Innovative Trial Design may have Cost Lilly’s Donanemab Accelerated Approval

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The FDA issued a complete response letter refusing accelerated approval for Eli Lilly’s Alzheimer’s disease candidate donanemab, the Indianapolis-based company announced Thursday night.

Lilly sought accelerated approval for the investigational antibody based on findings from the Phase II TRAILBLAZER-ALZ trial, which enrolled more than 100 participants but allowed patients to end treatment when amyloid plaques had been cleared past a certain pre-defined level. As a result of the study’s design, fewer than 100 patients were on donanemab for 12 continuous months.

In the letter, the regulator body requested data from at least 100 patients dosed continuously with donanemab for a minimum of 12 months. The FDA also said that unblinded controlled safety data from a Phase III confirmatory trial of donanemab will be needed.

Lilly took only a modest hit in the market as shares fell 3.2% after hours Thursday. 

In a statement issued Thursday, Howard Fillit, M.D., co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation, said, "This drug did what it was intended to do…” which is to remove amyloid plaques in the brain.

While the trial’s “innovative design” ultimately led to the lack of data that the FDA flagged in its response letter, Fillit noted it “is a mark of great progress in the Alzheimer’s field,” which could lead to more treatments.

Despite the setback, Lilly does not expect changes to its 2023 financial guidelines.

Donanemab is an investigational antibody designed to target N3pG, a particular modified form of beta-amyloid plaque. Last month, the drug aced all primary and secondary endpoints in the Phase III TRAILBLAZER-ALZ 4 trial, the first study to present active-comparator data in this indication.

Up against Biogen and Eisai’s Aduhelm (aducanumab), donanemab induced brain amyloid plaque clearance at 6 months in significantly more patients. Donanemab continued to outperform Aduhelm in the subset of patients with intermediate tau levels.

In its 2022 second quarter financial results, posted in August, Lilly announced the FDA had accepted donanemab’s accelerated approval application with Priority Review. Lilly is also running the TRAILBLAZER-ALZ 2 trial as the confirmatory study for donanemab.

In Thursday’s announcement, the company said that TRAILBLAZER-ALZ 2 will continue. Topline data from this study are expected in the coming months and will become part of donanemab’s application package for traditional approval.

“We anticipate this study will confirm the benefit and safety profile we observed in the TRAILBLAZER-ALZ Phase 2 study,” Anne White, executive vice president and president, Lilly Neuroscience, said, adding that full Phase III data will help patients and physicians make better treatment decisions.

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