Alzheimer’s disease (AD) is a neurological disease that is the most common cause of dementia, affecting an estimated 6 million Americans. Despite decades of research there has been little progress in developing medications or therapies that can improve symptoms or slow the progression of the disease. In its early stages, there was enthusiasm for a new drug, aducanumab, that targets beta-amyloid which is a plaque-like protein that accumulates in the brain and is thought to interfere with signalling and function.
Steven Novella and I both blogged about aducanumab when it was approved in the United States in 2021. Now branded Aduhelm, it was a very controversial approval which was based on the effect of the drug on a surrogate, or proxy for the disease. Importantly the drug has not yet been shown to actually give any meaningful clinical benefit. While ten out of eleven members of an advisory committee to the FDA voted against approving Aduhelm, the FDA did approve the product, requiring a clinical trial to show benefit.
Both Steven and I also raised the issue of the cost of Aduhelm when it was approved. The drug alone costs $56,000 per year, plus infusion and delivery costs. Given the prevalence of AD and the absence of effective treatments, there could be substantial demand and costs for a product. How insurers would react was a question. Now we have an answer from the biggest insurer in the United States, the Centers for Medicare & Medicaid Services (CMS) which recently released a proposed “National Coverage Determination” decision memorandum on the drug.
What is the CMS and why does this matter?
The CMS is the single largest payer for health care in the United States, covering almost 90 million Americans. A national coverage determination (NCD) is a statement regarding whether or not Medicare will pay for a specific service or treatment. These decisions are binding on Medicare contractors. In short, CMS has proposed it Medicare will only provide coverage for Aduhelm when it is administered as part of a clinical trial. Clinical trials will be reviewed to determine if they meet CMS standards. If they do, then recipients will be eligible to have the cost of the drug and the administration covered.
What did the CMS say?
The CMS decision memo provides an overview of AD and a good summary of the evidence for and against amyloid:
Alzheimer’s disease (AD) is a currently irreversible brain disorder that progressively degrades memory, cognitive function, and ability to carry out tasks of daily living. AD is the number one cause of dementia in older Americans, contributing to 60-80% of cases. Over 6 million older Americans are believed to have AD. This prevalence is expected to rise to 14 million by 2060 barring effective interventions (such as lifestyle changes, treatment of risk factors, and possibly combinations of Alzheimer’s drugs). AD is the sixth leading cause of death in the United States, but may rank from fifth to as high as third (after heart disease and cancer) as a cause of death for older Americans.
With respect to amyloid, it notes (I will cut and paste from the detailed but very readable summary):
The role of amyloid in Alzheimer’s disease remains complicated for at least three reasons. First, amyloid plaques are seen in other diseases, such as dementia with Lewy bodies, cerebral amyloid angiopathy, Parkinson’s disease, Huntington’s disease, and inclusion body myositis….Second, amyloid is associated with normal physiologic processes. …. Third, amyloid plaques can be detected in cognitively normal older adults. Autopsy studies demonstrate that approximately one-third of older individuals (20-65% depending on age) who are cognitively normal have amyloid accumulation at levels consistent with AD pathology.
CMS then summarizes the evidence it considered. It noted that beyond aducanumab, there are at least three other monoclonal antibodies in clinical trials. This guidance is applicable to all anti-amyloid monoclonal antibodies, as the drugs all have a similar function in the brain. It posed a specific question to answer:
Is the evidence sufficient to conclude that the use of monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease improves health outcomes for Medicare beneficiaries?
CMS searched different medical databases like Ovid Medline and PubMed for relevant articles, and then summarized all the trials and results into two tables. it discussed the two aducanumab clinical trials (EMERGE and ENGAGE) in detail:
Our conclusion is that Biogen’s secondary analysis cannot overturn, definitively confirm, or substitute for, the RCT evidence. With conflicting results from two RCTs (EMERGE and ENGAGE), and a secondary analysis that did not resolve the difference between the two RCTs, CMS believes that the available evidence is insufficient to establish that the treatment is reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act.
Acknowledging the need for better data and the current insufficient evidence to support the use of this product and related monoclonal antibodies for AD, CMS is proposing “coverage with evidence development” or CED which means that it will fund the products when part of a clinical trial that is seeking to provide better evidence to inform a permanent funding decision. As no trial has yet been able to show that aducanumab (or a related drug) provides a clinically meaningful improvement in outcomes that are relevant to patients, a trial must be able to answer the following if it is to be considered eligible for inclusion (and funding):
- Does use of monoclonal antibodies directed against amyloid for the treatment of AD result in both a statistically significant and clinically meaningful difference in decline in cognition and function?
- What is the frequency and clinical impact of adverse events associated with the use of monoclonal antibodies directed against amyloid for the treatment of AD?
What does this mean for patients?
Without well designed clinical trials, we will not be able to determine if aducanumab or related monoclonal antibodies provides any benefit for patients with AD. While the FDA approved aducanumab without any evidence of patient benefit, CMS’s bold decision will ensure that any funding put towards the drug will help answer this crucial efficacy question. This decision is a good one. It considers the needs of patients who want access to promising treatment, while ensuring that data is collected, rigorously and systematically, to bring us better evidence about these expensive therapies.