Last month the Food and Drug Administration (FDA) approved Aduhelm, Biogen’s new intravenous treatment to slow the progression of Alzheimer’s Disease (AD), and in doing so set off a firestorm of controversy that may take years to sort out. The FDA used the accelerated approval pathway, intended for a drug that treats a serious or life-threatening illness and that provides a meaningful therapeutic advantage over existing treatments. The agency and some patient advocates argue that, despite a lack of convincing evidence that the drug works, this is reasonable given that there are no effective medicines to slow or reverse AD, and none have been approved in almost 20 years. 

Of the 11 physician researchers and clinical experts on the independent FDA advisory panel, 10 voted against approval and one voted uncertain. They claimed that the available evidence created significant doubt that the drug will slow the progression of AD and may bring potentially serious adverse effects, with their own impact on cognition, such as brain swelling, brain bleeds, headaches, confusion, dizziness, and falling. The side effects are common and potentially serious enough to require all patients taking Aduhelm be monitored with routine MRI scans. Three members of the advisory panel resigned over the FDA’s disregard for the science, failure to communicate its change in position regarding endorsement, and a concern that the approval would slow meaningful progress in combating AD.

It seems that significant research targeting amyloid over the past twenty years has failed to produce convincing evidence of causality. Biogen had abandoned Aduhelm, stopping two clinical trials before their completion due to disappointing results. Only later upon closer examination did it note that findings in one of its studies suggested a slowing of the disease for patients with early cognitive decline. As part of its approval, the FDA will require Biogen to conduct a new randomized, controlled clinical trial to verify the drug’s clinical benefit. It has given them 9 years to complete the research. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug. Eli Lilly and others had invested in and shelved their drugs to treat the amyloid present in AD due to disappointing results. Lilly has now announced that it will seek approval for Donanemab during 2021 under the FDA’s accelerated approval process. Other similar drugs, previously shelved, are expected to also be presented for approval.

There is an ongoing debate about the clinical relevance of amyloid in cognitive decline. While amyloid plaques and protein tangles are commonly found in patients with AD, evidence that they cause the disease’s devastating memory loss or that reducing the amyloid will yield clinical improvement has yet to be demonstrated. Some researchers fear that approval of these drugs and their potential blockbuster profits will consume resources and research dollars better directed toward other causative factors, such as blood pressure or inflammation. Follow up interviews with members of the FDA advisory panel reveal that in November 2020 the FDA told them that it would not be counting the drug’s ability to reduce amyloid as an indication that Aduhelm might be effective, but in June and without further communication to or evaluation by advisory panel members, the FDA reversed course. Esteemed neurologists, other physicians, researchers, policy experts, and journalists are speaking out about the FDA’s action. Congress has initiated hearings into the relationship between Biogen and the FDA. 

Biogen has priced the drug at $56,000 annually per patient and projected it would be used by 1 to 2 million patients per year. With related imaging and other treatment costs, the expense is expected to be $100,000 per patient. While some think this utilization estimate is overstated, most agree that the expense is out of reach for even Medicare. Depending on the numbers, the drug is projected to add between $6 to $29 billion to Medicare Part B drug spending, more than the U.S. spends each year on NASA or the Environmental Protection Agency. Many claim that dollars would be better spent on developing better evidence for other therapeutic interventions that reduce the burden of disease. 

There is more to come on the outcome of this FDA decision. The Centers for Medicare and Medicaid is considering its options with regard to coverage of these unproven medications. While employer-based plans will have less demand for treatment and immediate financial impact than Medicare, we know all too well that the cost of U.S. health care is borne by all and most directly shouldered by American workers. Self-insured employers will want to discuss coverage options with their insurance partner and watch for CMS’ decision and the outcome of further investigations of the FDA’s decision. One thing seems clear, employers may need to reconsider their use of FDA approval as a standard for the efficacy and safety of a medication. Time will tell.

For those interested in the aging brain, 60 Minutes did a six-year update of findings from a NIH-funded research study at the University of California Irvine last fall. It provides a fascinating look at the lives of several nonagenarians and potentially instructive real world insight into the presence and impact of amyloid on memory and cognition. 

Warm regards, 

Louise Y. Probst

BHC Executive Director