FDA Advisory Committee Supports Donanemab in Alzheimer’s Disease

In a unanimous vote, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee members voted Monday 11 yes and 0 no on the question of whether Lilly’s donanemab is effective in treating patients with early symptomatic Alzheimer’s disease. They also voted 11 yes and 0 no on whether the benefits outweigh the risks of treatment with donanemab.

Committee members said overall the benefit-risk ratio of donanemab is positive. “There is a huge unmet medical need that hopefully can be addressed,” Sarah Dolan, a consultant at Critical Path Institute in Tucson and acting consumer representative.

Committee members, however, also said more data are needed on donanemab to treat patients in underrepresented patient groups, including Latin American and African American patients and special populations including Down syndrome and autodominant Alzheimer’s disease patients.

Kathleen L. Poston, M.D.

“The clinical data across subgroups, as well as the biomarker data, were convincing of the effect,” Kathleen L. Poston, M.D., MS, Edward F. and Irene Thiele Pimley Professor in Neurology and Neurological Sciences and director, Stanford Movement Disorders Center Stanford University,” said after the vote. “I agree with the concerns about some groups of patients, particularly the African American and the Hispanic and that will be important in the future to obtain to make sure these findings can be extrapolated to everyone in Alzheimer’s disease.”

Thomas J. Montine, M.D., Ph.D.

Committee Chair Thomas J. Montine, M.D., Ph.D., chair, department of Pathology Stanford Medicine Endowed Professor Stanford University School of Medicine Stanford, California, said the consensus of the committee provider and community education will be important so that everyone is clear on benefit and risk.

Alzheimer’s disease is a progressive disease caused by toxic amyloid proteins, and is the most common type of dementia, according to the Centers for Disease Control and Prevention. In 2020, about 5.8 million Americans were living with Alzheimer’s disease, and this is number is projected to increase to 14 million by 2060.

Donanemab is a monoclonal antibody that targets the N3pG epitope present in brain amyloid plaques.

The FDA had asked the advisory committee to discuss the results of the phase 3 TRAILBLAZER-ALZ 2 trial, which evaluated the efficacy and safety of donanemab in early symptomatic Alzheimer's disease. The trial had a unique design, including a 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.

Regulators asked the committee to discuss the effectiveness of donanemab in the phase 3 trial, as well as the tau positron emission tomography (PET) subgroups. They were asked to vote on whether donanemab is effective for treating patients with mild cognitive impairment and mild dementia.

Donanemab is under regulatory review for full approval to treat patients with early Alzheimer’s disease. A decision had been expected by the end of 2023. The FDA had previously said it wouldn’t grant accelerated approval of donanemab to treat patients with early Alzheimer’s disease. In a complete response letter in January 2023, the agency indicated that there too few patients with at least 12 months of data provided in Lilly’s submission. Lilly had resubmitted the application in July 2023 for full approval.

Full results from the TRAILBLAZER-ALZ 2 trial show that donanemab slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease. Almost half of participants at earlier stage of disease on donanemab had no clinical progression at one year. Additionally, analyses of patients at earliest stage of the disease had even greater benefit, with 60% slowing of decline compared with placebo.

The data were shared at the 2023 Alzheimer’s Association International Conference and also published in the Journal of the American Medical Association.

The TRAILBLAZER-ALZ 2 enrolled 1,736 patients with a broad range of cognitive scores and amyloid levels. Patients were stratified by their level of tau, a predictive biomarker for disease progression. The trial used the Amyvid and Tauvid PET scans to enroll patients with confirmed amyloid plaques, allowing investigators to confirm clearance or reduction of the pathology in later scans.

Among all patients, treatment with donanemab reduced amyloid plaque on average by 84% at 18 months, compared with a 1% decrease for patients taking placebo.

Patients were able to stop taking donanemab once they achieved pre-defined criteria of amyloid plaque clearance. About half of patients met this threshold at 12 months and about seven of every 10 participants reached this threshold at 18 months.