Lilly's Donanemab Approved by FDA for Treatment of Early Symptomatic AD

The FDA has approved donanemab for the treatment of adults with early symptomatic Alzheimer disease (AD). The indication for the once-monthly infusion, marketed by Eli Lilly as Kisunla, includes individuals with mild cognitive impairment (MCI) as well as those with the mild dementia stage of AD, with confirmed amyloid pathology, according to a news release.¹

Donanemab is the third antiamyloid therapy to be approved by the FDA, but it is the first with evidence to support limited-duration treatment based on amyloid plaque removal, according to Lilly. Almost half of participants in the pivotal phase 3 TRAILBLAZER-ALZ-2 trial completed the course of donanemab treatment in 12 months. In that study, donanemab reduced plaques on average by 61% at 6 months, 81% at 12 months, and 84% at 18 months. Once plaques had reached minimal levels, as evidenced by amyloid PET scan, participants were switched to placebo for the balance of the trial.²

Donanemab is administered monthly as a 350 mg/20mL injection for infusion. The ability to stop therapy can lead to fewer infusions for individuals as well as lower costs for treatment.

Donanemab joins antiamyloid lecanemab (Leqembi; Eisai/Biogen), granted full FDA approval in July 2023, in the category that earlier this year saw the removal from the market of aducanumab (Aduhelm; Biogen).

"Kisunla demonstrated very meaningful results for people with early symptomatic Alzheimer's disease, who urgently need effective treatment options. We know these medicines have the greatest potential benefit when people are treated earlier in their disease, and we are working hard in partnership with others to improve detection and diagnosis," Anne White, executive vice president and president of Lilly Neuroscience, Eli Lilly, and Company, said in the press release. “Each year, more and more people are at risk for this disease, and we are determined to make life better for them."¹

Phase 3 TRAILBLAZER-ALZ-2

Donanemab's approval was supported by data from TRAILBLAZER-ALZ-2 (NCT04437511), a large-scale, phase 3, double-blind, placebo-controlled trial that enrolled 1736 participants with early-stage AD who were randomly assigned to receive donanemab (n = 860) or placebo (n = 876) every 4 weeks for up to 72 weeks. The study’s primary outcome was least-square mean (LSM) change in integrated Alzheimer Disease Rating Scale (iADRS) score, with lower scores indicating greater impairment. Participants were categorized as having low/medium tau pathology (68.1%; n = 1182) or high tau pathology (31.8%; n = 552). Of note, it excluded those with no/very low tau.²

Treatment with donanemab significantly slowed cognitive decline in both treatment groups. In the low/medium tau population, LSM change from baseline on 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, reflecting a 35.1% slowing of disease progression. The results were less pronounced in the overall population, with between-group score differences of 2.92 (95% CI, 1.51-4.33; P <.001), representing a 22.3% slowing of disease progression.²

Regarding safety, Lilly reported the incidence of amyloid-related imaging abnormalities was consistent with the previous TRAILBLAZER study, citing amyloid-related imaging abnormalities (ARIA) E, related to brain swelling in 24% of treated participants, with 6.1% experiencing symptoms. ARIA-H, associated with microhemorrhages, was observed in 31.4% of treated patients and 13.6% of those who got placebo.²

"This approval marks another step forward in evolving the standard of care for people living with Alzheimer's disease that will ultimately include an arsenal of novel treatments, providing much needed hope to the Alzheimer's community. As a physician, I am encouraged by the potential to stop treatment, which could reduce out-of-pocket costs and infusion burden for eligible patients," Howard Fillit, MD, co-founder, and chief science officer at the Alzheimer's Drug Discovery Foundation, said in the Lilly release. "Diagnosing and treating Alzheimer's sooner than we do today has the potential to meaningfully slow disease progression, giving patients invaluable time to maintain their independence for longer."¹

References
1. Lilly's Kisunla (donanemab-azbt) approved by the FDA for the treatment of early symptomatic Alzheimer's disease. News release. Lilly. July 2, 2024. Accessed July 2, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early
2. Sims 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