Aducanumab: On the Regulatory Home Stretch in the USA

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In the third of a series of articles chronicling Biogen/Eisai’s Alzheimer’s Disease (AD) treatment aducanumab’s torturous journey to market, Dr Neil Cashman highlights what the next steps in the process will be, why US FDA approval for the drug will pave the way for researchers working on second-generation AD medicines, and how the future for AD is more promising than ever before.

 

While aducanumab’s path to this point has been marked by controversy and at times, confusion … I continue to expect a positive outcome

After a long and somewhat wandering path, aducanumab is in its regulatory home stretch. On August 7, 2020, Biogen and its partner Eisai announced US Food and Drug Administration (FDA) acceptance of their application submission for aducanumab, its amyloid-beta-targeting drug candidate for Alzheimer’s disease (AD). Significantly, the FDA granted Priority Review to the application, meaning that a regulatory decision could come as early as March 7, 2021, extremely positive news for the beleaguered community of Alzheimer’s patients, their affected families and the AD research community. While aducanumab’s path to this point has been marked by controversy and at times, confusion—a path I’ve chronicled in my May 2020 and March 2020 commentaries—I continue to expect a positive outcome. And, as I’ve suggested in the past, the most significant impact of aducanumab’s anticipated approval is on the path it has paved for researchers working on second-generation medicines.

Here’s where we stand now.

 

The FDA: seriously contemplating approval

In my May commentary, I described aducanumab as “a drug candidate with drama.” While that hasn’t changed, a recent spate of positive developments strengthens its likelihood of approval.

  • On July 8, 2020, Biogen announced that it had completed its Biologics License Application (BLA) for aducanumab. My May commentary offers a detailed analysis of the benefits of this particular regulatory approach, which nonetheless rattled investors when Biogen announced their plans to pursue it.
  • FDA acceptance of the BLA and subsequent Priority Review designation, announced August 7, 2020, reduces regulatory review from the standard 10 months to 6 months. The target action date is now March 7, 2021.
  • Notably, Biogen explained that the FDA granted Priority Review without the need for a Priority Review Voucher (which Biogen received from the FDA in December 2016 in response to its successful Spinraza application for the treatment of spinal muscular atrophy, a pediatric rare disease). This suggests the Agency believes aducanumab potentially represents a major advance in the treatment of AD. Biogen also indicated that the FDA stated that, “if possible, it plans to act early on this application,” all of which suggests the FDA is seriously contemplating approval.

 

Next up: The Panel

An approval means the FDA believes aducanumb demonstrates adequate safety and “substantial” evidence of effectiveness, a belief that normally requires two unequivocally positive studies. However, in the absence of any disease-modifying therapy (DMT) for AD, the outstanding question is whether FDA will conclude the current aducanumab dataset, which includes only one clearly positive study and two supporting studies, is sufficient to warrant approval.

To assist with their decision, the FDA will convene a committee of scientific advisors, a standard practice, at a yet-to-be-determined date within the next six months. These so-called FDA advisory committees are usually public with the media reporting on key decisions and noteworthy discussion points.

Despite aducanumab’s small treatment effect size in its phase 3 studies, leading clinical investigators have concluded repeatedly and publicly that the effects are meaningful for patients, and that the side effect of ARIA-E can be effectively managed. Also weighing significantly upon the decision, is the stark fact that there are no approved DMTs for AD to date. While I believe the FDA will in fact approve aducanumab as the first DMT for Alzheimer’s, regardless of the ultimate outcome, innovation supporting second-generation therapies continues. As I’ve maintained throughout aducanumab’s storied path, its success to this point has already reinvigorated the fight to resolve the most vexing drug-development challenge of our time. Today’s researchers are rapidly advancing “second-generation aducanumabs” that demonstrate very precise targeting for the toxic molecular form of amyloid-beta that drives AD, which are oligomers. I explain the copious data guiding this new generation of therapies in my March commentary.

The future for Alzheimer’s disease is more promising than it’s ever been. Clinical studies for next generation medicines will benefit from the use of fluid-based biomarkers, which will ensure faster, more efficient, less expensive studies; and, they’ll also ensure researchers advance only the best therapeutic candidates. The Alzheimer’s community owes a debt of gratitude to aducanumab’s supporters not only for delivering the anticipated first therapy for AD, but for strengthening the case for next-generation candidates that are not far behind.

 

Dr. Neil Cashman is chief scientific officer and co-founder of Toronto-based ProMIS Neurosciences, Inc. (TSX: PMN) (OTCQB: ARFXF), which is advancing an investigational antibody that binds to neurotoxic Aβ oligomers, as well as antibody candidates that target misfolded proteins implicated in a variety of neurodegenerative diseases.

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