James W. Kupiec, MD

Biogen and its partner Eisai announced on August 7, 2020 that the FDA 

accepted their biologics license application

 (BLA) for aducanumab and granted the application priority review. This earlier-than-expected news is very positive and, based on FDA’s receptiveness, I expect a positive outcome.

Biogen’s aducanumab is now in the home stretch, as the FDA expects to decide on its marketing application within 6 months by March 7, 2021.

In a sudden and unexpected turnaround, Biogen announced on October 22, 2019, that earlier conclusions from aducanumab’s interim futility analysis, released in March 2019, were incorrect. Based on the limited data available by the December 2018 “cut-off” date, the interim analysis conducted by Biogen biostatisticians showed a less than 20% chance for the 2 identical phase 3 clinical studies to meet their primary endpoint. Based on these analyses, the external monitoring board recommended in March 2019 that Biogen 

 (AD) for “futility” as it would be inappropriate to continue the studies to completion for both operational and ethical reasons. 

However, between December 2018 and March 2019, study subjects continued to be assessed according to the experimental protocol and generated additional, evaluable data. Biogen biostatisticians conducted a final analysis on this larger dataset after the decision to halt the phase 3 studies was made.

Although it is unusual for a final dataset to contradict an earlier interim analysis for futility, this is exactly what occurred; Biogen announced their revised assessment on October 22, 2019. At that time, they stated they had met with the FDA at least twice to review the new analyses and that they planned to submit a marketing BLA for aducanumab in early 2020. At the time, Biogen stated that “after consultation with the FDA, we believe that the totality of these data support a regulatory filing.”

Since October 2019, Biogen has provided additional phase 3 data as well as details around their FDA interactions.

  On December 5, 2019, Biogen provided an in-depth analysis of their phase 3 efficacy, safety, and biomarker data generated during the 

 at the 2019 Clinical Trials on Alzheimer’s Disease (CTAD) conference. The EMERGE study was unequivocally positive when the larger dataset became available and showed a 23% reduction in cognitive decline on the Clinical Dementia Rating scale Sum of Boxes assessment amongst those trial subjects administered high-dose aducanumab over a prolonged duration. The ENGAGE trial did not show an overall treatment benefit like the EMERGE trial for compelling reasons outlined by Biogen, but a post hoc analysis showed that the subset of ENGAGE participants who had consented to the high dose midway through the study had a treatment benefit similar to that observed in the EMERGE study.  Moreover, the smaller phase 1b PRIME study, which showed a clear dose-responsive benefit, supports the phase 3 conclusions. The totality of these data strongly argues that aducanumab may be the first disease-modifying therapy (DMT) for AD. For that reason, leaders in AD clinical research have acknowledged that the aducanumab phase 3 data represent a milestone achievement for our field.

  Biogen executives indicated that they had already begun to 

 via a rolling BLA process and that they expected it to be complete by the summer (a bit longer than originally projected). A rolling review process, introduced by the FDA in 1997 and now quite commonly used by sponsors, allows the FDA the option to commence review of individual application components, and enables both sponsors and the FDA the opportunity to work with greater efficiency to ensure the application is complete and ready for the FDA’s deep, integrated review. Biogen indicated the aducanumab application was complex and that compilation of the application had been hampered by the impact of COVID-19 on key project staff. Biogen also mentioned that they had formal Type C meetings with the FDA, but did not relay the contents of those discussions, saying, “We have continued constructive engagement with FDA.”

 followed a planned “pre-BLA meeting” with the FDA to ensure the entire application file was complete, that the file could be electronically navigated with ease, and that there were no major unresolved issues (this was the expected outcome considering the ongoing dialogue with the FDA during the rolling BLA). It was noted that the FDA would have up to 60 days to decide whether to “accept” the application for review. Biogen also stated they expected to hear whether the BLA would be granted a Priority Review designation in response to their request.

BLA filing accepted and Biogen’s Priority Review request granted on August 7, 2020:

  Just 30 days later, Biogen announced that the FDA had indeed accepted the BLA for review and opted to grant the application priority review, cutting the time allotted for the FDA to review the application from the standard 10 months to 6 months, with a Prescription Drug User Fee Act (PDUFA) target action date now set for March 7, 2021. In the announcement, Biogen indicated that the FDA granted priority review without Biogen needing to submit a Priority Review Voucher (which they had apparently received from the FDA in December 2016, in response to the successful nusinersen application for the treatment of spinal muscular atrophy, a pediatric rare disease). This FDA decision suggests that the FDA believes aducanumab potentially represents a major advancement in the treatment of AD.  Moreover, Biogen indicated that the FDA “has stated that, if possible, it plans to act early on this application,” suggesting that they are already well-informed regarding the data and are seriously contemplating approval.

Although all interactions between Biogen and the FDA to date suggest a high level of receptivity by the FDA for the BLA, the FDA will ultimately need to decide whether the application shows adequate safety and “substantial” evidence of effectiveness to win approval. For most diseases and potential therapies, 2 unequivocally positive studies are typically required to satisfy FDA requirements. In the absence of any DMT for AD, the outstanding question is whether the FDA will conclude the current aducanumab dataset of one clearly positive study and 2 supportive studies is sufficient to warrant approval. 

The FDA will convene a committee of scientific advisors ahead of the PDUFA date in order to help guide their final decision. Despite aducanumab’s small treatment effect size in the phase 3 studies, leading clinical investigators have concluded that the effects are meaningful for patients and that the adverse effect of amyloid-related imaging abnormalities, namely vasogenic edema, can be effectively managed. 

In the absence of any currently approved DMT for AD, it is my view that the FDA will in fact approve the aducanumab application and that aducanumab’s dataset will provide the first benchmark against which subsequent DMTs must demonstrate greater benefit and/or safety.

James W. Kupiec, MD, is chief medical officer of ProMIS Neurosciences, Inc. 

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