Accelerated Approval Denied for Alzheimer’s Therapy Donanemab

The U.S. Food and Drug Administration (FDA) has rejected Eli Lilly’s application for the accelerated approval of its amyloid-clearing antibody donanemab for treating Alzheimer’s disease.

An accelerated approval lets the FDA grant conditional marketing authorization for a treatment based on preliminary safety and efficacy data, but additional clinical testing is required before a traditional approval is granted.

Eli Lilly provided safety and efficacy data from the Phase 2 TRAILBLAZER-ALZ trial (NCT03367403) to support its application. However, the FDA said it expected data from at least 100 patients who received donanemab for at a least a year and cited the failure to meet that as the reason for the rejection.

The ongoing Phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511) is expected to provide the data Eli Lilly needs to apply through the traditional approval pathway, after top-line data become available in the coming months.

The news closely follows the FDA’s recent approval of Leqembi (lecanemab) — an anti-amyloid therapy developed by Eisai and Biogen — under the accelerated approval pathway.

“We look forward to our upcoming confirmatory TRAILBLAZER-ALZ 2 Phase 3 results and subsequent FDA submission, which we’ve always seen as the most impactful next steps for patients,” said Anne White, executive vice president and president of Lilly Neuroscience at Eli and Lilly Company, in a press release. “We are committed to working with the FDA to ensure the fastest possible path to bring this potential medicine to patients in need.”

Donamemab is an antibody designed to recognize a toxic form of the beta-amyloid protein that tends to form clumps, or plaques, in the brains of Alzheimer’s patients. In doing so, it marks the protein for clearance by the immune system, which is expected to slow Alzheimer’s progression.

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Donanemab’s effect on amyloid plaques

TRAILBLAZER-ALZ enrolled 257 adults, ages 60–85, with early symptomatic Alzheimer’s disease. Participants were randomly assigned into-the-vein donanemab (131 people), or a placebo (126 people) every four weeks for up to 76 weeks, or about 1.5 years.

The trial was designed to enable donanemab-treated patients who fell below a pre-specified threshold of amyloid plaques to switch to a placebo.

The study’s main goal was to assess changes in the integrated Alzheimer’s Disease Rating Scale (iADRS), a combined measure of cognitive and daily life abilities. A drop in iADRS score reflects cognitive decline.

Results showed donanemab-treated patients exhibited a 6.86-point drop in iADRS scores over 76 weeks, a significantly slower cognitive decline than in the placebo group, where iADRS scores dropped 10.06 points.

A significant reduction in amyloid plaques was seen with donanemab compared with placebo. The percentage of amyloid-negative patients rose from 40% after six months of treatment to 67.8% by the trial’s end in the donanemab group. No significant change was seen in the placebo group.

More than half of the donanemab-treated patients (54.7%) saw amyloid drops great enough to allow them to switch to placebo by week 56.

These reductions formed the basis of Eli Lilly’s application for accelerated approval, but because so many patients were able to stop treatment early, fewer than 100 received donanemab for at least a year.

“This drug did what it was intended to do — remove amyloid plaques in the brain — and because of the trial’s innovative design, treatment was halted for patients once the biomarker PET scans confirmed the plaques were gone,” said Howard Fillit, MD, co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation (AADF), in an AADF statement about the decision. “The ADDF applauds the design of the TRAILBLAZER-ALZ trial, which is a mark of great progress in the Alzheimer’s field, promising more treatments to come. We look forward to reviewing the phase 3 data later this year.”

The Alzheimer’s Association echoed that sentiment in a separate statement, noting the FDA’s decision “demonstrates the rigorous approach the agency takes in reviewing individual treatments.”

“On behalf of our constituents, we look forward to the Phase 3 trial top-line data readout expected later this year,” the Association stated.

TRAILBLAZER-ALZ 2 aimed to enroll up to 1,800 people with early Alzheimer’s at hundreds of sites worldwide. Participants were randomly assigned to received donanemab or a placebo for up to 76 weeks.

Its main goal is to assess changes in iADRS, with secondary goals including other measures of cognitive function, amyloid deposition in the brain, and safety.

“We anticipate this study will confirm the benefit and safety profile we observed in the TRAILBLAZER-ALZ Phase 2 study and believe that patients and physicians will be well served by having the full Phase 3 data available alongside our Phase 2 data when they need to make treatment decisions,” White said.

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