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What in the heck is the FDA thinking?


By John Vandermosten, CFA


One of the wildest roller coaster rides in biotech has been the aducanumab saga that has been taking place over the last few years. Aducanumab, branded as Aduhelm, is an amyloid beta-directed monoclonal antibody intended for use in the treatment of Alzheimer’s Disease (AD). Aduhelm binds to aggregated forms of amyloid beta and has demonstrated the ability to reduce its presence in the brain.

The drug, which was approved on June 7, 2021, was the first new product approved for treating AD since memantine (Namenda) in 2003. The 18-year dry spell was not due to a lack of trying as other candidates such as solanezumab, bapineuzumab, elenbecestat and lanabecestat from well-known biopharmas including as Lilly, Pfizer, Eisai and AstraZeneca among many others reached late stage trials before failing to prove any efficacy.

The aducanumab pivotal trials began as most do in the AD space with a pair of 78-week, Phase III registrational studies launched in late 2015. Each of the trials, designated ENGAGE and EMERGE, enrolled over 1,600 patients at several hundred study locations around the globe with a primary endpoint of Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Despite some Phase III AD failures in 2017 and 2018 for gantenerumab, crenezumab and solanezumab, most stakeholders held out hope for aducanumab’s success.

However, this confidence was shaken in March 2019 when Biogen (NASDAQ:BIIB) made the unexpected announcement that both of the AD trials were being halted due to futility. The trials’ Independent Data Monitoring Committee (IDMC) advised that the ENGAGE and EMERGE were unlikely to achieve their primary endpoints. The day of the announcement, Biogen stock lost 30% or almost $20 billion dollars in market capitalization.

Seven months later, and after further analysis, Biogen found that aducanumab did indeed have a dose-dependent effect on AD supported by amyloid-PET imaging and observations of reduced clinical decline in patients with early stage disease. Biogen announced its intent to submit a Biologics License Application (BLA) to the FDA. In July of 2020, the BLA was filed with the FDA and later accepted for priority review. Things were looking up for the candidate with the next hurdle being an advisory committee meeting scheduled in November 2020. This committee was asked to opine on whether or not the trials provided strong evidence that aducanumab was effective in treating AD. Much to the dismay of advocates, the advisory committee members overwhelmingly indicated that the trials did not.

Another seven months passed and after a few delays the eventual target action date was reached on June 7th, 2021. FDA approval was granted using the Accelerated Approval pathway, which is intended for medicines that treat serious diseases with an unmet need and where there is an expectation of clinical benefit, although the benefit may be elusive. We think that the FDA granted approval to aducanumab because the potential benefits of the therapy outweigh the risks.

Our opinion of explicit and implicit factors supporting the Accelerated Approval of aducanumab in AD:

➢ Serious and life threatening disease

➢ No other available disease modifying treatments for AD

➢ Severe unmet need

➢ Potential benefit outweighs the risks

➢ Stimulate further drug development efforts

➢ Provide hope to patients

➢ Requires post-marketing study, allowing further research


The decision to approve aducanumab was controversial and has been criticized from many angles. No doubt, there would have been condemnation from some patient advocates had the drug been rejected, citing the lack of treatment for a prominent disease. While the amyloid beta hypothesis still relevant and other compounds, such as ProMIS Neurosciences’ (TSX:PMN.TO) PMN310 and Eli Lilly’s (NASDAQ:LLY) donanemab providing more specificity than aducanumab, the battle is ongoing.

The disagreement over the justification of approval saw some members of the advisory committee resign because of the decision. However, the tremendous unmet need and the lack of any disease modifying therapies appears to be the driving factors behind the FDA’s decision. While the ultimate benefit to patients is uncertain, we do believe that allowing aducanumab on the market will improve the availability of capital for continued investment in Alzheimer’s Disease therapies.

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1. Source: Zacks Research System.

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