▎Edited by the WuXi AppTec content team
Recently, Eli Lilly and Company announced that the U.S. FDA will hold a meeting of the Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) to discuss its Phase 3 clinical trial, TRAILBLAZER-ALZ 2. According to industry media BioSpace,The meeting will mainly focus on this trial.How the unique design affects efficacy, with a particular focus onTime-limited dosing regimens based on amyloid plaque assessment results, and the selection of study participants according to tau protein levels.Currently, the FDA has not yet determined the specific date for the donanemab advisory committee meeting.
TRAILBLAZER-ALZ 2 is a Phase 3, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of donanemab in patients aged 60-85 with early symptomatic Alzheimer's disease, who present with mild cognitive impairment or mild dementia and have confirmed neuropathological features of Alzheimer's disease.The trial was conducted in 8 countries, recruiting 1,736 participants, who were screened through cognitive assessments, amyloid plaque imaging, and PET tau staging.Compared with other similar trials targeting amyloid plaques, the participants in the TRAILBLAZER-ALZ 2 trial had more severe conditions.All subjects, regardless of tau levels, benefited from the treatment with donanemab, especially patients in the early stages of the disease.Donanemab also demonstrated clinical benefits with a time-limited treatment regimen, with nearly half of the participants completing treatment within 6 or 12 months.The main treatment-related risk of Donanemab is amyloid-related imaging abnormalities (ARIA), a potentially life-threatening adverse reaction. Other most frequently reported adverse reactions include infusion-related reactions, headache, and nausea.Howard Fillit, M.D., co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, told BioSpace in an interview that the FDA wants to be clear on the safety of donanemab. For antibody therapies targeting amyloid, the risk of ARIA or brain swelling is a primary concern. In his view,Donanemab shows no significant difference in safety compared to other anti-amyloid antibody therapies.Another focus of the FDA is the innovative design of the TRAILBLAZER-ALZ 2 trial,It has two major innovations: First, part of the patient recruitment criteria is based on the level of tau protein in the brain; Second, once it is confirmed that amyloid protein has been successfully cleared, patients are allowed to stop treatment.The trial'sThe innovative design requires the FDA to adopt a different perspective to evaluate the efficacy and safety outcomes of the trial.
In addition, TRAILBLAZER-ALZ 2 recruited patients with early symptomatic Alzheimer's disease based on cognitive assessments, amyloid plaque imaging, and a relatively new measurement method—tau staging. Notably, the tau staging method has never been used in previous Alzheimer's disease trials.
Dr. Fillit pointed out,This approach can monitor patients and verify the clearance of amyloid from the brain.He believes that this treatment plan may reduce side effects and alleviate the burden on patients., and look forward to discussing the role of PET scans in confirming amyloid clearance at this advisory committee meeting.At the same time, Dr. Dawn Brooks, the global development lead for donanemab at Eli Lilly and Company, expressed confidence in this design during an interview. She mentioned that the trial data shows,Even in patients who stopped taking the drug after completing 6 or 12 months of treatment, those in the donanemab treatment group still demonstrated significantly greater efficacy compared to patients receiving a placebo., which suggests that once amyloid plaques are cleared, the therapeutic effect may persist.Dr. Brooks pointed out that Eli Lilly and Company incorporated tau assessment into the clinical trial design to better understand the stages of disease progression. Based on the results of the TRAILBLAZER-ALZ 2 study, she stated, "There is every reason to believe that patients with no or very low levels of tau at baseline may experience better outcomes."
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References:
[1] U.S. Food and Drug Administration to Convene Advisory Committee Meeting to Discuss the TRAILBLAZER-ALZ 2 Study of Donanemab，Retrieved March 13, 2024, from https://investor.lilly.com/news-releases/news-release-details/us-food-and-drug-administration-convene-advisory-committee
[2] Unique Trial Design Expected to be Focus of Upcoming Donanemab Adcomm，Retrieved March 13, 2024, from https://www.biospace.com/article/unique-trial-design-expected-to-be-focus-of-upcoming-donanemab-adcomm/
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