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Approval of Eli Lilly's Alzheimer Drug Donanemab Delayed as FDA Seeks More Information


Because of the unique trial design of the Phase III TRAILBLAZER-ALZ 2 study, the FDA is seeking additional input regarding the safety and efficacy of donanemab for the treatment of early symptomatic Alzheimer disease.

Image credit: Sebastian Kaulitzki | stock.adobe.com

Image credit: Sebastian Kaulitzki | stock.adobe.com

The FDA will convene a meeting of the Peripheral and Central Nervous System Drugs Advisory Committee to address findings from the Phase III TRAILBLAZER-ALZ 2 trial of Eli Lilly’s novel therapy donanemab for the treatment of early symptomatic Alzheimer disease.1

Eli Lilly stated that the FDA is seeking additional information regarding the safety and efficacy of the drug because of the unique trial design of TRAILBLAZER-ALZ 2. Among the issues the manufacturer was asked to address include the trial’s limited-duration dosing regimen, in which patients were included in the trial based on tau levels and could complete treatment based on an evaluation of amyloid plaque.1

"We are confident in donanemab's potential to offer very meaningful benefits to people with early symptomatic Alzheimer's disease,” Anne White, executive vice president of Eli Lilly and Company, and president of Lilly Neuroscience, said in a press release. “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.”1

Donanemab is an immunoglobulin G1 monoclonal antibody that targets a modified form of beta amyloid plaque called N3pG. The FDA granted the drug with Breakthrough Therapy designation in June 2021 based on Phase II TRAILBLAZER-ALZ trial data. Findings from the study suggested a relationship between reduced amyloid plaque in the brain and slowed cognitive decline among patients with Alzheimer disease who were administered donanemab.2

The primary outcome of clinical trials analyzing donanemab was change from baseline in the Integrated Alzheimer’s Disease Rating Scale (iADRS) score at 76 weeks, which ranges from 0 to 144, with lower scores indicative of greater cognitive and functional impairment.3,4

Donanemab was found to produce a clinically meaningful benefit at >20% in slowing of clinical progression on the iADRS and Clinical Dementia Rating Sum of Boxes (CDR-SB) scales. An estimated 47% of patients administered donanemab showed no evidence of disease progression in the CDR-SB at one year compared with 29% of participants administered placebo.

The double-blind, placebo-controlled Phase III TRAILBLAZER-ALZ 2 trial analyzed the safety and efficacy of donanemab in patients aged 60-85 years with early symptomatic Alzheimer disease with the presence of confirmed disease neuropathology. Investigators enrolled 1,736 patients across eight countries who were selected based on cognitive assessments in conjunction with amyloid plaque imaging and tau staging by positron emission tomography imaging. As opposed to similar trials analyzing other amyloid plaque-targeting therapies, Lilly stated that TRAILBLAZER-ALZ 2 participants had more progressed diseases at the time of enrollment.

The least-squares mean change in the iADRS score at 76 weeks was −6.02 in the donanemab cohort compared with −9.27 in the placebo cohort for the low/medium tau population and −10.19 in the donanemab cohort vs. −13.11 in the placebo cohort in the combined study population, both of which represented significant differences, according to the investigators.4

In terms of safety, amyloid-related imaging abnormalities (ARIA) of edema or effusion were observed in 205 participants (24.0%; 52 symptomatic) in the donanemab cohort compared with 18 participants (2.1%; 0 symptomatic during study) in the placebo cohort. Infusion-related reactions were reported by 74 participants in the donanemab cohort compared with four participants in the placebo group. There were three treatment-related deaths in the donanemab cohort and one in the placebo cohort.4

“All groups of trial participants, regardless of tau level, benefited from treatment with donanemab, with patients in earlier stages of the disease experiencing the strongest results,” Lilly stated in the release. “Donanemab also demonstrated clinical benefits using a limited-duration treatment regimen, with nearly half of clinical trial participants completing their course of treatment in six or 12 months. The key risk associated with donanemab is (ARIA), which can be serious and life-threatening. Other most commonly reported risks include infusion-related reactions, headache and nausea.”1

The FDA has yet to set a date for the advisory committee meeting and as such, the timing of the Prescription Drug User Fee Act date on donanemab will be delayed past the first quarter of 2024, according to Eli Lilly. The company added that the delay will not cause a change to its 2024 financial guidance.


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

2. Lilly releases donanemab data that demonstrated relationship between reduction of amyloid plaque and slowing of cognitive decline. News release. Eli Lilly and Co; July 29, 2021. Accessed March 8, 2024. http://lilly.mediaroom.com/2021-07-29-Lilly-releases-donanemab-data-that-demonstrated-relationship-between-reduction-of-amyloid-plaque-and-slowing-of-cognitive-decline

3. Mintun, Mark A., et al. “Donanemab in Early Alzheimer’s Disease.” New England Journal of Medicine, vol. 384, no. 18, 13 Mar. 2021, https://doi.org/10.1056/nejmoa2100708.

4. Sims, John R., et al. “Donanemab in Early Symptomatic Alzheimer Disease: The 4. Sims 4. JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512–527. doi:10.1001/jama.2023.13239

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