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Lilly Investigational Alzheimer Agent Donanemab Phase 3 Findings Under FDA Review


The surprise request for review of the phase 3 TRAILBLAZER-ALZ-2 clinical trial findings will delay the original PDUFA timing beyond first quarter 2024.

Lilly Investigational Alzheimer Agent Donanemab Phase 3 Findings Under FDA Review image credit Lilly logo :©MichaelV/stock.adobe.com

Eli Lilly has announced today that the US Food and Drug Administration's (FDA) Peripheral and Central Nervous System Drugs Committee will convene for a meeting to deliberate over its antiamyloid therapy donanemab, and the supportive phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511).1 The date of the advisory meeting has yet to be set by the FDA, and, as a result, the timing of expected FDA action for the treatment will be delayed beyond the first quarter of 2024.1

Donanemab, a humanized IgG1 monoclonal antibody designed for the treatment of symptomatic Alzheimer disease (AD), looks to be the third approved antiamyloid therapy for the neurodegenerative disorder, following the conditional approval of aducanumab (Aduhelm; Biogen) in 2021, and lecanemab (Leqembi; Eisai) in 2023. In its announcement, Eli Lilly noted that the agency would like to review topics related to the safety and efficacy of the therapy, including the safety results in donanemab-treated patients and the efficacy implications of the unique trial design of TRAILBLAZER-ALZ 2.1

"We are confident in donanemab's potential to offer very meaningful benefits to people with early symptomatic Alzheimer's disease," Anna White, executive vice president at Eli Lilly, and president of Lilly Neuroscience, said in the announcement.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. We will work with the FDA and the stakeholders in the community to make that presentation and answer all questions."

"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."


TRAILBLAZER-ALZ-2, a multicenter trial, included 1736 patients aged 60-85 years who received donanemab (n = 860) or placebo (n = 876) administered intravenously every 4 weeks for up to 72 weeks. Spanning across 277 medical sites in 8 countries, the primary outcome of the study was least-squares mean (LSM) change in integrated Alzheimer Disease Rating Scale (iADRS) score, with lower scores indicating greater impairment. The trial was different than others, categorizing patients into either low/medium tau pathology (68.1%; n = 1182) or high tau pathology (31.8%; n = 552).2,3

The data, published in JAMA and presented in full at the 2023 Alzheimer’s Association International Conference, revealed a greater impact of donanemab on low/medium tau population than the overall cohort. In the low/medium tau population, LSM change from baseline in the iADRS score at 76 weeks was –6.02 (95% CI, ­–7.01 to –5.03) in the donanemab group and ­–9.27 (95% CI, –10.23 to ­–8.31) in the placebo group, otherwise a 35.1% (95% CI, 19.90-50.23) slowing of disease progression. In the overall population, investigators recorded between-group differences of 2.92 (95% CI, 1.51-4.33; <. 001), representing a 22.3% (95% CI, 11.38-33.15) slowing of disease progression.2,3

Complete response letter. In January 2023, the FDA issued a complete response letter to Eli Lilly for its submission of donanemab, stating that the company needs to provide data from at least 100 patients who received a minimum of 12 months of continuous treatment with donanemab.4 The phase 2 TRAILBLAZER-ALZ study (NCT03367403), which served as the basis for the biologics license application of donanemab, included more than 100 patients; however, it was designed so that patients would complete the treatment course once they reached a predefined level of amyloid plaque clearance. At the time, the FDA indicated that the data to meet the exposure expectation would likely need to include unblinded safety data from TRAILBLAZER-ALZ 2 (NCT04437511) upon completion.4

Safety data. In terms of safety, 24% of donanemab-treated patients in TRAILBLAZER-ALZ 2 experienced amyloid-related imaging abnormalities (ARIA-E), a complication often seen with antiamyloid therapies.3 Most of these events were largely mild to moderate radiographically (94%), and first ARIA-E events radiographically resolved in 98% of participants, with a mean resolution time of around 10 weeks. Notably, 6% of patients on active treatment experienced recurrent ARIA-E.3

Additional data from the study showed that at 76 weeks, brain amyloid plaque levels decreased by 88.0 centiloids (95% CI, –90.20 to –85.87) with donanemab treatment and increased by 0.2 centiloids (95% CI, –1.91 to 2.26) in the placebo group in the low/medium tau population. In this group, 80.1% (95% CI, 76.12-83.62) of donanemab-treated patients achieved amyloid clearance by week 76 whereas no patients on placebo achieved the same. In terms of plasma phosphorylated tau (p-tau)217, an exploratory outcome, investigators observed differences of –0.25 (95% CI, –0.28 to –0.22; P <. 001) tau standardized uptake value ratio (SUVR) in the low/medium tau population relative to placebo and –0.22 (95% CI, –0.24 to –0.20; P <. 001) in the combined population at 76 weeks.


1. US Food and Drug Administration to convene advisory committee meeting to discuss the TRAILBLAZER-ALZ 2 study of donanemab. News release. Eli Lilly. March 8, 2024. Accessed March 8, 2024. Eli Lilly. https://investor.lilly.com/news-releases/news-release-details/us-food-and-drug-administration-convene-advisory-committee
2. Mintun M, Solomon P, Sims JR, Salloway S. Donanemab in early symptomatic Alzheiemr’s disease: efficacy and safety in TRAILBLAZER-ALZ 2, a phase 3 randomized clinical trial.
3. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239
4. US Food and Drug Administration Issues Complete Response Letter for Acceleterated APproval of Donanemab. News release. Eli Lilly. January 19, 2022. Accessed March 8, 2024. prnewswire.com/news-releases/us-food-and-drug-administration-issues-complete-response-letter-for-accelerated-approval-of-donanemab-301726325.html

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