When Biogen and Eisai terminated aducanumab’s Phase III program in early Alzheimer’s disease (AD) for futility in March 2019, a mere two months after Roche discontinued crenezumab, we wondered if it was the end of the line for anti-beta amyloid (Aβ) treatment in symptomatic AD. Shortly after the announcement, we removed all late-phase anti-Aβ drugs from our syndicated patient-based market forecast1.
At the time, we thought primary prevention in presymptomatic patients might be the last, best hope for the class. And in the months since the surprise announcement in October 2019 about their intention to file aducanumab for FDA approval, following a reanalysis of a larger dataset of patients receiving the highest dose in the EMERGE trial, we have continued to model a launch for the class as an upside case.
As speculation brewed about aducanumab’s launch prospects, we conferred with thought leaders about their reaction to the data, their opinion of the drug’s clinical profile, and their expectations for approval. Though some KOLs understandably continue to question the data and analysis, we have observed a shift in attitude from intense disappointment and frustration in 2019, to guarded optimism and increasing confidence in 2020:
"The data are convincing in the sense that there is clear clinical effect of the drug. I don’t think it’s a false positive. You see, aducanumab is, biomarker-wise, the strongest thing possible. We haven’t seen anything as strong as aducanumab before."
—Neurologist, United States (March 2020)
“I think that we are less concerned about ARIA than we were in the past… Even though there might be some concern, especially in the ApoE4 patients with ARIA complications, I don't think it's a limiting factor.”
—Neurologist, United States (June 2020)
"I am expecting that the FDA will approve aducanumab."
—Neurologist, United States (June 2020)
So close, but so far
A few short months may separate us from the first FDA-approved disease modifier for the treatment of AD (the PDUFA date is March 7, 2021), a watershed moment in a disease that defines unmet need and has not seen a novel therapy introduced in 17 years.
Many observers describe aducanumab’s chances for approval as more or less a coin toss, and not without reason—the submission is highly complex and unprecedented. We assume the Advisory Committee’s (AdComm) questions will center on whether the drug’s efficacy was adequately proven and whether the benefits outweigh the risks. The debate will be robust. Disagreement between the FDA’s final actions and AdComm recommendations is uncommon, and when it has occurred, the Agency has tended to be more, not less, restrictive2. That said, divergence between the two bodies has been associated with a lower degree of consensus among AdComm members, and we could envision less consensus over aducanumab. Data show that in 20% of cases where an AdComm voted no, FDA approval was still granted; the approval percentage is 60% when the vote was split3.
At this point, we believe it is more likely than not that the totality of evidence across the ENGAGE, EMERGE, and PRIME trials will support an approval decision. The drug is clearly biologically active and there appears to be a legitimate potential for efficacy with sufficient exposure to the 10 mg/kg dose. While ARIA poses an obvious and important concern, it is likely manageable through appropriate monitoring. A long-term safety trial4 is already underway.
The Agency’s continuous engagement with Biogen about the data and filing, its willingness to evaluate the application without additional studies, the rapid acceptance of the BLA with priority review, and the FDA’s intention to “act early”5 on the application if possible, also support a glass-half-full view. Moreover, given the drug’s strong biomarker data, the seriousness of AD, and the high level of unmet need, accelerated (conditional) approval with a requirement for confirmatory efficacy studies remains an option.
Forecast and outlook
We’ll be releasing our refreshed 2019-2029 AD forecast in October 2020, and in it, we expect to reintroduce three late-phase anti-Aβ MAbs beginning in 2021: aducanumab, Eisai/Biogen’s BAN-2401, and Roche’s gantenerumab. Our upside case projected the class would exceed $10 billion in ex-manufacturer sales by 2028, driven by premium pricing, visibility, population size, and market demand, despite assumed modest uptake owing to multiple access barriers (e.g., cost, coverage, eligibility criteria, access to biomarker testing). In the absence of clear analogues, making assumptions for uptake (pace, magnitude), changes in diagnosis and drug-treatment rates, pricing, and which drugs will launch in what geographies remains challenging as we reopen our forecast; many scenarios are plausible.
Putting aside the commercial implications of these drugs, what is most important is the fact that the current and projected impact of AD on individuals and society is staggering. It is our sincere hope that when the first disease modifier—whatever drug that is—comes forth, it can deliver real outcomes for at least some of the millions of patients and their families worldwide who will struggle with this devastating disease.
1. Disease Landscape & Forecast: Alzheimer’s Disease (2019).
2. Zhang A, et al. Association Between Food and Drug Administration Advisory Committee Recommendations and Agency Actions, 2008-2015. Milbank Q. 2019 Sep;97(3):796-819.
3. Cortellis Regulatory Intelligence. Accessed on August 18, 2020.
4. gov. NCT04241068. Accessed on August 18, 2020.
5. Biogen, press release, August 7th, 2020. https://investors.biogen.com/news-releases/news-release-details/fda-accepts-biogens-aducanumab-biologics-license-application