Ever since the controversial approval of Biogen and Eisai's Aduhelm, debate has swirled around the strength of the link between amyloid reduction and the cognitive benefits of potential Alzheimer's disease treatments. The FDA appears to have stepped back into this arena as part of fresh updates to its guidance on these drugs.
The agency isn’t going as far as to say that amyloid reduction can be considered a primary endpoint in Alzheimer’s trials, but the regulator is suggesting that the biomarker can serve as a surrogate endpoint for predicting clinical benefit, according to the draft guidelines released (PDF) March 11. Stakeholders can submit comments to the FDA regarding the new guidelines by June 10.
The guidance, titled “Early Alzheimer’s Disease: Developing Drugs for Treatment,” was originally published in 2013 and last updated back in 2018. The document is intended to help trial sponsors involved in the clinical development of drugs to treat the stages of sporadic Alzheimer’s occurring before the onset of overt dementia.
The advisory document didn’t specifically address amyloid reduction, a technique designed to get rid of beta amyloid plaques that build up in the brain and cause the neurodegenerative disorder.
Now, after the approval of Eisai and Biogen’s Leqembi, an antibody designed to take out amyloid beta aggregates, the FDA is zooming in on amyloids. The agency’s most recent draft considers “reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a surrogate endpoint that is ‘reasonably likely to predict clinical benefit’” in certain circumstances.
A surrogate endpoint assesses treatment effect using a measure that could correlate with a clinical endpoint but doesn’t 100% guarantee a relationship. Instead, a surrogate endpoint is “reasonably likely to predict clinical benefit,” according to the FDA.
Typically, Alzheimer’s studies use both cognitive and functional measures as co-primary endpoints, an approach the FDA still deems “generally acceptable.” Using that approach, the average duration of a clinical trial in the symptomatic stages of the condition is two years or less.
However, the FDA has acknowledged that it may take longer to establish clinically meaningful treatment effect among patients with early Alzheimer’s due to the very limited (if any) cognitive and functional deficits seen at those stages of disease. Additionally, many tools often used to measure functional impairment in patients with later stages of Alzheimer’s may not be able to identify subtle changes in early-stage disease, the agency explained.
Given these two factors, the FDA is considering other approaches, including endpoints based on cognitive assessments or surrogate endpoints, which may allow for shorter trial durations in the earliest stages of disease.
Direct measures of clinical benefit or validated surrogate endpoints may support a traditional approval, according to the FDA, while surrogate endpoints or intermediate clinical endpoints that don’t directly measure clinical benefit but are considered reasonably likely to predict clinical benefit may support the case for accelerated approval.
The draft guidance was released just days after the agency threw a wrench in Eli Lilly’s Alzheimer's plans, delaying an approval decision for donanemab by calling for an advisory committee meeting to discuss the phase 3 results underpinning the monoclonal antibody’s application.
The agency specifically wants to cover issues related to the safety of the med and efficacy implications of the trial’s unique design. According to Lilly, the FDA has questions about the limited-duration dosing regimen that lets patients stop treatment once they reach a certain lowering of amyloid plaque as well as inclusion of participants based on tau levels.