Researchers on the FDA’s advisory committee conducted a review of the studies and evidence ahead of the treatment’s PDUFA date on June 7, 2021.
G. Caleb Alexander, MD
Aducanumab has dominated conversations in the Alzheimer disease (AD) space over the last several months, with conflicting opinions and data concerning Biogen’s investigational amyloid-targeting agent stemming from terminated trials driving the discussion.
With its Prescription Drug User Fee Act (PDUFA) action date of June 6, 2021, around the corner, G. Caleb Alexander, MD, co-director, Center for Drug Safety and Effectiveness, Johns Hopkins Medicine, and colleagues Scott Emerson, MD, PhD, and Aaron S. Kesselheim, MD, JD, MPH, reviewed the evidence and literature on aducanumab to date.1 Alexander and Kesselheim serve on the FDA’s Peripheral and Central Nervous System Advisory Committee, which in November 2020 suggested the agency not approve aducanumab.
Eisai and Biogen previously discontinued the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 clinical trials in 2019, as well as the EVOLVE (NCT03639987) phase 2 safety study after they met criteria for futility in a planned interim analysis.2 Post-hoc analyses revealed that the studies had conflicting results, with ENGAGE reaching futility but EMERGE reaching statistical significance in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores in its high-dose cohort.
The treatment, which many had written off as a failure, was thrust back into the spotlight in 2019 when Eisai and Biogen presented the new analysis of the studies at the 12th Annual Clinical Trials in Alzheimer Disease (CTAD) conference demonstrating the statistically significant changes in CDR-SB scores in patients treated with aducanumab (P = .010; P = .031).3
“Post hoc analysis of trials that change the populations of interest, end points, or methods of analysis introduce what may be regarded as unacceptable threats to statistical validity and scientific rigor, and they are usually performed as hypothesis-generating exercises,” Alexander and colleagues wrote in their review.
In January 2020, in response to the new data, the FDA reignited hope for the treatment’s approval by approving the ongoing, open-label, phase 3b re-dosing clinical trial (NCT04241068) with a targeted enrollment of 2400 patients from 4 previous clinical trial programs in the aducanumab development program. The trial aims to demonstrate long-term safety and tolerability of aducanumab.4
“As pointed out by a statistical reviewer at the FDA, 8 analyses based on a post hoc selection of the better of 2 RCTs—the 1 reaching statistical significance—without methods that acknowledge this purposeful choice increase the risks of inadvertently selecting data precisely because those data were consistent with the outcomes that were hoped for,” Alexander and colleagues wrote concerning the analyses that prompted the re-dosing trial.
In January 2021, the FDA delayed the PDUFA date from March 7, 2021 to June 7, 2021, 3 months later.5 The biologic license application (BLA) was originally submitted in July 2020 and was first accepted for review the following month.6
Alexander and colleagues highlighted safety concerns from the aducanumab trials and pointed out the high rates of amyloid-related imaging abnormalities (ARIA), including vasogenic edema (ARIA-E) in aducanumab-treated vs placebo patients.
While ARIA is typically asymptomatic, its effects are not well understood, and as many as 0.9% of participants with ARIA experienced severe symptoms, including confusion, disorientation, gait disturbance, ataxia, visual disturbance, headache, nausea, falls, and blurred vision. The FDA’s statistical review also suggested evidence of potentially greater falls in the high-dose cohorts.
While Alexander and colleagues acknowledge the burden of AD on millions of patients and families, as well as the efforts of Biogen to reduce this burden, they concluded that the treatment’s earlier conclusion of futility was correct and the post-hoc analyses should not overturn this decision.
"There is no reason to favor the trial with the positive signal in 1 of 2 treatment groups over the trial with the negative outcome in both treatment groups, and there is no persuasive evidence to support approval of aducanumab at this time. Randomized trials should remain the primary means that regulators use to assess product efficacy, and that patients, physicians, and policy makers rely on, to have confidence in the safety and effectiveness of new therapeutics,” they wrote.
NeurologyLive previously spoke to Stephen Salloway, MD, MS, director of neurology and of the Memory and Aging Program, Butler Hospital, Providence, Rhode Island, and an investigator in the clinical development of aducanumab, about the investigational agent and current landscape of AD care.
"[Aducanumab] is akin to azidothymidine (AZT) for HIV. There was no treatment for HIV, and when AZT was approved, it had limited use, but it stimulated the community to really get going with developing better treatments, and now they have developed really potent treatments that affect the disease course for HIV. I’m hoping the same thing would happen for us, and AD. No drug has been approved for 17 years for AD,” Salloway said, supporting the approval of aducanumab.