When I first heard the news that the FDA had approved Aduhelm – Biogen’s anti-amyloid β, disease modifying therapy for Alzheimer’s disease (AD) – I was excited. I had followed the review process closely and had anticipated a ”no” from the FDA. The clinical data was mixed: Biogen completed two Phase 3 studies, EMERGE and ENGAGE, and while the drug reduced amyloid levels in both studies, clinical benefit was only observed in one. Consistent with this, the FDA advisory panel voted almost unanimously against approval. Yet, against the expectations of most “informed” observers like me, the FDA ultimately gave Aduhulem the green light. News of the approval provided an unexpected sense of promise, so much so that I immediately notified my friend, who’s mother had AD, to share the news. To be completely honest, it was not that I was convinced that it would help her clinically, but rather that it would give them something they had desperately been seeking since her diagnosis – hope.
The FDA’s approval of Aduhelm in June last year represented the first approval of a novel therapy for the disease in almost twenty years and the very first therapy with potential to deliver benefit beyond symptom control. However, not all approvals are created equal and unfortunately in this case uncertainty still remains regarding Aduhelm’s clinical benefit. The FDA approved Aduhelm using an accelerated approval pathway, an expedited approval process for serious conditions with high unmet need that enables approval based on a drug’s effect on a surrogate endpoint that is “reasonably likely” to predict clinical benefit, with the requirement for a Phase 4 confirmatory trial. This approval pathway has had a tremendous impact in the field of oncology, where surrogate endpoints – i.e. a reduction in tumour growth/size – are more predictive of clinical outcomes. However, what was surprising about the use of this pathway for Aduhelm was that the surrogate endpoint – clearance of amyloid beta – has not been demonstrated to translate to clinical benefit and remains a hypothesis. A widely held hypothesis, that hundreds of millions of academic and pharma research dollars have been pursuing since the 1980s.
We are unlikely to ever know exactly what drove the FDA to approve Aduhelm, and while some inappropriate agency/sponsor dealings have been suggested, it is likely that the FDA were heavily influenced by patient advocacy groups who lobbied for patient access. Unfortunately, despite the FDA’s best intentions, it is unlikely that many patients will get access to the drug with the US Centres for Medicare and Medicaid Services deciding earlier this month to dramatically limit coverage. With Biogen’s Phase 4 ENVISION Aduhelm trial expected to commence in May , Biogen/Eisai’s amyloid beta antibody lecanemab reading out in spring and a regulatory filing expected for Lilly’s donanemab later this year, we won’t have to wait long for the next instalment of this saga. If I had my time again, would I reach out to my friend about Aduhelm? Probably not. It now seems that the likelihood of patients in Australia ever getting access to this drug is so low that telling her family about it would not give them hope but rather unnecessary confusion and frustration and at a time when they should be making the most of every moment that they have together.
Dr Katherine Jackman has a PhD and postdoctoral training in stroke research at world leading institutions including Weill Cornell Medicine, New York and the Florey Institute. As part of the Investment Team at Brandon Capital, Kath uses her domain expertise to assess CNS-focused technologies.