The U.S. Food and Drug Administration (FDA) has declined to grant accelerated approval for Eli Lilly's anti-amyloid Alzheimer's therapy donanemab, requesting additional safety data before moving forward with the regulatory process.
In its complete response letter (CRL), the FDA specifically requested data "from at least 100 patients who received a minimum of 12 months of continued treatment on donanemab." While Lilly's phase 2 TRAILBLAZER-ALZ trial included more than 100 participants, many discontinued treatment early after successfully clearing amyloid plaques from their brains—a key feature of the drug's unique trial design.
Safety Concerns and Regulatory Scrutiny
The FDA's decision highlights ongoing regulatory caution surrounding amyloid-targeting therapies, which are associated with amyloid-related imaging abnormalities (ARIAs)—potentially serious side effects that can include brain swelling and microhemorrhages. The agency has scheduled an advisory committee meeting to further evaluate donanemab's safety profile and efficacy, though no date has been set.
"It was unexpected to learn the FDA will convene an advisory committee at this stage in the review process, but we look forward to the opportunity to further present the Trailblazer-Alz 2 results and put donanemab's strong efficacy in the context of safety," said Anne White, President of Lilly Neuroscience.
The regulatory delay comes despite promising efficacy data. In the Phase 3 TRAILBLAZER-ALZ 2 study, donanemab demonstrated the ability to slow disease progression by approximately 4-7 months, with patients in earlier disease stages showing the strongest benefits.
Competitive Landscape in Alzheimer's Treatment
The setback puts Eli Lilly further behind its competitor Eisai, which partnered with Biogen to secure accelerated approval for their anti-amyloid therapy Leqembi (lecanemab) earlier this year. Leqembi demonstrated a 27% reduction in cognitive decline compared to placebo in its CLARITY-AD study.
If eventually approved, donanemab would become only the second disease-modifying Alzheimer's treatment with convincing clinical evidence to reach the market. However, the delay impacts Lilly's ability to begin reimbursement negotiations with the Centers for Medicare and Medicaid Services (CMS), potentially giving Eisai and Biogen a significant head start in market access.
Path Forward for Donanemab
Despite the regulatory setback, Eli Lilly remains optimistic about donanemab's future. The company plans to submit a traditional approval application based on the complete results from its phase 3 TRAILBLAZER-ALZ 2 study, with top-line data expected in the second quarter of this year.
"We are confident in donanemab's potential to offer very meaningful benefits to people with early symptomatic Alzheimer's disease," White emphasized.
Unique Trial Design Under Scrutiny
Donanemab's distinctive trial design has become both a potential advantage and a regulatory challenge. Unlike most Alzheimer's treatments that require continuous administration, Lilly's protocol allowed patients to stop receiving the drug once amyloid plaques were sufficiently cleared—a design that complicates safety assessments but could offer practical benefits if approved.
The FDA specifically noted interest in understanding "the efficacy implications of the unique trial design of the TRAILBLAZER-ALZ 2 study, including its limited-duration dosing regimen that allowed patients to complete treatment based on an assessment of amyloid plaque and the inclusion of participants based on tau levels."
Market Implications
According to analysts at GlobalData, achieving full approval will be crucial for unlocking the commercial potential of anti-amyloid therapies. However, market adoption is expected to be relatively slow regardless of timing, partly due to lingering concerns from the controversial approval of Aduhelm (aducanumab), Biogen's earlier Alzheimer's drug that faced significant criticism over its efficacy, safety, and pricing.
For patients and physicians, the FDA's decision means that when donanemab eventually reaches the market, more comprehensive safety and efficacy data will be available to inform treatment decisions—potentially a silver lining in this regulatory delay.
