StemCell Therapy

This years Clinical Trials on Alzheimers Disease meeting began in mid-December with a bang and ended a few days later with hallway conversations laced with worry. The topic, in both cases, was aducanumab, an experimental drug for treating people with Alzheimers disease.

The meeting got off to celebratory start as a top Biogen scientist presented results showing that the highest dose of aducanumab may benefit people with mild cognitive impairment (MCI) and elevated amounts of a protein called amyloid in the brain. That presentation represented an about-face for the company, which had pulled the plug on two trials of the drug in March.

Yet even the most enthusiastic interpreters of the drugs effects on measures of cognition and function agreed that the benefit to patients was a mild slowing, not a halt, and it was certainly not a cure for Alzheimers disease.

advertisement

But we also learned that as aducanumab clears amyloid from the brain, it can cause both microscopic hemorrhages and swelling in the brain, particularly in individuals who have a heightened genetic risk of developing Alzheimers disease dementia.

With these facts in hand, aducanumab becomes a kind of thought experiment. What if we could treat mild cognitive impairment caused by Alzheimers disease with a somewhat effective but costly and risky drug? The answers are discomforting.

For much of the 20th century, America largely ignored dementia. It was widely believed that its most common cause was senility, an extreme stage of aging. That changed in April 1976 with a 1,200-word essay titled The Prevalence and Malignancy of Alzheimer Disease: A Major Killer in the Archives of Neurology. In it, neurologist Robert Katzman argued that older adults with disabling cognitive and behavioral problems did not have senility but had Alzheimers disease, a medical problem in need of the full force of American medicine to diagnose, treat, and ideally prevent.

Nearly half a century later, America hasnt come close to solving the problem of Alzheimers disease and other causes of dementia: We dont have effective treatments and we also dont have an effective physician workforce to prescribe and administer them.

Parsing out age-related cognitive complaints from mild cognitive impairment and explaining that diagnosis is a challenging task. There arent currently enough clinicians skilled to evaluate the millions of older adults with cognitive complaints, care for those with MCI and dementia, and prescribe a costly drug that slows but does not cure Alzheimers disease and poses risks to the very same brain they are trying to treat.

Imagine that the FDA approves aducanumab, or a drug like it. Individuals with mild memory problems who dont have MCI should be sent home with reassurance or with treatments for the problems causing their memory complaints, such as anxiety, too much alcohol, or poor sleep. Those with MCI thats about 15% of older Americans would be candidates for PET scans to measure the amount of amyloid in the brain.

To evaluate the millions of Americans who see a doctor because my memory isnt as good as it used to be, overworked and underskilled clinicians are likely to take shortcuts: Never mind diagnosing mild cognitive impairment. Just order the amyloid test. If its positive, prescribe the drug. Otherwise, dont prescribe it.

That approach will be costly. A PET scan for brain amyloid costs around $4,000. Less-costly spinal fluid tests could substitute, but few clinicians are skilled at performing them. Aducanumab, as a manufactured and injected monoclonal antibody, will be expensive. The risk of small swellings and bleeds in the brain would require MRIs to assess safety, which would increase the need for clinicians skilled in interpreting the scans and adjusting treatment plans.

A drug like aducanumab presents clinicians with other novel challenges. It is one of several drugs whose risks, and possibly its benefits as well, are associated with having the ApoE4 gene a gene known to increase an individuals lifetime risk of developing Alzheimers disease dementia. The decision to start the drug may well include ApoE testing so individuals can better understand their risks and possibly responses to the drug.

Genetic testing means that clinicians will have to practice genetic counseling at visits that may need to expand from the dyad of patient and caregiver to include an extended and worried family. A prescription for aducanumab would be startling news for a patients siblings, adult children, and grandchildren: You too may have the Alzheimers gene. You too may want to have an amyloid test.

A treatment that slows Alzheimers disease, that delays the onset of dementia, promises to reduce disability and preserve autonomy. The failure to properly prescribe it could, however, increase the spectacular tallies of the time and costs of caregiving that define much of the Alzheimers crisis.

Lets assume that additional studies show that aducanumab does indeed slow the progression of Alzheimers disease with benefits that exceed its risks. Some of those who take the drug will die of other causes, such as heart disease or cancer, before dementia takes hold. But others will, in time, experience more and more disabling cognitive impairments. As they do, theyll need care.

Some will be cared for in nursing homes or facilities devoted to dementia care. Most will be cared for at home. The Alzheimers Association estimates that in 2018, 16.3 million family members and friends provided 18.5 billion hours of unpaid care to people with Alzheimers and other dementias.

This care ought to include education and training for patients and caregivers. It should also include activity programs tailored to patients abilities and disabilities. These include memory cafs, where people come together not as patients but persons, and centers whose staff members are skilled at creating days that are safe, social, and engaging, with activities such as reminiscence, music, theater, art, and exercise.

Although these ought to be the standard of care, few of them are routinely available to caregivers and patients. Doctors dont typically prescribe them, and their costs are mostly paid out of pocket. A 2013 report estimated that these out-of-pocket costs, together with the time caregivers devote to care, make up as much as half of the diseases annual $200 billion-plus cost.

A disease-slowing treatment that reduces disability ought to reduce the time spent on caregiving. But it will not allow the U.S. to ignore its fractured and disorganized system of dementia care and how this nonsystem offloads much of the costs onto patients and families. Medicare, which was created in 1965, does not pay for long-term care. We must update this antiquated law and support long-term care.

The ability to control Alzheimers disease with a drug will also demand that we engage with difficult issues regarding life and death. Disease-slowing treatments for Alzheimers will challenge our criteria for access to hospice care, as well as to physician aid in dying. Individuals with a chronic and progressive disease like Alzheimers may, in time, decide they no longer want treatment. A robust ethic of respect for persons supports their right to stop treatment. It is entirely possible that some patients, as they decline, may decide: Enough. This disease has progressed. I want to stop treatment.

After that decision or if the drug doesnt work what kind of palliative care is available when death is not in six months away but may be six years away, or longer? Medicares hospice benefit is available only to individuals with six months or fewer to live.

Physician aid in dying, which is available to residents of nine states and the District of Columbia, is also not an option. Individuals who choose this route must have a prognosis of living six months or fewer, be able to decide to end their life, and be able to take the lethal dose of medication.

We ought to be deeply concerned that the limited access to care and its cost are not perverse incentives to seek aid in dying.

We should also expect that the more we control the natural history of Alzheimers disease, the more well begin to question when were dying of it and how we should die.

Katzman foreshadowed this in closing his 1976 essay: In focusing attention on the mortality associated with Alzheimer disease, our goal is not to prolong the lives of severely demented persons, but rather to call attention to a disease whose etiology must be determined, whose course must be aborted, and ultimately a disease to be prevented.

In 2012, the National Plan to Address Alzheimers Disease premiered a strategy to achieve Katzmans vision. Goal number one was that by 2025 we will prevent and effectively treat the disease. Research on aducanumab and other drugs in the pipeline that target amyloid and other causes of neurodegeneration is one route to achieving this. Equally important is disseminating strategies that promote brain health exercise, education, smoking cessation, and the like that have been decreasing the risk of developing dementia since the 1970s.

We do this research with hope that drug interventions will help address the economic and moral costs that have transformed Alzheimers from Katzmans common disease into a crisis. At the same time, we must be mindful that these interventions will present new economic and moral costs. If we fail to address them, the crisis will endure.

Jason Karlawish, M.D., is co-director of the Penn Memory Center and a site investigator for clinical trials sponsored jointly by the National Institute on Aging and Novartis (Generations program) and the NIA and Eli Lilly (the A4 Study). You can follow him on twitter @jasonkarlawish.

See the original post:
Aducanumab isn't the simple solution to the Alzheimer's crisis - STAT - STAT

This entry was posted on December 21, 2019 at 5:44 pm and is filed under Genetic medicine. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |