It’s probably the most controversial drug launch in the history of Alzheimers’ disease. Aducanumab (Aduhelm) is a monoclonal antibody that’s been approved to treat Alzheimer’s in the early stages, for people with mild cognitive impairment (MCI). Produced by American company Biogen and Japanese firm Eisai, it failed its clinical trials but was resurrected when the figures were reexamined and showed that a small number of people with MCI had been marginally helped by large doses over a long period.
The controversy began last June when the Regulator at the FDA (Food and Drug Administration) approved it against the advice of its own independent advisory panel of experts. It was released on the Agency’s accelerated approval lane, allowing Biogen to market the drug while it conducts research to confirm the benefit. The company has nine years to do that work, and some experts have questioned how the trial will be possible when the therapy is already on the market.
The approval led three eminent neurologists on the FDA panel to resign. One, Dr. Aaron Kesselheim, a Professor at Harvard Medical School and director of the Program On Regulation, Therapeutics, And Law at Brigham and Women’s Hospital said the FDA was greenlighting Aduhelm despite not having enough proof that the drug will help people with Alzheimer’s and that ‘it was probably the worst drug approval decision in recent U.S. history’.[i]
The controversy is due in part to the ‘surrogate target’ of the drug,` which is not to reverse the disease or improve cognition, but to remove the plaques on the brain that are said to cause it.
The plaques are part of an ‘amyloid hypothesis’ that has never been universally accepted, and critics point to the numerous failed drug trials on this basis over the last 20 years. [ii] Many older people’s brains have plaques but do not develop Alzheimer’s.
Another major criticism of the FDA’s decision is that the drug is not a harmless placebo. A pooled analysis of two phase 3 studies showed that 41% of patients who took it had swelling or bleeding on the brain. Retired neurologist Daniel Gibbs had received only four monthly doses of Aduhelm in a clinical trial in 2017 when he ended up in an intensive care unit. He never took any further treatments. [iii] In November 2021, a 75 year old patient experienced brain swelling and bleeds, and convulsions, and died.[iv]
Uptake of Aduhelm has been so low that Biogen cut the cost from $56,000 per year per person for the infusion alone not including costs of medical care, to $28,000.
Rejection by major health providers
Since its release Aduhelm has been rejected by several health providers and insurance companies, among them the European Medicines Agency. It said it could cause harm; and the benefits did not outweigh its risk.
The American Academy of Neurology referred to the principle of beneficence, stating that ‘neurologists should inform patients that aducanumab will not cure Alzheimer’s disease or restore cognitive function and they should be aware of potential conflicts of interest that may compromise beneficence.’[v] The Academy also said that there are insufficient grounds to warrant offering aducanumab to patients with moderate or advanced Alzheimer’s dementia or to patients without biomarker evidence of brain β-amyloid.’
The Department of Veterans Affairs also decided not to cover Aduhelm, citing insufficient evidence of “a robust and meaningful clinical benefit” and concerns about safety. [vi]
A particular concern to Biogen was the stance taken by Medicare, the federal health insurance program for people who are 65 or older. Medicare will provide Aduhelm treatment only for certain patients enrolled in clinical trials. Medicare officials outlined two questions the potential clinical trials should be designed to answer: whether the drug has any significant clinical benefit for patients, and whether the drug has damaging side effects. The clinical trials must be conducted in a hospital-based outpatient setting. However, a number of prominent hospitals and academic medical centres have refused to administer the drug at all.
A different Story
Karl Herrup is Professor of neurobiology and investigator in the Alzheimer’s Disease Research Center at the University of Pittsburgh School Medicine, and Jonathan Goulazian is a senior at the University of Pittsburg majoring in neuroscience and economics. In an article discussing the FDA approval, they point out that a broad spectrum of scientists and physicians, including the FDA’s own panel of experts, have made it clear that the data needed for approval were simply not there. ‘Biogen was forced to paper over weak science with intense lobbying. With the help of advocacy groups that they financially support, such as the Alzheimer’s Association, the FDA was pressured to go against the advice of its own analysts.’
They observe that as the cost and relatively poor perform of the drug become evident, trust in the FDA will erode. The FDA should have sent a clear message to the [pharmaceutical] industry that it needs to drop its ‘amyloid-B’ approach to Alzheimer’s.
Pressure from the Alzheimer’s Associations.
There was huge pressure from the Alzheimer’s Associations (AA) on the FDA to approve the drug, On May 6, 2021, the AA launched a campaign called “More Time” to support the FDA approval of the drug. There were full-page advertisements in the Wall Street Journal (WSJ) and USA Today and an open letter from Harry Johns, CEO of AA. ‘In effect, Johns’ statement constituted a promise that the drug Aduhelm will modify the course of Alzheimer’s disease,’ noted Eilon Caspi, assistant professor at the Institute for Collaboration on Health, Intervention, and Policy at the University of Connecticut. [vii]
In conversation, Dr Caspi noted, Johns added that the “negative voices” focused on criticizing the FDA decision are “not pro-patient.” Voices of people with dementia are not being heard. So together with Lori La Bey, founder, ‘Alzheimer’s Speaks’, Dr Caspi co-facilitated a Dementia Chats video session with several individuals who are living with cognitive impairment.
One of those interviewed was Dr.Jennifer Bute, who used to diagnose dementia in England before she herself was diagnosed with Alzheimer’s disease. She said,
“One of my great concerns is this business of trust. I feel that there has been false reporting as well as incomplete reporting and people who desperately want hope will have had this unfair false hope brought to them and when eventually it must be realized it isn’t there, will that dent their trust in other medication, other treatment, the medical profession, and research? So that really does concern me.”
And Paulan Gordon, who is an educator, author, and advocate living with vascular dementia, said, “I am sceptical about the drug…I hate to see people manipulated…people who are suffering and really want help and that upsets me probably more than anything about the whole thing. I don’t have a lot of confidence in the drug…” She added, “I just hate to see it play on people’s heart strings…people who are desperate for a cure following something that could be very risky.”
It’s worth reading Caspi’s well written and referenced article, ‘Trust at Stake: Alzheimer’s Association’s role in FDA’s approval of Aduhelm.’ (https://changingaging.org/blog/trust-at-stake-alzheimers-associations-role-in-fdas-approval-of-aduhelm/).
Ultimately, the results of Aduhelm treatments will speak for themselves. They will either confirm the validity of the amyloid-B hypothesis or finish it off once and for all. Perhaps then other cures and vaccines will be able to emerge, free from a controlling ‘cabal’ that has driven research for so long. https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/. And there may be more investment in promoting lifestyles that help prevent dementia.
[i] https://www.npr.org/2021/06/11/1005567149/3-experts-have-resigned-from-an-fda-committee-over-alzheimers-drug-approval?t=1644148690224
[ii] https://www.nature.com/articles/d41586-018-05719-4
[iii] https://www.statnews.com/2021/08/01/retired-neurologist-with-alzheimers-knows-firsthand-the-risks-of-aduhelm/?utm_source=STAT+Newsletters&utm_campaign=5718bdf4ee-Pharmalot&utm_medium=email&utm_term=0_8cab1d7961-5718bdf4ee-153685150
[iv] https://www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html
[v] https://www.medpagetoday.com/neurology/alzheimersdisease/95759?xid=nl_mpt_DHE_2021-11-19&eun=g1930076d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%20Top%20Cat%20HeC%20%202021-11-19&utm_term=NL_Daily_DHE_dual-gmail-definition
[vi] Statnews.com/pharmalot/2021/08/11/alzheimers-aduhelm-drug-veterans-affairs/#:~:text=The%20Department%20of%20Veterans,notice%20issued%20by%20the%20agency
[vii] https://changingaging.org/blog/trust-at-stake-alzheimers-associations-role-in-fdas-approval-of-aduhelm/
