Last week’s qualified Medicare announcement, the tumultuous responses, related news and opinions are swirling around the anti-amyloid drug Aduhelm ™, indicated for Alzheimer’s Disease (AD).
Before discussing that, it might be instructive to look at a substantial review of AD and how it discusses the presumed role of amyloid-beta . It was published just weeks before the FDA leadership gave Aduhelm the nod that has generated so much controversy.
Nature Reviews Disease Primers: Alzheimer’s Disease , May 2021, touches on most of the basics, the way a primer should, with academic writing and a few graphics. It seems balanced, discussing molecular pre-clinical and some clinical research. It doesn’t try to cover everything.
About Mechanisms: ” … While the biology of amyloid precursor protein and tau protein is featured throughout this Primer,… the apparent primacy of these proteins…fails to acknowledge the many other covert mechanisms….that have been hypothesized as relevant. Understanding how the mechanisms that underlie AD lead to synaptic and neuronal loss, which are the likely causes of cognitive impairment, has been a matter of substantial investigation yet much remains to be learned.” [edited for space].
The review mentions, in passing, hot topics like inflammation and the glymphatic system. The review later discusses clinical symptoms, behavioral issues, quality of life and therapies.
Here it discusses aducanumab, the generic name for Aduhelm: “…Claims of efficacy for aducanumab were made based on a slowing of decline on the Clinical Dementia Rating scale but are complicated because the trials were terminated prematurely for futility; however, additional data review found evidence supporting an efficacy claim….” It also mentions donanemab and lecanemab, other drugs in the class.
Now the Vortex: The swirling started last year, right after FDA leadership approved Aduhelm over the negative vote from its own advisory committee. Numerous articles and viewpoints were published. Quick reviews with academic publications cited can be found in blog pieces here: FDA “approval is conditional” June 2021, ” still controversial” Aug 2021.
Since then, the whirlwind had continued. The US VA health system has declined to approve it, as have other US hospital systems. The European Medicines Agency declined it. Because of that decision, the company has evidently held off requesting approval in the UK. Japan declined it for now, delaying a decision, despite the partnership of the Japanese company Eisai. Biogen, the manufacturer, cut the cost in half.
Then CMS / Medicare, the most important paying “customer,” announced a proposal Jan 11 [link here is the CMS press release] to approve reimbursement for Aduhelm’s use, but only for those patients enrolled in a clinical trial that gathers more data. Some are reporting that CMS has a proposed Medicare premium increase of ~$20/month that factors in payment for Aduhelm. There is evidently precedent for this kind of reimbursement requiring clinical trial enrollment; it is not a total denial of coverage.
The response was swift. Harry Johns, the CEO of the non-profit Alz Assn, calls the CMS proposal “shocking discrimination” and complains about the “audacity” that CMS used data from an Alz Assn “Facts and Figures” report. Us Against Alzheimer’s, another non-profit, calls the CMS proposal “absolutely unacceptable” and their news headline says “Medicare slams the door on Alzheimer’s treatments.” Neither press release mentions how the drug had been totally declined elsewhere or mentions any scientific issues.
Public Citizen, a non-profit which has been critical of the FDA for approving Aduhelm, supported Medicare’s proposal.
Ethicists recently wrote of their concern about the FDA in evaluating the safety and efficacy of Aduhelm, and adhering to its own mission statement, to protect consumers and enhance public health, given the negative scientific review. The authors discuss the role of patient testimonies, often with elements of desperation, as part of the process (also seen with diseases like cancer and ALS). It discusses five considerations for the FDA in the “ethics of desperation.”
AlzGadfly points out that Medicare’s proposal would help accelerate the research and data gathering to convincingly answer the basic effectiveness question. The company did not present such an answer, at least not compelling enough for scientific medical experts here and in other parts of the world. AlzGadfly would also point out that there has been some transparency in the process, but Public Citizen and others have called into question some pre-decision maneuvers from the company and non-profits.
In the meantime, other manufacturers are now applying for accelerated approval for their own amyloid-beta monoclonals, like donanemab (Lilly); in the NEJM paper, the investigators said it did not achieve their clinical goals. Lecanemab (Eisai/Biogen), is going the same route. And gantenerumab, a third monoclonal, got a recent FDA “breakthrough designation” for its effects on amyloid PET scans, even while failing cognitive endpoints in previous trials. That basically means the company can plan more work and expect a priority review.
Re-trying failed agents, exposing more subjects: AlzGadfly is glad not to be sitting on any ethical or protocol review boards!
BACE inhibitor trials seem to show an effect on amyloid in subjects so burdened, but many had cognitive worsening, and none of the three agents recently tested has gone forward for the approval process. However the recent atatbecestat study, stopped for toxicity, seemed to have subjects that bounced back to near baseline on their cognitive tests. Could the toxicity be deemed acceptable, like brain imaging changes or even swelling and hemorrhages after Aduhelm?
If one can improve PET scans but not improve the patient’s cognitive or other abilities, would the drug be worth it to a patient? An academic longitudinal study implies that simply drinking coffee might improve one’s brain autopsy amyloid findings (a pre-PET scan era study), albeit without improving dementia.
BTW, one online news item left it unclear about whether the first author of the Primer, DS Knopman of the Mayo Clinic, was removed, or he recused himself from the FDA scientific committee. He had been a clinical investigator for Biogen, and was once chair of the scientific committee for the Alz Assn, but some thought he was a critic of Aduhelm. It didn’t matter, since evidently no one left on the Aduhelm scientific committee voted for unqualified approval anyway.
Just about ten years ago, FDA pulled the accelerated approval of Avastin for metastatic breast cancer. That announcement created some sturm und drang (which is not German for “storm drain”). Since then FDA has approved dozens of new cancer drugs and indications, some only marginally effective with surrogate endpoints, but usually meeting scientific criteria without drama.
It all seems as thrilling as the original Vortex Roller Coaster, with all its ups, downs, inversions and sensations of free-falling. Feeling the vertigo yet? AlzGadfly would offer you some motion sickness pills, but they tend to be anticholinergic and might be linked to later dementia!
