On June 7th, the U.S. Food and Drug Administration (FDA) approved Aduhelm (aducanumab) for the treatment of Alzheimer’s, a disease affecting 6.2 million Americans. Aduhelm was approved using the accelerated approval pathway, which can be used for a drug for a serious or life-threatening illness that provides a meaningful therapeutic advantage over existing treatments. Accelerated approval can be based on the drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, with a required post-approval trial to verify that the drug provides the expected clinical benefit.
Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research emphasized the novel nature of the treatment for Alzheimer’s: “Currently available therapies only treat symptoms of the disease; this treatment option is the first therapy to target and affect the underlying disease process of Alzheimer’s.”
The following article outlines the controversies related to the approval of aducanumab and provides insights for physicians outlined by MCMS physician member Eric Jeffries, M.D., a board-certified neurologist, and David Holtzman, M.D., a past president of the American Neurological Association.
Member Perspective: Board-Certified Neurologist Eric Jeffries, M.D.
Eric M. Jeffries, M.D., a Board-Certified Neurologist at The Neurology Center in Silver Spring wrote the following statement regarding Aducanumab. For referrals, you can contact Dr. Jeffries at 301.562.7200. MCMS thanks him for his critical contribution to this article.
Until 20 days ago, no medications for the treatment of Alzheimer’s disease (AD) had been approved by the FDA for more than 15 years. This, despite billions of dollars of research and numerous failed trials over that period.
As a community neurologist, the dementias are the disease category afflicting the greatest number of my patients and there have been no medications to reverse their devastating effects. Given this, no one, save the patients and families themselves, has been more eager for safe and effective therapies for these diseases than my colleagues and I.
So it was that the Neurology community eagerly and hopefully followed the clinical trials process surrounding Aducanumab since at least 2018. Given the outcomes of Phase 1 and 2 trials, there was cautious optimism that this might be the breakthrough we have all been hoping for. In March 2019, however, those trials were stopped because a futility analysis suggested that Aducanumab was unlikely to outperform placebo. At that time, it was widely accepted that another promising treatment had failed.
As has been widely publicized, Aducanumab was revived through a series of subgroup analyses, which ultimately resulted in the trial outcome that this drug was effective in patients with Mild Cognitive Impairment or early AD, who were on the highest dose they evaluated. This was found in one of the two studies. When these data were presented and fully evaluated by the FDA medical advisory committee, eight of the 11 voting members said that they did not even think the single study provided strong evidence that the drug was effective; two said they were uncertain. When the panel ultimately voted, in November 2020, 10 of the 11 members voted against its approval. Nevertheless, as we all know, the FDA granted accelerated approval to the medication earlier this month, with a label much broader than anticipated. This appears to be based primarily on the drug’s ability to clear amyloid in the brain, as opposed to any compelling evidence that it slows cognitive decline.
It is important to note that, in trials, 41% of the treatment group experienced side effects, which including amyloid-related imaging abnormalities (ARIA), with cerebral edema or micro- hemorrhages, as well as headaches and dizziness, compared with 10% of the placebo group.
Beyond this, this medication is anticipated to cost approximately $56,000 per year and it is not yet clear what testing will be required, though it is anticipated that amyloid-PET scanning or LP would be necessary to determine appropriate candidates, and serial MRIs would be indicated to evaluate for ARIA.
All of this in the face of a medication that has been shown, at best, to slow symptoms for roughly four months over an 18 month period. To wit: the FDA has charged Biogen with performing a “confirmatory trial”, for which it has given the company nine years to complete.
As a neurologist, I have been more eager than most for a medication that will effectively combat the scourge of Alzheimer’s Disease. This drug, with its limited-at-best efficacy, its concerning risk profile, the ongoing monitoring burden, and its enormous cumulative cost, which has the potential to materially impact the entire medical economy, is sufficiently far from ideal that I am unlikely to prescribe it without compelling Phase 4 evidence that its benefits outweigh what are clearly significant individual and economic risks.
End of statement.
Other Anti-Amyloid Antibodies
Shortly after the drug’s approval, the American Neurological Association spoke with its Past President David Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and Chairman of Neurology, Professor of Developmental Biology, Associate Director of the Alzheimer’s Disease Research Center, and scientific director of the Hope Center for Neurological Disorders.
When asked what research seemed likely to impact the standard of care after the approval of Aduhelm, Dr. Holtzman noted, “in addition to Aducanumab, there are at least three different anti-amyloid antibodies that all show promise. There are also other targets that are very promising that are being actively worked on including trying to target tau, inflammation, and other pathways.” Read the full Q&A.
Dr. Holtzman’s words of since proved prescient with Eli Lilly announcing that it plans to file for accelerated approval of its Alzheimer’s disease prospect donanemab later this year. Donanemab is an investigational antibody that targets a modified form of beta-amyloid called N3pG.
In the intervening weeks since the FDA accelerated approval of Biogen’s Aduhelm, the treatment has faced controversy in two areas– its price and its clinical efficacy.
The treatment will cost $56,000 per year, per patient. The Alzheimer’s Association released a statement arguing that the wholesale price is “simply unacceptable” and that, for many people, it “will pose an insurmountable barrier to access … and may further deepen issues of health equity.” The organization also expressed gratitude that the drug was approved in response to a “vast unmet need,” but called on Biogen to change the price.
Payors are now considering coverage for the costly treatment. In an attempt to provide a sense of scale, The New York Times ran an article titled “New Drug Could Cost the Government as Much as It Spends on NASA“.
Regarding the drug’s clinical efficacy, concerns rose after news broke that the FDA’s own independent advisory committee recommended against the new medication. Three members of the committee subsequently resigned. Public Citizen, a nonprofit watchdog organization, sent a letter to HHS Secretary Betera outlining a “lack of evidence that the drug provides any meaningful clinical benefit” and “a well-documented risk of potentially serious brain injury.”
Other clinical concerns related to the approval include the unexpectedly broad label which states that the drug is indicated “for the treatment of Alzheimer’s disease” and places no restrictions on how this must be diagnosed, as well as the accelerated approval of the drug based on a surrogate endpoint (the reduction of amyloid-beta plaque).
In an attempt to quell the clinically related controversy, the FDA released additional details on June 23 related to the accelerated approval, including 83 pages of internal documents. Biospace reports that “according to the documents, there were disagreements by officials on how to deal with the drug, partially because the data on its effectiveness was confusing. One of the primary clinical trials failed to show clinical benefit while another late-stage study and an early-stage trial suggested the drug helped.”
- FDA Press Release
- FDA Approval Process
- Clinical Information from FDA
- Washington Post’s Coverage of the Decision
- From ABC News: Doctors Face Dilemma on Whether to Recommend New Alzheimer’s Drug
- From Health Affairs: The FDA’s Approval Of Aduhelm: Potential Implications Across A Wide Range Of Health Policy Issues And Stakeholders
- From STAT News: How Biogen used an FDA back channel to win approval of its polarizing Alzheimer’s drug
- The ANA Q&A: Dr. David Holtzman | Alzheimer’s Disease