FDA Questions Donanemab Efficacy for the Treatment of Alzheimer Disease


The FDA is convening a committee to discuss phase 3 data after the planned action date, which delays drug availability to patients.

The FDA may delay the approval of donanemab for the treatment of Alzheimer disease (AD) and is convening an advisory board to discuss findings from the phase 3 TRAILBLAZER-ALZ 2 study, which evaluated donanemab for safety and efficacy in patients with early symptomatic AD and confirmed AD neuropathology, according to a Lilly press release.1

“It was unexpected to learn the FDA will convene an advisory committee at this stage in the review process,” said Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience, in the press release.1

Physician examining brain scans, neurology images

Image credit: BillionPhotos.com | stock.adobe.com

AD is a cognitive disease that affects more than 6 million individuals in the US. Currently, there is no cure or treatment that restores associated memory loss or cognition.2 Donanembab is an immunoglobulin G1 monoclonal antibody that targets β-amyloid in brain amyloid plaque. Current study results show that it can be more supportive for early-stage disease, which resonates with the growing hypothesis that targeting AD earlier can provide the best outcomes.2

During TRAILBLAZER-ALZ 2, donanemab most significantly slowed the progression of AD in patients with early disease, although it did demonstrat benefits for all patients. More specifically, it was effective as part of a limited-duration treatment regimen; almost 50% of participants completed treatment within 6 months to 1 year.1

Early symptomatic AD is also known as mild cognitive impairment or mild dementia due to AD. It is characterized by the deposition of β-amyloid in the brain, which can cause an amyloid cascade of neurofibrillary tangles formed by tau proteins, along with other adversarial brain changes.2

Recently, investigators began to hypothesize that inhibiting this amyloid cascade can slow the progression of AD, although many amyloid-targeting therapy trials did not significantly slow disease progression. Donanemab is 1 of 3 agents that have been able to remove amyloid plaque, which may promote slower disease progression.2

The phase 3 TRAILBLAZER-ALZ 2 study set out to confirm results from the phase 2 TRAILBLAZER-ALZ study, which support donanemab as an effective treatment against pathological amyloid plaque. During the trial, donanemab significantly reduced the progression of AD in patients with low-to-medium tau, and it slowed clinical progression in patients with combined low-to-medium and high tau pathology.According to the results, 80% of patients with low-to-medium tau and 76% of patients with low-to-medium and high tau achieved amyloid clearance at 18 months.2

"We are confident in donanemab's potential to offer very meaningful benefits to people with early symptomatic AD,” White said in the press release.1

The most common adverse events associated with donanemab include infusion-related reactions, headache, and nausea. However, it has been associated with life-threatening amyloid related imaging abnormalities.1

“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,” White said in the press release.1


1. U.S. Food and Drug Administration to Convene Advisory Committee Meeting to Discuss the TRAILBLAZER-ALZ 2 Study of Donanemab. Lilly. News Release. March 8, 2024. Accessed on March 8, 2024. https://investor.lilly.com/news-releases/news-release-details/us-food-and-drug-administration-convene-advisory-committee

2. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239

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