When the FDA approved aducanumab (Aduhelm) on June 7th, 2021 “…for the treatment of Alzheimer’s…” it created a firestorm of controversy. That’s because a panel of highly regarded outside researchers and clinicians who served on the FDA’s Advisory Committee recommended against FDA approval. In a highly unusual move, the agency ignored its own experts and gave the green light to aducanumab. I refer to this as the “Aduhelm Boondoggle.” Perhaps that is why the drug company behind Aduhelm is now abandoning this anti-amyloid Alzheimer’s drug.
The Inside Story on the Aduhelm Boondoggle:
On June 10, 2021 I asked the question:
Here is my executive summary on the Aduhelm boondoggle:
- The FDA has relied almost exclusively on “surrogate end points” in its approvals of drugs against Alzheimer’s disease. That is, a reduction in a bio-marker called amyloid-beta (Aβ). These anti-amyloid medications have done little, if anything, to actually reverse the course of Alzheimer’s disease (AD).
- Scientists still do not understand the underlying cause of dementia. Is Aβ the chicken or the egg? In other words, what actually triggers the accumulation of amyloid beta in the brain? Why have so many anti-amyloid drugs flamed out? That is, why have they not led to clinical improvement in AD? Read about the failures at this link.
- The CDR-SB scale has been used to determine drug effectiveness. It stands for Clinical Dementia Rating sum of boxes. This tool assesses a patient’s problem solving ability, memory and personal care performance. The 18-point scale goes from 0 (no cognitive impairment) to 18 (very severe Alzheimer’s disease). Aducanumab improved patients’ scores by 0.39 points.
The results were so disappointing that an article in JAMA (March 30, 2021) noted:
“Approximately halfway through the phase 3 studies, a planned interim analysis met prespecified futility criteria and, in March 2019, the sponsor announced termination of the trials.”
“Futility” means what you think it means.
“It is our opinion that previous failures of anti-AD drugs suggest that soluble Aβ and tau are not appropriate drug targets.”
- Anti-amyloid drugs like Aduhelm to treat Alzheimer’s disease have some serious side effects. They include swelling in the brain, bleeding in the brain, headaches, dizziness, confusion (hardly helpful if someone has AD), digestive distress, disorientation and a risk of falling (also problematic for someone with AD). Brain shrinkage is also a worrisome feature of anti-amyloid drugs like Aduhelm.
A Fitting End to the Aduhelm Boondoggle:
“Biogen to Realign Resources for Alzheimer’s Disease Franchise”
That’s a nice way of saying the drug company is abandoning Aduhelm.
Here is the exact wording of the news release:
“Biogen Inc. (Nasdaq: BIIB) today announced plans to reprioritize its resources in Alzheimer’s disease (AD), a strategic therapeutic area expected to drive near and long-term growth. The company will continue to advance LEQEMBI® (lecanemab-irmb), the first anti-amyloid beta treatment with FDA traditional approval in the United States, and will accelerate development of potential new treatment modalities, including its ASO targeting tau (BIIB080) and an oral small molecule inhibitor of tau aggregation (BIIB113). The company will discontinue the development and commercialization of ADUHELM® (aducanumab-avwa) 100 mg/mL injection for intravenous use and will terminate the ENVISION clinical study. This decision is not related to any safety or efficacy concerns. A large portion of the resources released resulting from termination of the ADUHELM program will be redeployed in Biogen’s AD franchise.”
Don’t you just love the concept of a reprioritization of resources? That is a sanitized way of saying we’re pulling the plug on Aduhelm.
A Neuroscientist Explains the Aduhelm Boondoggle:
Dr. Jason Karlawish is a heavy hitter. He is “professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine and co-director of the Penn Memory Center. In the past three years, he has been a site co-investigator on clinical trials sponsored by Biogen, Eisai, and Lilly.”
That description accompanies an article he wrote for the publication STAT (Feb. 6, 2024).
In it, he states:
“In the eight years between the drug’s spectacular 2016 debut on the cover of Nature and its ignominious end, Biogen made multiple, really bad decisions. I don’t condone the company’s behavior, but I do understand it. In America, corporations develop drugs, and corporations are made up of ambitious, competitive people. Their measure of success is a simple language: profit.”
Dr. Karlawish describes the “mess” the FDA allowed Biogen to “walk itself into”:
“The first is the FDA’s use of evidence of amyloid lowering with no evidence of clinical benefit as sufficient to approve aducanumab. This surrogate endpoint standard remains controversial.
“And yet, the FDA seems oblivious. It continues to use this weak surrogate to review anti-amyloid drugs, first Eisai’s lecanemab (approval) and then Lilly’s donanemab (no accelerated approval). Unlike with Aduhelm, my colleagues and I shrugged off these decisions.”
Final Words on the Aduhelm Boondoggle:
I have been nipping at the FDA’s heels for years when it comes to approving anti-amyloid drugs for Alzheimer’s disease. Like Dr. Karlawish, I want some proof of meaningful clinical benefit. So far, the FDA has completely ignored my anguished pleas for a new way of thinking.
Patients and their families want treatments that don’t just slow the decline into dementia a tiny bit. We all want medications that actually reverse the decline. We want therapies that will help people remember their loved ones. Where are the drugs that could enable people to balance a checkbook, drive and, most important of all, stay out of nursing homes?
A lot of money has been spent trying to prove that anti-amyloid drugs work. So far, I have found the results worse than disappointing. It’s time neuroscientists and drug company executives use some very creating thinking and start looking beyond amyloid-beta for meaningful new treatments.
Please share your own thoughts in the comment section below.