Despite being delayed twice, the approval chances for Eli Lilly’s anti-amyloid therapy donanemab have significantly improved after a US Food and Drug Administration (FDA) Advisory Committee (AdCom) panel unanimously voted in favour of approving it as a potential treatment for Alzheimer’s disease.

Donanemab is a monoclonal antibody (mAb) treatment designed to ablate amyloid plaques that aggregate in patients with Alzheimer’s disease. The therapy was evaluated in the Phase III TRAILBLAZER-ALZ 2 (NCT04437511) study, which demonstrated that donanemab slowed disease progression in patients with high levels of tau, a protein that accumulates as neurofibrillary tangles as the disease advances.

The FDA is not mandated to follow the AdCom’s verdict but has historically done so. One major exception was in the case of Biogen’s Alzheimer’s disease drug Aduhelm (aducanumab), which was not supported by a similar AdCom, but was later granted an accelerated approval. However, earlier this year, Biogen cut ties with Aduhelm after reprioritising resources.  

Though an approval decision for donanemab was initially expected in late 2023, the FDA first extended the timeline to Q1 2024 and eventually decided to convene an AdCom panel after the agency raised questions on the pivotal study’s trial design as well as the safety and efficacy data within the enrolled population.

If approved, donanemab will join Eisai and Biogen’s marketed therapy, Leqembi (lecanemab), which shares a target for modifying disease pathology.

All members of the committee voted yes for the two questions asked at the end of the meeting; on whether the the drug was an effective treatment for the enrolled population, and if the benefits of the therapy outweighed the risks.

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Chief among the topics of discussion at the committee hearing were the lack of diversity in the enrolled population and the inadequate characterisation of safety and efficacy data within a subset of patients with homozygous apolipoprotein E4 (ApoE4), a major genetic driver of Alzheimer’s.

While the available data show that donanemab is effective and indicative of a positive benefit-risk ratio in enrolled patients who are heterozygous for ApoE4 and ApoE4 negative, there is insufficient data for patients who are homozygous for the ApoE4 allele, the panellists agreed.

“There wasn’t a statistically significant clinical benefit for the ApoE4 homozygote individuals who also appear to be at the highest risk for the side effects,” said panellist Dr. Nilüfer Ertekin-Taner, professor of Neuroscience and Neurology at Mayo Clinic in Jacksonville, Florida.

AdCom member Dr. Kathleen Poston, professor in Neurology and Neurological Sciences at Stanford University also noted the heterogeneous patient experience, emphasising the younger age of onset and more “ominous” progression of dementia within the homozygous ApoE4 population. “The risk in the small [homozygote] group that was included in the study was higher, particularly for both amyloid-related imaging abnormalities (ARIA) H and ARIA E,” explained Poston.

The committee also commented on the lack of data for underrepresented groups such as the African American and Hispanic patients as well as genetically predisposed patients with underlying Down Syndrome and autosomal dominance—which is important to ensure the entire diverse Alzheimer’s patient population will be served.

The panel also raised concerns about extrapolating the overall trial results for patients with no or low tau levels. However, the majority of the committee members agreed that imposing requirements for tau imaging would be impractical and lead to “serious” accessibility concerns for the treatment.