Dr Neil Cashman examines the recent news around Biogen’s Alzheimer’s treatment aducanumab, assuages some investor fears, and underlines the treatment’s solid fundamentals and potential.
On April 2020, Biogen initiated regulatory review for aducanumab, its investigational therapy for Alzheimer’s disease. Investors reacted negatively, and this reverberated throughout the Alzheimer’s research and patient communities, causing—in my view—unnecessary concern. Aducanumab’s fundamentals remain solid. Biogen has elected to submit a rolling BLA, a slightly longer regulatory path, which I feel is more appropriate for what will be a complex application. And, the US Food and Drug Administration (FDA) Fast Track designation remains. Perhaps most importantly, the innovation driving second-generation drug candidates continues unabated.
A drug candidate with drama
Like any trailblazer, aducanumab has generated controversy. In a March 2020 article, I shared my perspective on its renewal, Biogen’s controversial decision to seek regulatory review for aducanumab after cancelling its two global phase 3 studies (ENGAGE and EMERGE) in March 2019. In my article, I explained why a deeper analysis of the data showed aducanumab worked at high doses and over a longer period of time. In short, aducanumab binds some of the neurotoxic amyloid oligomers (aggregates) that drive Alzheimer’s disease; it just can’t bind enough, and off-target binding to amyloid plaque leads to unwanted and potentially serious side effects. I explained how next-generation therapies that were highly selective for only the neurotoxic form of amyloid—without off-target binding—were already generating data showing the kind of attributes commonly found in second-generation candidates.
Deconstructing negativity: Understanding the rolling review
In my opinion, investors reacted negatively to Biogen’s news because they don’t like delays. Disregarding the effect of the global pandemic on Biogen, referred to as “ground zero” for COVID-19’s spread throughout Massachusetts, the delay can also be attributed to Biogen’s decision to pursue a rolling Biologics License Application (BLA) for aducanumab.
Introduced in 1997, a rolling BLA allows companies to submit the various application modules and documents of a New Drug Application in a series of steps over time rather than one large submission. Originally, Biogen intended to pursue the latter, predicting complete BLA submission by March 31, 2020. The complexity of the application coupled with the pandemic’s effect on staff likely spurred the change, shifting completion to no later than September 30, 2020. While no one likes delays, FDA review has indeed commenced, and my view is that a rolling BLA supports the best chance for a successful outcome.
There are clear benefits to a rolling review.
- Ongoing communication with regulators: A rolling review involves early and more frequent communication with the FDA, which is optimal for an application of this size and complexity.
- Pre-BLA meeting: Biogen plans to have a pre-BLA meeting with the FDA this summer. Pre-BLA meetings ensure that the application is complete, that it can be electronically navigated with ease and that there are no major unresolved issues. Clearly, this final check can reduce the risk of any future problems with the application that could lead regulators to refuse parts of the application or reject it outright, which occurs often enough when submitted as one big bolus. Pre-BLA meetings can help mitigate these potential (and monumental) delays.
- Fast Track status remains: Biogen requested and received the FDA’s coveted Fast Track designation for aducanumab, signifying its potential to offer treatment for serious or life-threatening conditions and address an unmet medical need. The designation ensures expedited regulatory review and again facilitates more frequent communication with regulators to support a successful outcome.
- Beyond Fast Track, there’s Priority Review: Fast Track designation and a rolling review creates the opportunity for Biogen and the FDA to discuss the application’s potential for accelerated review. If they agree that aducanumab represents a major advance in the treatment of Alzheimer’s, a Priority Review designation reduces the review timeframe to 4-6 months.
The year ahead
Once Biogen and the FDA agree the application is complete, the review clock begins to tick. Indeed, this is a delay. However, for investors, the delay supports a more successful outcome. For those living with an Alzheimer’s diagnosis and their families, I recognize acutely the risks and emotional toll of treatment delays, especially true for the many clinical trial participants who have experienced disease improvement and, it should be noted, whose sacrifice has allowed us to arrive at this point. I hope sincerely that preparations are underway to deliver an approved treatment to this very deserving patient community as soon as possible following a potential approval.
It’s significant to note that regardless of aducanumab’s fits and starts, innovation supporting second-generation therapies continues and will continue regardless of the FDA’s decision. Today’s researchers are blending supercomputing, biology and physics to create potential medicines with very precise targeting for only the toxic protein forms that drive Alzheimer’s disease, nothing more. Researchers engaged in second-generation medicines can also benefit from repeat measurement of non-invasive biomarkers to bring these treatments to patients faster. So, while aducanumab captures media headlines, researchers armed with the knowledge of two decades of Alzheimer’s drug attempts are diligently working to bring new, better therapies to patients faster and more efficiently. Regardless of aducanumab’s future, this will remain unchanged.
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 several antibody candidates that target the toxic oligomers of other misfolded proteins implicated in a variety of neurodegenerative diseases.