The FDA Advisory Committee’s Endorsement of Donanemab for Early Alzheimer’s Disease

The FDA advisory committee unanimously supported the investigational drug donanemab for treating early Alzheimer’s disease in a recent 11-0 vote. The committee highlighted that the benefits of donanemab outweighed its risks for Alzheimer’s disease patients with mild cognitive impairment and mild dementia who were enrolled in clinical trials involving the drug.

In addition to the unanimous vote in support of donanemab, the committee also voted 11-0 that available data showed that donanemab was effective in treating Alzheimer’s disease in the target population. Despite some initial concerns raised by FDA staffers about the exclusion of Alzheimer’s patients with low tau levels in the pivotal donanemab trial, the committee agreed that the drug should not be restricted based on tau burden.

During the meeting, committee members voiced concerns about the lack of data on donanemab and other anti-amyloid drugs in African-American and Hispanic populations. It was emphasized that future studies should address this gap to ensure that the benefits observed in clinical trials can be generalized to a broader population of Alzheimer’s disease patients.

While the risks associated with donanemab, particularly amyloid-related imaging abnormalities (ARIA), were acknowledged, FDA advisors suggested that these risks could be mitigated with proper safeguards. Suggestions were made for implementing an MRI program and providing training to safely manage the risks associated with donanemab treatment.

Neurologist Marwan Sabbagh, MD, shared the sentiments of many Alzheimer’s patients during the public hearing, emphasizing the significant deterioration and loss of autonomy experienced by individuals with the disease. Despite the risks associated with donanemab treatment, the potential benefits were seen as outweighing these risks in the context of Alzheimer’s disease progression.

Donanemab was evaluated in the phase III TRAILBLAZER-ALZ 2 trial involving 1,736 early Alzheimer’s patients. The drug demonstrated positive outcomes, meeting the trial’s primary endpoint of slowing decline on the Integrated Alzheimer’s Disease Rating Scale (iADRS) compared to a placebo. Additionally, donanemab showed less decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 76 weeks as a key secondary endpoint.

Similar to other anti-amyloid drugs, the safety profile of donanemab was centered around ARIA, with specific considerations for ARIA with edema or effusion (ARIA-E) and ARIA with microhemorrhages and hemosiderin deposits (ARIA-H). The occurrence of ARIA was noted to be more frequent in APOE4 homozygotes compared to heterozygotes or noncarriers.

If approved, donanemab will become the third amyloid-targeted drug to enter the market, following aducanumab (Aduhelm) and lecanemab (Leqembi). The regulatory decision on donanemab by the FDA is pending, and no official date has been announced for the final decision regarding the drug’s approval.

The FDA advisory committee’s endorsement of donanemab for early Alzheimer’s disease represents a significant milestone in the treatment landscape for this condition. The unanimous support and positive data from clinical trials underscore the potential of donanemab to address the unmet needs of Alzheimer’s patients with mild cognitive impairment and mild dementia. While concerns about safety and inclusivity remain, ongoing research and regulatory considerations will play a crucial role in shaping the future of Alzheimer’s disease treatment.