Editor’s note: With all the recent news on the FDA’s approval of Aduhelm (aducanumab), the new drug used to treat Alzheimer’s, ASA wanted to give our readers informed opinions on the topic from experts in the aging sector. Below is a piece arguing against the FDA approval of Aduhelm. Click here to read the piece arguing in favor of the FDA approval.
The opinions expressed in this article are those of its author. They do not necessarily reflect the opinions or views of ASA management or its members.
Evidence is absent that aducanumab, the new BioGen medication to treat Alzheimer’s disease (AD), has clinical benefit. Two truncated studies and one ascending dose trial did not demonstrate clinical benefit for people with prodromal AD (MCI due to AD) or mild AD dementia. Even if one chose to value a claimed, “pre-specified,” post-hoc, unadjusted P = 0.012 for the primary outcome in one of the trials, while ignoring the wholly negative and discordant outcomes of companion trial, the “best case” effect of 0.39 drug-placebo mean difference on the CDR-sb (Clinical Dementia Rating scale) is trivial. It’s a difference so small that it can’t be clinically recognized.
Moreover, the –1.4-point mean difference on the ADAS-cog14 (Alzheimer’s Disease Assessment Scale) represents a small fraction of the effect of marketed cholinesterase inhibitors like donepezil. As comparisons, the established mean clinically important difference (MCID) for the CDR-sb is 1.0 point and for the ADAS-cog11 is about 3.0 points.
Aducanumab’s rejection should have been without controversy. Both the FDA’s independent statistical reviewer and the PCNS (Peripheral and Central Nervous System) advisory committee could not infer evidence for clinical benefit for it, the latter unanimously voting 10 to 0, with 1 uncertain vote, against approval.
‘The FDA nonetheless approved aducanumab using an alternative accelerated approval pathway.’
Indeed, the FDA eventually agreed with this assessment, recently issuing explanatory memos (June 22, 2021) that aducanumab didn’t show efficacy or clinical benefit that would support regular marketing approval. That is, the FDA would not provide approval based on the FDA’s typical substantial evidence standard for effectiveness. In an ironic piece of regulatory jujitsu, however, the FDA nonetheless approved aducanumab using an alternative accelerated approval pathway.
In a nutshell, accelerated approval is full approval (not provisional approval as is often thought) but based on a surrogate biomarker that is considered “reasonably likely” to predict clinical benefit. The latter phrase is FDA-speak meaning the surrogate marker is unvalidated, without sufficient clinical data behind it, but simultaneously expressing hope that in the future the surrogate biomarker may be validated or shown to correlate with clinical outcome. In brief, accelerated approval is marketing approval based on an unvalidated biomarker.
Redefining Alzheimer’s, and Its Treatment
The prescribing label for aducanumab states it is indicated for treating Alzheimer’s disease based on reduction in amyloid beta plaques observed in patients treated with it. Period. This subtlety may be lost or, more likely, ignored by most consumers, physicians, and stakeholders who will have been influenced by others to talk about clinical efficacy. Publicity campaigns by the Alzheimer’s Association saying that aducanumab alters clinical decline or preserves function, or gains time at home, are without foundation.
Like many senescence-related conditions, Alzheimer’s and other dementias are complex conditions with multiple determinants. A single intervention, even if tied to pathogenetic pathways, is unlikely to show distinct benefit. Thus far the disease has defied effective treatment except for cholinesterase inhibitors' small effect on cognition. One approach when faced with a daunting, intractable challenge is to redefine the problem and reconceptualize the solution.
The idea of defining Alzheimer’s disease based strictly on biomarkers has taken hold in some quarters. In this formulation, Alzheimer’s is seen as a proteinopathic diathesis manifesting simply as amyloid plaques, misfolded abnormal tau protein and neuronal loss, i.e., essentially what pathologists see on microscopic examination.
This definition then reduces to simple equations. Alzheimer’s pathology equals amyloid plaques; Alzheimer’s disease equals plaques and tau tangles. As both are detected by PET scan and inferred from CSF analysis, this “new” Alzheimer disease can be reliably defined by biology alone. Just as rationally, it follows that, as plaques are the defining element of Alzheimer’s, the absence or removal of plaques must mean “not-Alzheimer’s” in the former and effective treatment in the latter. But this doesn’t necessarily mean a benefit for cognition; and, indeed, there is no meaningful correlation between change in plaques and clinical ratings.
‘One approach when faced with a daunting, intractable challenge is to redefine the problem and reconceptualize the solution.’
The FDA, biotech, and Alzheimer’s advocacy fields are now in a conundrum the public may not yet quite appreciate. Having changed the definition of Alzheimer’s and the criteria for substantial effectiveness of treatment to plaque removal they have no basis for reversing this approval or requiring confirming studies that would clearly demonstrate clinical benefit. Plaque reduction is the benefit.
There is no doubt that aducanumab markedly reduces plaque to normal in nearly half of patients treated with it. Actual clinical benefit, although much desired, appears optional. Requiring Biogen to prove clinical benefit, if possible, would not be a good look for scientific reductionism explained above.
This FDA, Biogen, Alzheimer’s Association collaborative approval of aducanumab is fundamentally flawed. By removing clinical effectiveness standards, the FDA has pari passu lowered safety standards. In the absence of clinical benefit, no treatment is safe. We may believe that most brain edema and hemorrhage, very common potential side effects of aducanumab, are asymptomatic and can be managed, but some of it is quite severe. We will learn much more about safety over the next year of marketing and prescribing.
Advertising from Biogen and the Alzheimer’s Association, as well as the litany of paid promotional events from physicians will gin up the perceived need for aducanumab, and exacerbate older people’s, with or without cognitive impairment, fear of missing out. Physicians and other clinicians have an intrinsic wish to help and will be inherently incented to prescribe. This will drive demand, consume energy, and allow many to feel they are fighting the good fight. We have much work to do to understand any potential for aducanumab.
Lon S. Schneider, MD, holds the Della Martin Chair of Psychiatry and Neuroscience, professor of psychiatry, neurology, and gerontology at the Keck School of Medicine of USC and the USC Leonard Davis School of Gerontology in Los Angeles. Schneider also directs the USC State of California Alzheimer’s Disease Center and the clinical core of USC National Institute on Aging Alzheimer’s Disease Research Center clinical core. He served as a senior scientific advisor at the NIMH, on the American Psychiatric Association Committee for Practice Guidelines in Alzheimer’s and Other Dementia, the World Federation of Societies of Biological Psychiatry Task Force on Dementia.