The U.S. FDA has just approved Eli Lilly and Company's Kisunla (donanemab) for the treatment of adults with early symptoms of Alzheimer's disease (AD). These patients include those with mild cognitive impairment (MCI) and those in the early stages of mild dementia with confirmed amyloid pathology. According to the press release, the monthly Kisunla is the first amyloid plaque-targeted therapy with evidence to suggest that treatment can be stopped after amyloid plaque clearance, thereby reducing treatment costs and infusion frequency.
This approval is based on the results of the TRAILBLAZER-ALZ 2 trial. According to data presented by Eli Lilly at the 2023 Alzheimer's Association International Conference (AAIC), donanemab significantly slows cognitive and functional decline in patients with early symptoms of Alzheimer's disease, delaying disease progression. Subgroup analysis shows that participants in the earliest stages of the disease benefit most significantly, with a 60% reduction in cognitive and functional decline compared to placebo. Subgroup analysis also shows that patients under 75 years old benefit more from donanemab. Additionally, regardless of the patient's baseline pathological stage, donanemab treatment significantly reduces their amyloid plaque levels.
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▲ Changes in iADRS and CDR-SB from baseline to 76 weeks in trial patients (Image Source: Reference [3])
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▲ Brain amyloid, plasma phosphorylated tau (P-tau 217), and disease progression risk results in trial patients (Image Source: Reference [3])
At 18 months, in all participants, donanemab treatment resulted in an average 84% reduction in amyloid plaques, compared to only 1% in the placebo group. When patients reach the designated amyloid plaque clearance criteria, they can stop using donanemab. Approximately half of the participants reached this threshold at 12 months, while about 7 out of 10 participants could achieve this threshold at 18 months.
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▲ Summary of Safety Results (Image Source: Reference [2])
In terms of safety, the incidence of amyloid-related imaging abnormalities (ARIA) in this Phase 3 clinical trial is similar to previous clinical trials. ARIA is an adverse reaction associated with amyloid plaque-clearing antibody therapy, typically manifesting as temporary brain swelling (ARIA-E) or microhemorrhage (ARIA-H) in one or more regions of the brain, detectable by magnetic resonance imaging (MRI). Analysis showed that in the donanemab group and the placebo group, 205 patients (24.0%; 52 symptomatic cases) and 18 patients (2.1%; 0 symptomatic cases during the trial) experienced ARIA-E, respectively. Additionally, 3 cases in the donanemab group and 1 case in the placebo group were considered treatment-related deaths.
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Donanemab is a monoclonal antibody targeting beta-amyloid (Aβ), specifically binding to an Aβ subtype called N3pG. By targeting this subtype, donanemab can selectively bind to amyloid plaques in the brain, thereby promoting their clearance.
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▲ Global Clinical Progress Inventory of Active Aβ-Targeted Alzheimer's Disease Therapies as of December 2023
Note: This table was compiled by the WuXi AppTec content team based on publicly available information and is not exhaustive. Additional information is welcome.
Currently, there are 3 Aβ-targeted Alzheimer's disease therapies in active development globally, approved for marketing in the United States or Japan, all of which are monoclonal antibody therapies. The remaining investigational Alzheimer's disease therapies targeting the Aβ target are divided into three categories: monoclonal antibodies, preventive and/or therapeutic vaccines, and small molecule drugs. Among them, two monoclonal antibody therapies from Eli Lilly have progressed rapidly and have entered Phase 3 clinical trials.
Reference:
[1] Lilly's Kisunla™ (donanemab-azbt) Approved by the FDA for the Treatment of Early Symptomatic Alzheimer's Disease. Retrieved July 2, 2024 from https://www.prnewswire.com/news-releases/lillys-kisunla-donanemab-azbt-approved-by-the-fda-for-the-treatment-of-early-symptomatic-alzheimers-disease-302188299.html
[2] Results from Lilly's Landmark Phase 3 Trial of Donanemab Presented at Alzheimer's Association Conference and Published in JAMA. Retrieved July 17, 2023 from https://investor.lilly.com/news-releases/news-release-details/results-lillys-landmark-phase-3-trial-donanemab-presented
[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

The US FDA has approved Eli Lilly and Company's Kisunla (donanemab) for the treatment of early-stage Alzheimer's disease in adults. This therapy can significantly slow down cognitive and functional decline in patients, especially benefiting early-stage patients and those under 75 years old. The approval is based on the results of the TRAILBLAZER-ALZ 2 trial. Kisunla is the first amyloid-targeted therapy with evidence to support treatment cessation after amyloid plaque clearance, expected to reduce treatment costs and decrease infusion frequency

World's first! FDA approves Eli Lilly's Alzheimer's disease therapy