FDA advisory committee to review donanemab for early Alzheimer’s

Eli Lilly: Meeting 'unexpected;' ready to present TRAILBLAZER-ALZ 2 results

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by Andrea Lobo |

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A U.S. Food and Drug Administration (FDA) advisory committee is expected to meet to discuss data from a Phase 3 trial of the anti-amyloid therapy donanemab in people with early Alzheimer’s disease.

Developer Eli Lilly asked the FDA last year to approve donanemab, based on the Phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511) that showed it significantly slowed cognitive decline. A regulatory decision was expected by the end of 2023, but a date for the FDA’s Peripheral and Central Nervous System Drugs advisory committee to meet hasn’t been set yet, meaning a decision will be delayed beyond the first quarter of this year.

“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,” Anne White, executive vice president of Eli Lilly and Company, and president of Lilly Neuroscience, said in a company press release.

In Alzheimer’s disease, toxic protein clumps, particularly of amyloid-beta and tau, accumulate inside the brain’s nerve cells, or neurons. An antibody, donamemab is designed to clear amyloid plaques.

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Results of Phase 3 TRAILBLAZER-ALZ 2 study

TRAILBLAZER-ALZ 2 compared donanemab to a placebo in 1,736 participants, ages 60-85, with early symptomatic Alzheimer’s disease, including mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s. The participants had confirmed brain amyloid-beta clumps and were divided into having low, medium, or high tau levels.

In the group with low to medium tau, the treatment significantly slowed the rate of cognitive worsening by 35.1%, compared with the placebo, as measured by the Integrated Alzheimer’s Disease Rating Scale score.

Moreover, fewer patients progressed from MCI to mild dementia or from mild to moderate dementia. The benefits were more significant in those younger than 75 and those with MCI relative to those with early dementia.

The patients’ brain amyloid-beta levels were evaluated after six months and one year of treatment. This let about half the patients (52%) stop treatment early and be switched to the placebo, as their brain amyloid-beta levels were deemed negligible.

The most common side effects with donanemab were amyloid-related imaging abnormalities (ARIA), including brain swelling and brain bleeding. These events were serious in 1.6% of the patients and included hospitalization, supportive care, and/or corticosteroid use. Three participants died after serious ARIAs. The risk for developing ARIA was higher in those with APOE4, the strongest genetic risk factor of Alzheimer’s.

The trial’s full results were published last year.

“We are confident in donanemab’s potential to offer very meaningful benefits to people with early symptomatic Alzheimer’s disease,” White said. “We will work with the FDA and the stakeholders in the community to make that presentation and answer all questions.”