pembrolizumab) in Combination with Chemotherapy Met Primary Endpoint of Progression-Free Survival (PFS) as First-Line Treatment for...

BOTHELL, Wash. and TOKYO, Feb. 10, 2020 /PRNewswire/ --Seattle Genetics, Inc.(Nasdaq: SGEN) and Astellas Pharma Inc.(TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") today announced updated results from the phase 1b/2 clinical trial EV-103 in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for treatment with cisplatin-based chemotherapy. Forty-five patients were treated with the combination of PADCEV (enfortumab vedotin-ejfv) and pembrolizumab and were evaluated for safety and efficacy. After a median follow-up of 11.5 months, the study results continue to meet outcome measures for safety and demonstrate encouraging clinical activity for this platinum-free combination in a first-line setting. Updated results will be presented during an oral session on Friday, February 14 at the 2020 Genitourinary Cancers Symposium in San Francisco (Abstract #441). Initial results from the study were presented at the European Society of Medical Oncology Congress in September 2019.

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.1,2

"Cisplatin-basedchemotherapy is the standard treatment for first-line advanced urothelial cancer; however, it isn't an option for many patients,"said Jonathan E. Rosenberg, M.D., Medical Oncologist and Chief, Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York."I'm encouraged by these interim results, including a median progression-free survival of a year for patients who received the platinum-free combination of PADCEV and pembrolizumab in the first-line setting."

In the study, 58 percent (26/45) of patients had a treatment-related adverse event greater than or equal to Grade 3: increase in lipase (18 percent; 8/45), rash (13 percent; 6/45), hyperglycemia (13 percent; 6/45) and peripheral neuropathy (4 percent; 2/45); these rates were similar to those observed with PADCEV monotherapy.3Eighteen percent (8/45) of patients had treatment-related immune-mediated adverse events of clinical interest greater than or equal to Grade 3 that required the use of systemic steroids (arthralgia, dermatitis bullous, pneumonitis, lipase increased, rash erythematous, rash maculo-papular, tubulointerstitial nephritis, myasthenia gravis). None of the adverse events of clinical interest were Grade 5 events. Six patients (13 percent) discontinued treatment due to treatment-related adverse events, most commonly peripheral sensory neuropathy. As previously reported, there was one death deemed to be treatment-related by the investigator attributed to multiple organ dysfunction syndrome.

The data demonstrated the combination of PADCEV plus pembrolizumab shrank tumors in the majority of patients, resulting in a confirmed objective response rate (ORR) of 73.3 percent (33/45; 95% Confidence Interval (CI): 58.1, 85.4) after a median follow-up of 11.5 months (range,0.7 to 19.2). Responses included 15.6 percent (7/45) of patients who had a complete response (CR)and 57.8 percent (26/45) of patients who had a partial response. Median duration of response has not yet been reached (range 1.2 to 12.9+ months). Eighteen (55%) of 33 responses were ongoing at the time of analysis, with 83.9% of responses lasting at least 6 months and 53.7% of responses lasting at least 12 months (Kaplan-Meier estimate).The median progression-free survival was 12.3 months (95% CI: 7.98, -) and the 12-month overall survival (OS) rate was 81.6 percent (95% CI: 62 to 91.8 percent); median OS has not been reached.

"These updated data are encouraging and provide support for the recently initiated phase 3 trial EV-302 that includes an arm evaluating PADCEV in this platinum-free combination in the first-line setting," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.

"These additional results support continued evaluation of PADCEV in combination with other agents and at earlier stages of treatment for patients withurothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.

About the EV-103 TrialEV-103 is an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial of PADCEV alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive, locally advanced and first- and second-line metastatic urothelial cancer.

The dose-escalation cohort and expansion cohort A include locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. Patients were dosed in a 21-day cycle, receiving an intravenous (IV) infusion of enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At the time of this initial analysis, 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion cohort A) with locally advanced and/or metastatic urothelial cancer had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.

The primary outcome measure of the cohorts included in this analysis is safety. Key secondary objectives related to efficacy include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression free survival (PFS) and overall survival (OS). DoR,PFS and OS are not yet mature.

Additional cohorts in the EV-103 study will evaluate enfortumab vedotin:

More information about PADCEV clinical trials can be found at clinicaltrials.gov.

About Bladder and Urothelial CancerIt is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020.5 Urothelial cancer accounts for 90 percent of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.6 Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide.7

The recommended first-line treatment for patients with advanced urothelial cancer is a cisplatin-based chemotherapy. For patients who are ineligible for cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens.8

About PADCEV PADCEV (enfortumabvedotin-ejfv) 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 may be contingent upon verification and description of clinical benefit in confirmatory trials.9

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.2,9Nonclinical 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).9PADCEV is co-developed by Astellas and Seattle Genetics.

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, hemoglobin decreased, phosphate decreased, lipase increased, sodium decreased, glucose increased, urate increased, neutrophils decreased.

Drug Interactions

Specific Populations

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

About Seattle GeneticsSeattle Genetics, Inc. is a global biotechnology company that discovers, develops and commercializes transformative medicines targeting cancer to make a meaningful difference in people's lives. The company is headquartered in Bothell, Washington, and has offices in California, Switzerland and the European Union. For more information on our robust pipeline, visit https://www.seattlegenetics.comand follow @SeattleGenetics on Twitter.

About AstellasAstellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. For more information, please visit our website at https://www.astellas.com/en.

About the Astellas and Seattle Genetics CollaborationSeattle Genetics and Astellas are co-developing enfortumab vedotin-ejfv under a collaboration that was entered into in 2007 and expanded in 2009. Under the collaboration, the companies are sharing costs and profits on a 50:50 basis worldwide.

Seattle Genetics Forward-Looking StatementsCertain statements made in this press release are forward looking, such as those, among others, relating to the EV-103 and EV-302 clinical trials; clinical development plans relating to enfortumab vedotin; the therapeutic potential of enfortumab vedotin; and its possible safety, efficacy, and therapeutic uses, including in the first-line setting. 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 possibility that ongoing and subsequent clinical trials of enfortumab vedotin may fail to establish sufficient efficacy; that adverse events or safety signals may occur and that adverse regulatory actions or other setbacks could occur as enfortumab vedotin advances in clinical trials even after promising results in earlier clinical trials. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption "Risk Factors" included in the company's Annual Report on Form 10-K for the year ended December 31, 2019 filed with the Securities and Exchange Commission. Seattle Genetics 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.

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.

1 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.2 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):3003-13.3 Rosenberg JE, O'Donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2019;37(29):2592-600.4 ClinicalTrials.gov. A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103). https://clinicaltrials.gov/ct2/show/NCT03288545.5 American Cancer Society. Cancer Facts & Figures 2020. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed 01-23-2020.6National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed 05-01-2019.7International Agency for Research on Cancer. Cancer Tomorrow: Bladder. http://gco.iarc.fr/tomorrow. 8 National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 4; July 10, 2019. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.9 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.

SOURCE Astellas

http://www.seattlegenetics.com

Here is the original post:
Seattle Genetics and Astellas Announce Updated Results from Phase 1b/2 Trial of PADCEV (enfortumab vedotin-ejfv) in Combination with Immune Therapy...

Back in the thirties we were told we must collectivize the nation because the people were so poor. Now we are told we must collectivize the nation because the people are so rich. William F. Buckley Jr.

Today, we revisit a 'Tier 3' biotech stock whose stock has been under some recent pressure. However, it has two potential significant catalysts on the horizon. We update our investment case on this intriguing small-cap concern in the paragraphs below.

Omeros Corporation (OMER) is a Seattle based commercial-stage biopharmaceutical concern focused on the development of small molecule and protein therapeutics for the treatment of inflammation, complement-mediated diseases, central nervous system disorders, and immune-related diseases, including cancer. The company has one commercial asset, one late-stage candidate being evaluated for three indications, and several early and preclinical compounds. Omeros was formed in 1994 and went public in 2009, raising net proceeds of $61.8 million at $10 a share. The company completed a secondary offering at $13.10 in December 2019 following the release of positive data on its late-stage candidate, OMS721 (narsoplimab). The current market capitalization of OMER is just under $700 million.

Product:

Omidria. Omeros revenue is generated from Omidria, a phenylephrine and ketorolac intraocular solution that is approved for use during cataract surgery or intraocular lens replacement to maintain pupil size by preventing intraoperative miosis (pupil constriction) and reducing postoperative pain. Omidria was launched in 2015 and in 2017 generated net revenue of $64.8 million. However, the Centers for Medicare and Medicaid Services (CMS) determined to let its separate reimbursement under Medicare Part B expire on January 1, 2018, causing sales to plummet ~90%. Fortunately for Omeros, an act of Congress circumvented the CMS and reinstated its pass-through status for two years starting October 1, 2018. Omidria sales rebounded, likely eclipsing $110 million in 2019.

The reason for the pushback from the CMS regarding Omidria has to do with the fact that its active ingredients (phenylephrine and ketorolac) have been around for decades and a similar solution can be prepared by surgeons at a fraction of Omidrias cost. Omeros continues to pursue permanent separate reimbursement for Omidria and the CMS left the door open, indicating a need to find non-opioid alternatives. However, despite the company providing evidence demonstrating Omidria use reduced the need for fentanyl by nearly 80%, the CMS own study suggested otherwise, and it declined to grant Omidria separate payment status. News of this rejection sent shares 16% lower on November 4, 2019.

The CMS continues to analyze and monitor Omidria, and Omeros will exhaust all legislative and administrative avenues to secure permanent or similar status before the September 2020 expiration, including bipartisan anti-opioid legislation that could grant Omidria separate payment status for up to an additional five years. Management remains confident in its ability to gain permanent or similar status beyond September 2020. If it does not prevail, the blow to its top line will be harsh but not likely as severe as in 2018, owing to Omidria receiving its own J-Code in October 2019, which expands separate payment across commercial Med Advantage and Medicaid insurers, as well as in the office setting.

It goes without saying that Omidrias status will alter by a number of years how fast the company will achieve cash-flow positive levels.

Pipeline:

OMS721. In the meantime, Omeros has initiated a rolling BLA for OMS721, its monoclonal antibody (MAB) targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a protein involved in the activation of the complement system, a branch of the bodys immune system that destroys and removes foreign particles and is engaged in the bodys inflammatory response. OMS721 is currently being evaluated in the treatment of three diseases that are all the result of complement system dysfunction.

The indication for which Omeros is filing a BLA is hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), a multifactorial disorder induced by systemic vascular endothelial injury that can be triggered by several mechanisms during the transplant process. It occurs in ~40% of the ~60,000 patients undergoing allogenic HSCT in the U.S. and EU annually and is characterized by aggressive blood clotting usually resulting in acute renal failure. Severe cases have a mortality rate north of 90%. There are currently no approved therapies for HSCT-TMA.

That may change as the FDA was impressed enough with February 2018 interim data from OMS721s Phase 2 HSCT-TMA trial, in which median overall survival in 19 patients improved to 347 days versus the historical norm of 21 days (p<0.0001), to treat the small proof-of-concept study as registrational. Omeros released additional data on December 4, 2019, showing OMS721 demonstrated a 68% complete responder rate and a 100-day mortality rate of 19% versus the historical norm of 53% in HSCT-TMA patients who received at least four weeks of dosing. This prompted a 6% rally in shares of OMER, the trading session before the secondary offering was announced.

It should be noted that there are other candidates in the clinic for the HSCT-TMA indication, including Alexions (ALXN) already approved (for other indications) C5 inhibitor Ultomiris. However, Alexion is well behind, planning to initiate a Phase 3 trial (pending FDA feedback) in 1H20. The same can be said regarding Akari Therapeutics (AKTX) nomacopan, which plans to initiate a Phase 3 pediatric study in 1Q20. These schedules should give OMS721 a significant jump on any competition, which should have its BLA completed in 1H20. In addition to Breakthrough Therapy designation from FDA, OMS721 has Orphan drug status in both the U.S. and Europe and will likely receive a priority review from the FDA for HSCT-TMA.

OMS721's second most advanced indication is Immunoglobulin A (IGA) nephropathy, an ailment characterized by inflammation and kidney damage due to a buildup of the IgA antigen that affects 130,000150,000 people in the US and ~200,000 people in Europe with no approved remedies. After positive data from a very small Phase 2 study in which OMS721 reduced proteinuria in IgA nephropathy patients by 50-90%, Omeros finalized the particulars of a Phase 3 trial with the FDA in January 2019. The trials primary endpoint is the same: the relatively novel reduction in proteinuria levels at week 36. By obtaining approval on this endpoint (versus say renal function as measured by estimated glomerular filtration rate), it could potentially shorten the approval process by several years. Enrollment in the ~280-patient study is ongoing and accelerating. For this indication, OMS721 has received Breakthrough Therapy designation from the FDA and Orphan status in both the U.S. and EU.

To date, OMS721 has not been menaced by any significant safety or tolerability issues, which will help it in its pursuit of approval in the treatment of atypical hemolytic uremic syndrome (aHUS), a very rare disorder characterized by uncontrolled activation of the bodys complement system, manifesting itself in strokes, heart attacks, and kidney failures. Approximately 65% of patients diagnosed with aHUS die, require dialysis, or incur permanent renal damage within one year after diagnosis. The only approved treatment on the market is Alexions mAb Soliris, which has a Black Box warning due to risk of fatal infections as a result of suppression of the immune system. In most instances, patients must be immunized with a meningococcal vaccine at least two weeks prior to first administration of Soliris.

Armed with Fast Track and Orphan designations, Omeros only needs to conduct a 40-patient, single-arm (i.e., no control group), open-label Phase 3 trial to satisfy both the FDA and EMA for accelerated and full approvals, respectively. To achieve full approval in the U.S., OMS721 will need to add ~40 patients to the study. The issue confronting Omeros is that the trial began enrollment in 4Q16 and three years later management has not provided any definitive timetable regarding the trials progress, providing a frustrating connotation of accelerated approval for investors.

OMS527. Omeros other clinical asset is OMS527, which is being investigated in patients with addictions and compulsive disorders. After a successful Phase 1 study readout in 3Q19, OMS527 is expected to enter a Phase 2a trial in 2020 with a focus on nicotine addiction.

OMS906 and GPR174. The company also has assets that have demonstrated promise in the pre-clinic. OMS906 is a MASP-3 inhibitor for paroxysmal nocturnal hemoglobinuria and other alternative pathway disorders. Pre-clinical research on GPR174 inhibition has displayed promise in immuno-oncology. OMS906 is expected to enter the clinic in 1H20; GPR174 inhibitors will see the clinic when the company has more resources.

On that front, Omeros raised net proceeds of $54.5 million in a December 2019 secondary, which should leave it with ~$70 million at YE19. It has convertible debt with a face value of $210 million ($155 million carrying value) due 2023. The company also has an untapped vehicle through which it can borrow 85% of its receivables up to $50 million. Its cash runway will be contingent on securing separate payment status for Omidria post-September 2020 and the cadence of its development programs.

Like the investment community, Street analysts are somewhat split on Omeros prospects with one outperform rating sandwiched in between two buys and two holds. Their median twelve-month price target, however, is around $25 a share.

There are some unknowns regarding Omeros. Besides Omidrias status, the timing surrounding the completion of two of its pivotal OMS721 trials is still unclear in one instance, after three years. What does seem clear is that the FDA wants to approve OMS721. Given the lack of approved remedies for these complement systems diseases, OMS721 has relatively low hurdles to jump. If eventually approved for all three indications, OMS721 has blockbuster potential. If Omidria obtains five years of separate payment status, it will pave the way for Omeros to finance its own R&D without any more trips to the capital markets. With many shots on goal and what appears to be a helping hand from the FDA, continued investment in the shares of OMER is merited.

Idealism is fine, but as it approaches reality, the costs become prohibitive. William F. Buckley

Bret Jensen is the Founder of and authors articles for the Biotech Forum, Busted IPO Forum, and Insiders Forum

The Biotech Forum sports one of the liveliest collections of seasoned biotech investors on Seeking Alpha along with a 20-stock model portfolio. Join us during every trading day on Live Chat where the community swaps trading ideas, breaking news and opinions around all things Biotech. Initiate your risk-free, two week trial into The Biotech Forum by clicking HERE.

Disclosure: I am/we are long ALXN,OMER. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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Omeros: 2 Major Catalysts On The Horizon - Seeking Alpha

All events are free. Other topics covered include the impact of new and emerging global infectious diseases such as coronavirus; innovative new methods for detecting ovarian cancer; the promises and pitfalls of gene editing; the rise of antibiotic-resistant superbugs; the worlds second HIV cure; and using stem cells to regenerate damaged tissues.

Using state-of-the-art technology, researchers are now able to grow organoids miniature versions of organs. In Mini-organs in a dish: how organoids are revolutionising research (12 March), Dr Emma Rawlins, The Gurdon Institute, explains how organoids are grown and discusses why this new technology is so important for biomedical research.

Dr Rawlins said: Scientists have been growing animal and human cells in the laboratory for more than 60 years. While these lab-grown cells are a powerful research tool, providing the basis for important developments in modern medicine, including some cancer drugs, anti-HIV therapies and vaccines, they are grown in very artificial conditions and therefore dont resemble any cells in our bodies. Ten years ago, Professor Hans Clevers and colleagues in the Netherlands invented a more complex cell culture system in which mini-organs, or organoids, could be grown. This discovery has led to a worldwide revolution in cell growth.

Scientists in Cambridge are at the forefront of this research, and mini-guts, livers, lungs, kidneys, placentas and even brains are growing in labs all over the city. This ability to study cells in a more natural setting provides many new and interesting research opportunities. Organoid technology has already been used to study human embryonic development, to test personalised treatments for cystic fibrosis and to replace some of the animals used in drug testing. Scientists are now exploring its potential for growing replacement organs, repairing damaged genes and providing personalised treatments for other diseases.

Researchers are also exploring whether they can print biomaterials to repair organs amongst other healthcare benefits. In 3D printing for healthcare (14 March), Dr Yan Yan Shery Huang, Department of Engineering, gives an overview on how 3D printing technologies could transform the way implants are produced, drugs are screened or perhaps even how damaged organs are repaired.

3D printing is already making impacts on patients needing artificial limbs, where the plastic-based prosthesis can be made 'personalised' to shapes and sizes, with relatively low-cost and short production time, Dr Huang said. For 3D printed personalised implants it is more technologically demanding; although, non-biological material-based implants are making their ways to the market and patients, such as 3D printed dental implants and implants for bone structural reconstruction.

Research is now focused on overcoming challenges in using 3D printing for biological materials and even living materials like cells. Applications are focused on two main streams: bioprinting for tissue and organ function replacements, including printing a scaffold for a heart, a human ear, and a blood vessel-permeated-bioreactor; and bioprinting for drug testing pseudo-models of different levels of complexities, from brain to muscles have already been created. Research is continuing, with the aim to reduce and replace animal studies and to improve the predictive power of the models.

Hardening of the arteries is a widespread condition that is a major cause of cardiovascular disease, including heart attacks and stroke. Stroke is also linked to vascular dementia and is one of the nations major causes of adult disability there is a stroke every five minutes in the UK and costs the economy 26b per annum. This figure is expected to triple by 2035. Despite the huge impact that hardened arteries have for human health, there are still no cures. In More than a blocked pipe: the hardening of arteries and their role in stroke and heart attacks (18 March), Dr Nick Evans, Department of Medicine, and Professor Melinda Duer, Department of Chemistry, discuss their combined efforts to find better diagnoses and treatments. They reveal new research and findings on how hardened arteries can be diagnosed more precisely through PET (positron emission tomography), which is proving to be an excellent way to assess carotid calcification in patients and could lead to potential new drug treatment.

Speaking ahead of the event, Professor Duer said: To stop artery calcification, we need to stop the mineral from forming in the artery wall in the first place. We have very recently discovered that a molecule known as poly(ADP ribose), produced by cells in the artery wall that are stressed from fatty deposits around them, is responsible for initiating the formation of the mineral deposits. poly(ADP ribose) gathers calcium and sticks it to the collagen and other molecules in the artery wall, so concentrating the calcium into specific spots in the artery wall which then allows mineral to form. The exciting treatment possibility is to stop stressed cells from making poly(ADP ribose) if it works, it will be the first drug treatment for vascular calcification.

Dr Evans added: Our newly presented research also shows how we can identify the microcalcification in patients using PET and how it gives us an understanding of the different processes causing atherosclerotic plaques (the hardening of arteries) to become damaged and trigger clots to form that cause a stroke.

Scientists and researchers at the forefront of tackling ovarian cancer are also making breakthroughs. In Tackling ovarian cancer: turning the tide on one of the toughest cancers (19 March), Cancer Research UK Cambridge Institute (CRUK CI), the Department of Radiology and AstraZeneca discuss how they are rapidly turning the tide on ovarian cancer using innovative new detection methods and through new treatments, such as Olaparib which was made available in the UK in December 2019.

The new detection methods currently being researched by CRUK CI include liquid biopsy, a process that uses advanced genomic technologies to extract cancer tumour DNA fragments from patients blood plasma. The process offers earlier detection and is far less invasive for patients. Another method is virtual biopsy using state-of-the-art imaging techniques, which is also being researched by the Department of Radiology, University of Cambridge.

The final day of the Festival, Sunday 22nd March, is dedicated to health with over 50 events hosted across Cambridge Biomedical Campus (CBC). Events include Gene editing: rewriting the future! Dr Alasdair Russell, CRUK CI, talks about the CRISPR genome editing revolution, its promise and its pitfalls. In The story of HIV Public Health England and partner organisations discuss the history of HIV in England and show how we have come so far in the diagnosis, treatment and care of people living with the illness. During Open science at the Jeffrey Cheah biomedical centre, visitors can learn more about the new kids on the block on the CBC and chat with scientists about stem cells, infectious diseases, cancer and new therapies. Tours of Royal Papworth Hospital offer a look inside one of the worlds leading heart and lung hospitals and a chance to meet the outstanding teams involved in delivering patient care.

Further related health-related events:

Bookings open on Monday 10 February at 11am.

The full programme can downloaded via Cambridge Science Festival>>>

Image: Talking science with the Department of Materials Science and MetallurgyCredit: Domininkas Zalys

Keep up to date with the Festival on social media via Facebook and Twitter #CamSciFest and Instagram.

This years Festival sponsors and partners are Cambridge University Press, AstraZeneca, Illumina, TTP Group, Anglia Ruskin University, Cambridge Epigenetix, Cambridge Science Centre, Cambridge Junction, IET, Hills Road 6th Form College, British Science Week, Cambridge University Health Partners, Cambridge Academy for Science and Technology, and Walters Kundert Charitable Trust. Media Partners: BBC Radio Cambridgeshire and Cambridge Independent.

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Cambridge Science Festival showcases new research at the forefront of healthcare and medicine - Cambridge Network

Anemia also known as iron-poor blood is a condition that develops when either the blood doesn't have enough red blood cells or the concentration of hemoglobin in red blood cells is very low. Hemoglobin is the iron-containing protein in red blood cells that carries oxygen from the lungs to the rest of the body. When there are fewer red blood cells than normal or low levels of hemoglobin, the body doesn't get enough oxygen-rich blood for healthy functioning, which is what causes the symptoms of anemia.

Anemia is the most common blood disorder in the United States, affecting nearly 3 million Americans, according to the Centers for Disease Control and Prevention (CDC).

The term anemia is a broad one that represents several hundred different conditions some of them mild and treatable, others that are quite serious, said Dr. Nancy Berliner, chief of hematology at Brigham and Women's Hospital in Boston. There are three reasons that people are anemic, Berliner said: Either their body can't make enough red blood cells, something is destroying the red blood cells faster than their body can make news ones or blood loss (from menstrual periods, colon polyps or a stomach ulcer, for example) is greater than blood cell production.

There are more than 400 different types of anemia, according to the Pacific Heart, Lung & Blood Institute. Here are a few of the more common and better understood types:

Iron-deficiency anemia: The most common form of anemia is caused by low-iron levels in the body. Humans need iron to make hemoglobin, and most of that iron comes from dietary sources. Iron-deficiency anemia can result from a poor diet or from blood loss through menstruation, surgery or internal bleeding.

Pregnancy also increases the body's need for iron because more blood is needed to supply oxygen to the developing fetus, which may quickly drain the body's available iron stores, leading to a deficit. Problems absorbing iron from food because of Crohn's disease or celiac disease can also result in anemia.

Vitamin deficiency anemia: Besides iron, the body also needs two different B-vitamins folate and B12 to make enough red blood cells. Not consuming enough B12 or folate in the diet or an inability to absorb enough of these vitamins can lead to deficient red blood cell production.

Sickle cell anemia or sickle cell disease (SDC): This inherited disease causes red blood cells to become crescent-shaped rather than round. Abnormally shaped red cells can break apart easily and clog small blood vessels, resulting in a shortage of red blood cells and episodes of pain, according to the Mayo Clinic. People become chronically anemic because the sickle-shaped red cells are not pliable and can't get through blood vessels to deliver oxygen, Berliner said.

SDC occurs most often in people from parts of the world where malaria is or was common, according to the CDC; the sickle cell trait may provide protection against severe forms of malaria. In the U.S., SDC affects an estimated 100,000 Americans.

Thalassemia: Thalassemia is an inherited blood disorder that results in lower-than-normal levels of hemoglobin. This type of anemia is caused by genetic mutations in one or more of the genes that control the production of hemoglobin, according to the National Heart, Lung & Blood Institute (NHLBI).

Aplastic anemia: Aplastic anemia is a rare, life-threatening condition that develops when bone marrow stops making enough new blood cells, including red cells, white cells and platelets.

Aplastic anemia may be caused by radiation and chemotherapy treatments, which can damage stem cells in bone marrow that produce blood cells. Some medications, exposure to toxic chemicals like pesticides, viral infections and autoimmune disorders can also affect bone marrow and slow blood cell production.

Hemolytic anemias: This disorder causes red blood cells to be destroyed faster than bone marrow can replace them. Hemolytic anemias may be caused by infections, leaky heart valves, autoimmune disorders or inherited abnormalities in red blood cells, according to the American Society of Hematology.

Anemia of inflammation: Also called anemia of chronic disease, anemia of inflammation commonly occurs in people with chronic conditions that cause inflammation. This includes people with infections, rheumatoid arthritis, inflammatory bowel disease, chronic kidney disease, HIV/AIDS and certain cancers, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

When a person has a disease or infection that causes inflammation, the immune system responds in a way that changes how the body works, resulting in anemia. For example, inflammation suppresses the availability of iron, so the body may not use and store the mineral normally for healthy red blood cell production, Berliner said. Inflammation may also stop the kidneys from producing a hormone that promotes red blood cell production.

The risk for anemia is higher in people with a poor diet, intestinal disorders, chronic diseases and infections. Women who are menstruating or pregnant are also prone to the disorder.

The risk of anemia increases with age, and about 10% to 12% of people over 65 are anemic, Berliner said. But the condition is not a normal part of aging, so the cause should be investigated when it's diagnosed, she said. Older adults may develop anemia from chronic diseases, such as cancer, or iron-deficiency anemia from abnormal bleeding.

According to NHLBI, the following types of people have an increased risk of developing anemia:

Mild forms of anemia may not cause any symptoms. When signs and symptoms of anemia do occur, they may include the following, according to the NHLBI:

The first test used to diagnose anemia is a complete blood count, which measures different parts and features of the blood: It shows the number and average size of red blood cells, as well as the amount of hemoglobin. A lower-than-normal red blood cell count or low levels of hemoglobin indicate anemia is present.

If more testing is needed to determine the type of anemia, a blood sample can be examined under a microscope to check for abnormalities in the size and shape of the red cells, white cells and platelets.

Related: This man's taste buds disappeared because of a blood condition

The treatment of anemia depends on the specific type of anemia, Berliner said, and anemias caused by nutritional deficiencies respond well to changes in diet. People with iron-deficiency anemia may need to take supplemental iron for several months or longer to replenish blood levels of the mineral. Some people, especially pregnant women, may find it hard to take iron because it causes side effects, such as an upset stomach or constipation, Berliner said.

For vitamin-deficiency anemias, treatment with B12 or folate from supplements (or a B12 shot) and foods, can improve levels of these nutrients in the blood, Berliner said.

Serious problems, such as aplastic anemia, which involves bone marrow failure, may be treated with medications and blood transfusions. Severe forms of thalassemia might need frequent blood transfusions.

Treatment for sickle cell anemia may include pain medications, blood transfusions or a bone marrow transplant.

Additional resources:

This article is for informational purposes only, and is not meant to offer medical advice.

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Anemia: Causes, symptoms and treatment - Livescience.com

It's no secret that Americans aren't doing all that well in the savings department. An estimated 39% of U.S. adults don't have the money on hand to cover a $400 emergency, and 45% of Americans have no money earmarked for retirement savings.

If your savings efforts have been far from fruitful in recent years, it's time to do better -- even if that means going to a bit of an extreme to get there. Here are a few far-out but effective methods of boosting your savings -- and buying yourself the financial security you're currently missing.

IMAGE SOURCE: GETTY IMAGES.

If you're not familiar with no-spend periods, they involve not forking over so much as a dime on non-essentials for different periods of time. It's common to have an occasional no-spend week or no-spend month, but if you're really intent on boosting your savings, you may want to extend that restriction for a full year. That's right -- no restaurant meals, non-work clothing, or paid entertainment for an entire 12 months.

Will that be difficult? Absolutely. But imagine you currently spend $600 a month on dining out, leisure, apparel, and other items you enjoy having but can technically live without. In the course of a year, you'll be $7,200 richer.

Housing is the typical American's greatest monthly expense, so if you're able to reduce it substantially, you're apt to boost your savings in a very meaningful way. Imagine you currently rent a three-bedroom, 2000-square-foot apartment with your spouse and child for $2,000 a month. If you were to downsize to a one-bedroom (yes, you read that correctly) that takes up 800 square feet, you might reduce your rent to $1,000.

Will living in cramped quarters for a year be easy? Not at all. But if it saves you $12,000, it's a sacrifice worth making.

It costs $9,282 a year, on average, to own a vehicle, according to AAA. If you're willing to give yours up, you could wind up banking that much cash in the course of a year instead.

Now if you live in an area where public transportation is abundant, that's not such a huge ask. But if you live in suburbia, it could prove more challenging. That doesn't mean it can't be done, though. You could consider carpooling with your spouse (meaning, downsize from a two-car household to a single car), catching rides with friends or colleagues, or biking to and from work if that's a reasonable thing to do (if your office is 40 miles away, it's not).

Will giving up a car limit you logistically and socially? Probably. But think about it this way -- if it's harder to get around, you may be less inclined to dine out or spend money on entertainment, which will help your savings efforts.

The typical American spends $3,456 a year on restaurant meals and food outside the home, according to the U.S. Bureau of Labor Statistics. But restaurants generally charge a 300% markup on the items they serve, which means that if your spending is in line with the typical American's, you could save yourself close to $2,600 in the course of a year by cooking every meal you eat at home.

Will that constitute a time investment? It sure will. But you never know -- you may discover that you enjoy cooking your own food, and that doing so is healthier for you anyway.

If you're doing reasonably well financially -- meaning, you're on track for retirement and have a healthy emergency fund -- then there's certainly no need to go to any of the above extremes (unless, of course, you happen to love a good challenge). But if your near-term and long-term savings are virtually nonexistent, then you may need to take drastic measures to build them up. The good news? You don't need to commit to these extremes for a lifetime. Make any of the above moves for a single year, and your savings could easily take a turn for the much improved.

The $16,728 Social Security bonus most retirees completely overlook If you're like most Americans, you're a few years (or more) behind on your retirement savings. But a handful of little-known "Social Security secrets" could help ensure a boost in your retirement income. For example: one easy trick could pay you as much as$16,728 more... each year! Once you learn how to maximize your Social Security benefits, we think you could retire confidently with the peace of mind we're all after.Simply click here to discover how to learn more about these strategies.

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Hundreds of lives will be saved from spring 2020 when the law on organ donation in England changes.

The switch means anyone over 18-years-old who dies (with the exception of special groups) will automatically be considered for organ donation this will significantly improve outcomes for minority groups.

Naomi Adams 38 from north London who has end stage kidney failure and needs a transplant says the change gives hope to people from minority ethnic backgrounds.

Ms Adams said: For me personally, the law change brings a renewed hope that instead of feeling resigned to a life of dialysis and poor health, I may be one day closer to receiving the call that will change my life, to simply regain my strength, confidence and ability to enjoy life without limitations again.

NHS data showed in 2018/19 deceased white donors accounted for 92.4% far outweighing the number of white people on the donor waiting list at 68.6%.

During the same period the number of deceased black donors was just 1.3% significantly lower than the number of black people on donor waiting list at 10.5%.

Ms Adams commented: The current system of asking people to opt-in doesnt appear to be making a significant enough impact on the number of people waiting for a life saving organ transplant.

In fact, the number of people waiting for a transplant from ethnic minority backgrounds has been steadily rising over time.

African Caribbean Leukaemia Trust (ACLT) work to improve the odds of finding stem cell, blood or organ donor matches, by registering potential donors with a focus on African and Caribbean communities

ACLT founder Beverley De-Gale OBE said: ACLT fully supports the change in law around organ donation. Black people must stand up and be prepared to help save other lives, especially when matching depends upon racial identity.

Although organ transplants can be carried out between parties of different ethnic backgrounds, tissue rejection is less likely and positive long-term results are far higher, the closer the ethnic match.

According to an NHS report, in 2018/19 organ donation consent rates from white people were at 71% compared to 41% for black, Asian and minority ethnic people.

This number becomes even more acute when looking more closely at the different ethnic groups.

The same report cites the main reasons minority families gave for denying consent were religious/cultural beliefs or being unsure if the patient would have agreed to donation.

Ms Adams said: We need to leave behind the historic, cultural or supposed religious reasons that have been holding us back. Ethnic minorities just arent as willing to donate as others. Something needed to change.

ACLTs Ms De-Gale agrees: People should not listen or read the damaging social media fake news and instead make up their own mind based upon the truth. Black lives matter, well heres our chance to prove it.

Ms Adams concludes: I feel on the whole this change is a positive step to helping the many thousands waiting for a call that could change their lives for the better.

Someday it could save the life of the very person who resists change.

Excluded from the law change are under 18s, people who lack mental capacity to understand the new arrangements, and people who have lived in England for less than 12 months or not living here voluntarily.

Written by: Jacqueline Shepherd

First published 08.01.20: https://www.swlondoner.co.uk/bame-lives-to-be-saved-as-new-organ-donation-law-rolls-out/

Before you go, weve noticed youve visited Keep The Faith a few times; we think thats great! Its regular support from readers, like you, that makes our work worthwhile. So, heres a heartfelt thank you from our team.

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KARACHI: There is an urgent need for educating people on the means of transmission and prevention of sexually transmitted diseases and address the social stigma and fear attached to HIV/AIDS. A potentially life-threatening disease, HIV/AIDS, has reached alarming proportions in the country, also reporting drug resistance in patients on medications.

These points were highlighted by Dr Saeed Khan, a professor of pathology associated with the Dow International Medical College, at the last day of a three-day conference titled PROBE (Physiology Resonates and Ozonizes Biological Existence) 2020 Conference organised by the department of physiology at Karachi University (KU).

The Human Immunodeficiency Virus (HIV) is the causative agent of AIDS that causes patients immune system to become ineffective and exposes the body to secondary infections. In Pakistan, the HIV-1 subtype A has been observed to be more prevalent among different high-risk groups, including injection drug users, said Dr Khan.

According to him, Pakistan, which was earlier reporting low prevalence of HIV/AIDS, now has concentrated epidemic in high-risk groups with greater presence of HIV-1 subtype.

Over the past few years, however, it has been observed that several different HIV subtypes and recombinant forms are circulating [in] the country, also reporting cases with drug resistance in patients receiving medications, he explained, adding that drug resistance might also be due to treatment failure.

Larkana outbreak

He also spoke about the HIV outbreak in Larkana and referred to the Sindh AIDS Control Programme statistics according to which 26,041 people had been screened for HIV since the start of the outbreak and 751 people were tested positive for the disease.

The root cause or transmission factors behind this epidemic are still a mystery and the data on the molecular characterisation, drug resistance and its origin of spread is not available.

Talking about HIV prevention and effective treatment and rehabilitation, Dr Khan said it was important to address the social stigma, fear of social disapproval and denial of accepting the reality in response to this disease.

In our culture, topics related to sexual encounters and safe sex are considered as a taboo so they are not openly discussed, increasing vulnerability of population especially of the youth to the infection.

He emphasised that society must take steps to reduce the stigma related to HIV/AIDS so that people could speak up and talk about the disease and its modes of transmission.

This will also increase social acceptance of people living with HIV and help them attain their fundamental rights to quality education, health and better employment. In this respect, we all need to play a positive role since we know that government resources are limited, he said, adding that no one was safe unless everyone was safe.

Thalassaemia management

Dr Saqib Hussain Ansari, a consultant haematologist and bone marrow transplant physician at Childrens Hospital Karachi, talked about thalassaemia management without blood transfusion and said it had a great prospect especially in the middle- and low-income countries where the burden of transfusion transmissible infections and iron overload were increasing.

According to him, stem cell transplantation (in Pakistan) is not a practical option due to multiple factors, for instance financial costs, donor unavailability and scarcity of transplantation facilities.

Referring to some data, he said the childrens hospital registered 1,135 patients with beta thalassaemia between January 2004 and December 2017. Of them, 221 left treatment for different reasons.

Focusing on the challenges posed by diabetes, Prof Mohammad Kamran Azim, dean of the faculty of life sciences at Mohammad Ali Jinnah University, said Type-2 diabetes had emerged as a growing health issue affecting more than 170 million individuals worldwide.

Citing WHO statistics, he said the number of Type-2 diabetes patients in Pakistan was expected to rise from 4.3m in 1995 to 14.5m in 2025, making Pakistan the fourth most diabetes-affected country in the world.

Scientists, he pointed out, had not yet fully understood this disease. Though its well known that diabetes is associated with inflammation and altered immune response, the specific cellular and molecular mechanisms involved in the disease are yet to be fully understood, he said.

Dr Syed Aqeel Ahmed, chief operating officer at the Tabba Kidney Institute, also spoke.

A large number of students and researchers participated in the conference, including those from the Bahauddin Zakaria University (Multan), Islamia University (Bahawalpur), University of Health Sciences (Lahore) and University of Sindh (Jamshoro).

Partnered with the Pakistan Physiological Society and the South Asian Association of Physiologists, the event was supported by the Higher Education Commission Pakistan, the Pakistan Science Foundation, the Office of Research, Innovation and Commercialisation and the World Poultry Science Association.

Published in Dawn, January 10th, 2020

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HIV drug resistance an emerging threat, expert warns - DAWN.com

Tommy Joyce is no cinephile. The last movie he saw in a theater was the remake of True Grit nearly a decade ago. Id rather watch squirrels run in the woods than sit through most of what appears on the big screen, he said.

But theres a film that opened Dec. 5 at the Regal Cinemas at Grand Central Mall thats attracting a lot of attention in his community. Dark Waters a legal thriller starring Mark Ruffalo, with a script inspired by a 2016 New York Times article tells the epic story of the DuPont corporations failure to inform residents of the Mid-Ohio Valley of the considerable health risks of a perfluoroalkyl substance [PFAS] called perfluorooctanoic acid, or C8, for its chain of eight carbons.

The chemical was used in DuPonts production of Teflon and other household products at its Washington Works facility just outside Parkersburg, along the Ohio River. C8 is found in nonstick pans, waterproof clothing, stain-resistant carpets, microwave popcorn bags, fast-food wrappers and hundreds of other products. According to a 2007 study, C8 is in the blood of 99.7% of Americans. Its called a forever chemical because it never fully degrades.

DuPont had been aware since at least the 1960s that C8 was toxic in animals and since the 1970s that there were high concentrations of it in the blood of its factory workers. DuPont scientists were aware in the early 1990s of links to cancerous tumors from C8 exposure. But company executives failed to inform the Environmental Protection Agency [EPA] or the public.

Weathered signage on the Point Park floodwall greets passersby in downtown Parkersburg, West Virginia. Photo: Lexi Browning/100 Days in Appalachia

Joyce graduated from Parkersburg High School in 1992, went off and earned three degrees and came home. He now serves as mayor of the city of Parkersburg population: 30,000.

Joyce said hes heard more about his communitys long struggle with corporate environmental malfeasance in the past few weeks than in his previous two and a half years in office. He attributes this to the release of Dark Waters.

Even David-and-Goliath tales often have complicated backstories, and Joyce knows well that such is the case with Parkersburg and DuPont. DuPont has been in the Ohio Valley for 70-plus years, and has been a tremendous employer, he said. Without question, DuPont was the place to work in the Mid-Ohio Valley for a lot of years. Many of his classmates grew up in DuPont families.Though Chemours, a spinoff company of DuPont, now operates the Washington Works plant, DuPont maintains a presence in the community. A DuPont spokesperson provided an overview of its financial and volunteer support initiatives and wrote that the company supports programs and organizations focused on revitalizing neighborhoods and enhancing quality of life; STEM-related initiatives in local schools; and initiatives that help protect the environment through clean-up or restoration efforts and allow for DuPont Washington Works to show we are a leader in minimizing our environmental footprint within the community.

A probable link between C8 and six conditions: testicular cancer, kidney cancer, thyroid disease, ulcerative colitis, pregnancy-induced hypertension and high cholesterol.

Parkersburg, said Doug Higgs, is the kind of town where everybody knows everybody. Higgs graduated from Parkersburg High a year after Joyce, and Joyces mother, Barbara, taught him Sunday school.

Everybody knows everybodys business, Higgs said, but nobody talked about C8. It was a matter of not wanting to bite the hand that fed you.

Well-paying jobs, great benefits, Little League sponsorships, investments in the arts but at a cost. The hand that fed did clench.

Higgs, now an emergency room physician living in Richmond, Virginia, recalls returning from road trips with his family asleep in the back seat, awakened as they approached home by the familiar waft of chemicals.

Two of the Higgs most immediate neighbors died in their early 50s of renal cell cancer. Higgs father has ulcerative colitis, and his brother received treatment for polycystic kidney disease in high school.

We all have stories of friends and family, neighbors, dying too young or being diagnosed with various medical problems, Higgs said.

He knows, of course, the distinction between correlation and causation. But the high incidence of a range of diseases has staggered this community. Its unfair, Higgs said, that a community should have to perpetually ask what exactly it has been exposed to, and where and when the consequences will end.

An aerial view of Parkersburg, West Virginia, taken from Fort Boreman Park. Photo: Lexi Browning/100 Days in Appalachia

A vehicle slows down at the corner of Fourth and Market streets in Parkersburg, West Virginia. Photo: Lexi Browning/100 Days in Appalachia

DuPonts own documentation specified that C8 was not to be flushed into surface waters, but the company did so for decades. The chemical seeped into the water supplies of the communities of Lubeck and Little Hocking, immediately west of Parkersburg, and the city of Belpre, Ohio, just across the river; and three other water systems.

In 2004, DuPont paid $70 million in a class-action lawsuit and agreed to install filtration plants in the affected water districts. In 2005, it reached a $16.5 million settlement with the EPA for violations of the Toxic Substances Control Act.

Ohio River Communities are Still Coping with Teflons Toxic Legacy

A collective decision was made to use the money won in the class-action suit to conduct an epidemiological study in which nearly 70,000 of the 80,000 plaintiffs stopped into one of six clinics set up throughout the community, provided their medical histories and offered their blood. They were each paid $400.

A science panel, comprised of public health scientists appointed by DuPont and lawyers representing the community, was convened to examine the immense database. In 2012, after seven years of study, the panel released a report documenting a probable link between C8 and six conditions: testicular cancer, kidney cancer, thyroid disease, ulcerative colitis, pregnancy-induced hypertension and high cholesterol.

In 2015, DuPont spun off its chemical division into a new company called Chemours, which now occupies the Washington Works facility on the Ohio. In 2017, DuPont and Chemours agreed to pay $671 million to settle some 3,500 pending lawsuits.

The Washington Works facility, formerly of DuPont, in Parkersburg, West Virginia, is seen from across the Ohio River. Photo by Lexi Browning/100 Days in Appalachia

You grew up with the fear of DuPont leaving town, said Ben Hawkins. Hawkins was student body president of the Parkersburg High class of 1993. He remembers DuPonts participation in his schools Partners in Education program and riding in parades on DuPont-sponsored floats.

Among Hawkins classmates who have been diagnosed with pancreatic cancer was Mike Cox, a local dentist. Cox, Hawkins and Higgs were among a pack of guys who ran together in high school and stayed close after. Cox was a big Ozzy Osbourne fan, and after a grueling regimen of chemo, Hawkins helped arrange backstage passes to a concert, where Osbourne pulled Cox near and shared his own familys experience with cancer. Post-diagnosis, Cox had begun performing stand-up comedy routines that incorporated flute solos. He died Jan. 28, 2017, at the age of 41, a father of three.

Hawkins, who now lives in the Washington, D.C., area, views his Partners in Education experiences somewhat differently today: It wasnt a partnership; it was a page from a public relations playbook. It was the old hey-look-over-here! move to keep the Teflon dollars flowing into their bank account.

His classmate Beth Radmanesh has similar cynical recollections of DuPonts role in her childhood. Radmanesh grew up less than a mile from the Washington Works plant. Today, she has high cholesterol. Her dad suffers from discoid lupus, causing sores the size of 50-cent pieces on his forehead. Her brother has lupus and had colon cancer, and her sister-in-law has also been diagnosed with lupus.

But Radmanesh said her mom is a proponent of bringing another controversial industry to the valley: fracking for natural gas. I said to her, Weve already had our water contaminated once. Do you want your water [to be] flammable? Because thats what will happen. Her moms response was, Oh, Beth. Thats it. Oh, Beth.

Joe and Darlene Kiger live just a few miles from where Radmanesh grew up. Joe, a physical education teacher, is now quite well known in the community for having raised awareness of the dangers of C8 called the devils piss by some in local water supplies. He and his wife, Darlene, joined the class-action suit that was settled in 2004.

Darlene said that when she and Joe are out around town, there are a lot of whispers behind your back. They dont know what to say. The experience has taken a toll these people all looking at you as bringing this on them, Joe said but theyve never considered leaving. Why would you leave the fight? he said. What would it look like if we packed up?

Theres a lot, Joe said, that DuPont hasnt yet been held accountable for. Earlier this year, Chemours was cited by the EPA for the unregulated release of new chemical compounds from its West Virginia and North Carolina facilities. Im not done yet, Joe said.

Joe Kiger and his wife Darlene Kiger are photographed at their residence in Washington, West Virginia. The Kigers have spent the last two decades working to uncover the impacts and effects of C8 exposure in the region. Weve been through hell over the last 20 years, Joe Kiger said. Photo: Lexi Browning/100 Days in Appalachia

Attorney Harry Deitzler poses for a portrait in his office at Hill, Peterson, Carper, Bee and Deitzler, PLLC, in Charleston, West Virginia. Deitzler was involved in settling the C8 groundwater contamination suit against DuPont in Parkersburg, WV. Photo: Lexi Browning/100 Days in Appalachia

Harry Deitzler served as a lead attorney, among others, in representing the Kigers and tens of thousands of others in the class-action suit. Deitzler was the architect of the decision to use the $70 million to conduct the study.

Parkersburg adopted me in 1975, Deitzler said of his arrival in town. Hed come for a summer internship in the prosecuting attorneys office. The position didnt pay enough to cover his room and board, so he took a job in a bar called Friar Tucks.

By the end of the summer, the community was my family, Deitzler said. I asked the prosecutor if hed hire me as an assistant the next year, and he said, Sure; youll get $6,000 a year. And I said, Thatll be great.

Most people thought I was a recovering alcoholic because I never drank a beer, because I couldnt afford to buy one. Three years later, at 27, he was appointed as prosecuting attorney. Such a wonderful, accepting community.

But, some three decades later, there was a price to pay for taking on DuPont.

There was a misperception that we were trying to put DuPont out of business, and, of course, that was created intentionally by the people in Wilmington, Deitzler said, referring to DuPonts Delaware headquarters. When you have a community of that size, and youve got several thousand people employed there, and multiply that by the families and their relatives its very upsetting. Some folks were unsure of what to make of Deitzler.

Longtime resident Nancy Roettger characterizes the communitys reaction to the revelation of what DuPont had done as a weird mix.

There were women that immediately went out and changed their frying pans, Roettger said. But a lot of those same people decided that Harry Deitzler is a horrible person for his role in exposing DuPont.

Its like, they dont want that frying pan anymore, she said, but they dont want anything negative, and theyre very resentful of the people that stirred up the trouble.

Candace Jones, a neighbor and longtime friend of Roettgers, said she hates the perception that the community has been divided between the DuPonters and everyone else.

Were a community and we all need each other, Jones said. I think its terrible, absolutely horrendous what happened because of decisions made for monetary gain. But I dont believe we can blame the everyday worker. Her father-in-law worked in the Teflon division. He just went to work every day; he provided for [his family].

Candace Jones, a native of Vienna, WV, is photographed downtown. Jones, who has lived in the area for most of her life, recalled DuPonts heavy involvement in the community, from sponsoring community activities and education to employing a great deal of the areas residents. (Photo by Lexi Browning/100 Days in Appalachia

Tracy Danzey grew up in Parkersburg, West Virginia, but now lives on the opposite side of the state in its Eastern Panhandle. Danzey was diagnosed with a rare form of bone cancer that led to the amputation of her leg. Doctors couldnt trace the cause of the cancer, but Danzey believes it was caused by exposure to industrial waste in the waters of Parkersburg that she drank and swam in. Photo courtesy of Seth Freeman Photography

Jones friend Janet Rays husband passed away 16 years ago from pancreatic cancer. He worked for BorgWarner, a manufacturing company on the river. There are about a dozen houses along Rays street in Vienna, a Parkersburg suburb, and I think just about every house during the time Ive lived on the street has been affected by cancer.

Ray said she sometimes feels guilty, thinking that perhaps the livelihood her family has enjoyed as a result of her husbands employment might have caused health problems for others. I certainly hope it didnt.

Tracy Danzey was raised in the quiet of Vienna, there with the Rays, the Joneses, the Higgs family. She now lives on the other side of the state, in West Virginias Eastern Panhandle. Danzey was a competitive swimmer growing up. When not competing, we were on the river we were playing in the creeks. I was always in the water.

Its hard to look back at that time now and see it as idyllic, Danzey said.

At age 20, her thyroid began malfunctioning. Five years later, the socket of her hip shattered while running with her husband. She was diagnosed with an atypical form of bone cancer in her right hip. Her hip and leg had to be amputated; she underwent 18 months of high-dose chemotherapy.

Six leading pathologists from across the country were unable to identify the specific type of cancer. They said its very pathologically unusual. Research has indicated to Danzey, whos a nurse, that pathologically unusual cancers are not uncommonly associated with industrial poisonings.

Danzeys stepfather is retired from DuPont and her stepbrother works on the Teflon line. Yes, it is complicated, her mother, Carolyn Tracewell, said. When her kids were growing up, when someone was hired at DuPont, therewas a celebration the good pay, the benefits, and they did treat their employees well.

But my heart hurts, Tracewell said, to think that her daughters illnesses might be a consequence of all that.

Danzey said her mom mostly just feels pain for me, worries about her stepson and is anxious about the future. Her stepfather wonders if one day his pension check will no longer arrive as a result of all the financial fallout.

None of them argue with Tracy about the source of her illnesses. They know what happened. They allow her to sit in this truth regardless of how it affects them. That means a lot.

Danzey is among those who believe that in regard to perceptions of DuPont in the Parkersburg community, theres a generational divide: Those in their 40s and younger tend to hold a less charitable view than baby boomers and their parents.

There likewise appears to be a generational divide in willingness to drink the water, despite the filtration installed as a result of the settlement.

On the September Saturday afternoon of the annual Parkersburg Paddlefest, kayaker Travis Hewitt, 31, stood ashore of the point where the Ohio meets the Little Kanawha and said that few people he knows truly believe the waters safe. Sure, he paddles in it, but I try not to get it on me and never swims in it. He has a filter installed in his kitchen.

Tommy Joyce, the mayor of Parkersburg, is bullish on West Virginia: Weve got enough coal to light the world, gas to heat the world and brains to run the world.

Fellow Parkersburg High grad Brian Flinn, an engineer, worked for DuPont for eight and a half years; he worked with the raw materials of Teflon. Hes seen both sides. Hes heard, If DuPont leaves, were done. This area will be like most other towns in West Virginia; itll collapse. Hes also aware of the inherent dangers in living within the shadow of the chemical industry. So the sentiment goes, he said, You take the good with the bad, right?

But Danzey is unwilling. I love West Virginia, she said. I really do. I love this state. I dont want to be anywhere else. But she wants better for West Virginians. Industries come into their communities, do well for a while, screw up the environment and then leave.

Its time for something new in West Virginia, she said. Its time for us to expect more.

Tracking the Health Impacts of C8 Exposure

Pondering that future keeps Ben Hawkins up at night. Whats next? Whats next for the community, and where does this end? Or does it? What sort of positivity can come to that community? They need it and they deserve it.

Hawkins asks this: Think about how loyal the people of the Parkersburg community have been to DuPont. What if they had the opportunity to extend that same loyalty to a company thats equally invested in the economic, physical and emotional health of the community?

Thats home and always will be home, Hawkins said of Parkersburg. We came from that community and that community did a lot to shape us. We all want the best for that community whatever form that can take.

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Top photo: Tracy Danzey grew up in Parkersburg, West Virginia, but now lives on the opposite side of the state in its Eastern Panhandle. Danzey was diagnosed with a rare form of bone cancer that led to the amputation of her leg. Doctors couldnt trace the cause of the cancer, but Danzey believes it was caused by exposure to industrial waste in the waters of Parkersburg that she drank and swam in. Photo courtesy of Seth Freeman Photography

Good River: Stories of the Ohio is a series about the environment, economy and culture of the Ohio River watershed, produced by seven nonprofit newsrooms. To see more, please visit ohiowatershed.org.

Link:
A Lasting Legacy: DuPont, C8 Contamination and the Community Left to Grapple With the Consequences - alleghenyfront.org