Q&A: Questions remain about the efficacy, safety of aducanumab for Alzheimer’s disease

Late last year, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee met to discuss a Biologics License Application for aducanumab, an anti-amyloid antibody in development for Alzheimer’s disease.

The advisory committee decided not to recommend approval for the agent at the time. As a result, the FDA review process for aducanumab is ongoing. A decision regarding the approval of the Biologics License Application for the agent is now expected by June 7, 2021, according to a new release issued by Biogen, the maker of aducanumab, following the advisory committee meeting.

A viewpoint published in JAMA earlier this month examined different aspects of the FDA’s decision not to recommend approval for aducanumab. The authors looked at the conflicting evidence and the determination of futility in the two “nearly identically designed” phase 3 double-blind, placebo-controlled randomized clinical trials of high-dose and low-dose aducanumab. They also examined the ability of a single trial to enable the FDA to approve a new drug and whether post hoc analyses could explain why the results from the two aducanumab trials differed.

Healio Neurology spoke with G. Caleb Alexander, MD, MS, professor of epidemiology and medicine at Johns Hopkins Bloomberg School of Public Health, founding codirector of the Center for Drug Safety and Effectiveness and principal investigator of the Johns Hopkins-FDA Center of Excellence in Regulatory Science and Innovation, about the viewpoint that he coauthored to learn more about the questions related to aducanumab.

Healio Neurology: What prompted this publication?

Alexander: AD is a common and costly disease and can be devastating for patients and their loved ones alike. Because of this, it should come as no surprise that there has been enormous interest in aducanumab, especially because of the drug’s unusual regulatory history. My coauthors and I all served on an FDA advisory committee that evaluated the evidence supporting aducanumab’s review and we felt there was an important opportunity to synthesize the evidence and consider its scientific and regulatory importance.

Healio Neurology: Can you provide an overview of your main points?

Alexander: Two nearly identical pivotal trials of aducanumab were conducted, one of which failed and the other which suggested a possible very modest effect in one of two treatment arms. While there is historical precedent for the FDA approving a product based on a substantial evidence from a single adequate and well-controlled clinical trial, the evidence generated for aducanumab doesn’t meet this threshold. Aducanumab’s sponsor, Biogen, has undertaken several post-hoc analyses to explain why the trial results weren’t more compelling; these post-hoc analyses may be useful for hypothesis generation, but also introduce unacceptable threats to statistical validity in this type of setting. In other words, it is always easier to explain why your team lost on the day after the big game.

In addition, there are potentially serious concerns regarding aducanumab’s safety that must be considered as well, including the relatively common prevalence of amyloid-related imaging abnormalities, or ARIA, that, in some cases, can be quite severe and may also be hard to disentangle from AD itself.

Healio Neurology: What are the primary concerns with aducanumab?

Alexander: There are reasons to question both the safety and efficacy of aducanumab from the data that have been publicly released. Both elements are important when considering its regulatory fate. As we note in our JAMA paper, more than 25 randomized trials testing the “amyloid cascade hypothesis” have failed; thus, the discordant results from aducanumab’s pivotal trials, while a disappointment to all, are consistent with a “Type 1”, or false positive, error.

Healio Neurology: What are the next steps for this agent?

Alexander: No number of post hoc analyses of the trials that have been performed to date can take the place of new, prospectively designed, well-controlled clinical trials that meet or exceed the statutory thresholds for market access in the United States: substantial evidence of safety and efficacy. Of course, undertaking further clinical trials is a big step, and there are also non-trivial opportunity costs incurred. Should aducanumab not be approved, the sponsor will have to consider whether further study of this product is the right move. Regardless, it is also important that the pivotal trials that have already been conducted are published in the peer-reviewed literature.

References:

Alexander GC, et al. JAMA. 2021;doi:10.1001/jama.2021.3854.

Biogen. Update on FDA Advisory Committee’s meeting on aducanumab in Alzheimer’s disease. Available at: https://investors.biogen.com/news-releases/news-release-details/update-fda-advisory-committees-meeting-aducanumab-alzheimers. Accessed May 19, 2021.