Lilly's donanemab wins unanimous FDA support

An FDA advisory committee has expressed strong confidence in the overall benefit of donanemab, Eli Lilly’s treatment for Alzheimer’s disease, deeming it to outweigh the risks. This confidence was reinforced during a recent meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, which praised the drug for its innovative approach but also highlighted gaps in data for certain subgroups.

The committee addressed two critical questions: whether the available data shows donanemab’s effectiveness in treating Alzheimer’s among trial participants with mild cognitive impairment and mild dementia, and whether the benefits of the treatment outweigh its risks for the same group. Unanimously, the committee voted 11-0 in favor of donanemab on both counts, supporting its approval. Although the FDA is not obligated to follow the committee’s recommendations, it generally does.

Mark Mintun, M.D., Lilly's group vice president of neuroscience research and development, expressed satisfaction with the committee’s unanimous recognition of donanemab’s positive benefit-risk profile. The drug was tested in a phase 3 trial named TRAILBLAZER-ALZ 2, involving 1,736 patients, which assessed changes in baseline using the integrated Alzheimer’s Disease Rating Scale (iADRS) over 76 weeks. This scale helps detect disease progression and treatment efficacy.

The committee also discussed the relevance of tau PET imaging in supporting donanemab’s efficacy. Lilly used this imaging type to identify patients likely to progress during the study. However, the FDA questioned the exclusion of patients with low-to-no tau, who were not specifically studied. Despite this, the committee concurred that tau imaging should not be mandatory, citing practical and accessibility concerns.

Another noteworthy aspect of the discussion was Lilly’s trial design, which ceased dosing once amyloid clearance was achieved. The committee found this approach innovative but anticipated challenges in its clinical implementation. Clinicians may find it difficult to decide when to perform follow-up PET scans to determine the need for dosing continuation. Longer-term follow-up in Lilly’s ongoing studies could provide clearer guidance for physicians.

The committee acknowledged the significant risk associated with donanemab, particularly amyloid-related imaging abnormalities (ARIA), which can indicate brain bleeds or swelling. There have been deaths linked to ARIA, including three in the donanemab trial. The lack of data for various subgroups, especially patients with the ApoE ε4 genetic variant who are at higher risk for side effects, was a major concern. Approved drugs in this class already carry warnings to test for ApoE ε4 status.

Dr. Nilüfer Ertekin-Taner from the Mayo Clinic suggested that the benefit-risk ratio is less favorable for ApoE ε4 carriers, recommending that this be reflected on the drug's label. Patient advocate Colette Johnston argued that for Alzheimer’s patients, who face a debilitating disease, the potential benefits of donanemab outweigh the risks. Dr. Daniel Press from Beth Israel Deaconess Medical Center added that patients should have the option to choose the therapy despite its risks, as long as they are fully informed.

Heartfelt testimonies from patients and caregivers underscored the urgency of making donanemab accessible. Maria Gates, whose husband has seen improvements while participating in the TRAILBLAZER-ALZ studies, highlighted the personal impact of the drug.

While the committee urged Lilly to continue gathering data on underrepresented populations, it agreed that donanemab should be made available to patients without delay. Dr. Costantino Iadecola from Weill Cornell Medicine emphasized the importance of extending access even if some subgroup data is lacking. The committee also called for more research involving diverse patient groups, including those with Down syndrome and African Americans.

In summary, the FDA advisory committee's support for donanemab signals a significant step forward in Alzheimer’s treatment, balancing innovative approaches with cautious optimism about the drug's risks and benefits.