On 17 July 2023, at the Alzheimer’s Association International Conference (AAIC) in Amsterdam, Netherlands, Eli Lilly and Company (Lilly) presented the full results of its TRAILBLAZER-ALZ2 randomised clinical trial looking at whether the drug donanemab provides clinical benefit in early symptomatic Alzheimer’s disease (AD). TRAILBLAZER-ALZ 2 assessed the safety and efficacy of donanemab, a monoclonal antibody designed to clear brain amyloid plaques. Topline results were announced in a company press release earlier in the year (3 May), and the full trial results were shared at AAIC during a featured symposium and simultaneously published in the Journal of the American Medical Association (JAMA).
TRAILBLAZER-ALZ 2 was a global phase III placebo-controlled, double-blind, parallel-group and randomised study which enrolled 1,736 people with mild cognitive impairment due to AD or mild AD dementia, with confirmed accumulation of amyloid and tau proteins in the brain. Participants from Australia, Canada, Europe, Japan and US received either donanemab or a placebo, via a monthly intravenous infusion. Lilly previously announced that donanemab met the primary and all cognitive and functional secondary endpoints in the phase III study.
Topline results revealed that the study met its primary endpoint at 18 months (76 weeks). In participants with early symptomatic AD and amyloid and tau pathology, results showed that donanemab treatment significantly slowed clinical progression, using the global cognitive and functional scale, iADRS, which showed a 22% reduction in decline for all participants receiving donanemab compared to those receiving placebo. Lilly highlighted that the primary analysis population, 1,182 participants with intermediate levels of tau in the brain, had a 35% reduction in clinical decline on the iADRS scale. These individuals were at an earlier stage of disease progression, relative to the 552 participants with high levels of brain tau at baseline.
Additional data presented at AAIC reinforced that, regardless of baseline clinical or pathological stage of disease, treatment with donanemab resulted in cognitive and functional benefits relative to placebo:
1. A pre-specified subpopulation analysis of low-medium tau participants based on clinical stage showed greater benefit of donanemab in those at earlier stage of disease:
• In 214 participants with mild cognitive impairment, donanemab slowed decline by 60% on iADRS and 46% on CDR-SB. In comparison, for 534 participants with mild dementia due to AD, donanemab slowed decline by 30% on iADRS and 38% on CDR-SB, respectively.
2. Similarly, a post-hoc subgroup analysis of low-medium tau participants based on age showed greater benefit of donanemab in patients under the age of 75:
• In 542 participants under the age of 75, donanemab slowed decline by 48% on iADRS and 45% on CDR-SB.
• In 551 participants aged 75 or greater, donanemab slowed decline by 25% on iADRS and 29% on CDR-SB.
3. Results were similar across other subgroups, including participants who carried or did not carry an allele of the ApoE4 gene.
4. The overall treatment effect of donanemab continued to grow throughout the trial, with the largest differences versus placebo seen at 18 months.
Regarding the safety of the drug, the study found that amyloid-related imaging abnormalities (ARIA) were the most common side-effects of treatment. ARIA occur across the class of amyloid plaque-clearing antibody therapies and these findings were therefore consistent with other investigational therapies in the same class. The incidence of ARIA and infusion-related reactions was also consistent with the previous TRAILBLAZER-ALZ study. ARIA, which are detected using MRI scans, are most commonly observed as swelling in an area or areas of the brain (ARIA-E) or as brain microbleeds (ARIA-H). While many cases of ARIA are temporary or asymptomatic, ARIA can be serious and even fatal in some cases. In the donanemab treatment group, brain swelling (ARIA-E) occurred in 24% of TRAILBLAZER-ALZ 2 participants. Brain microbleeds (ARIA-H) occurred in 31.4% of participants receiving donanemab, compared to 13.6% of participants on placebo. The majority of ARIA cases were mild to moderate, with 1.6% of participants experiencing serious ARIA.
The company noted that this risk should be managed with careful observation, monitoring with MRIs, and appropriate actions if ARIA is detected. Lilly has completed the US Food and Drug Administration (FDA) regulatory submission of donanemab and expects a decision by the end of 2023. Submissions to other global regulators are currently underway, with the company hoping to complete the majority of these by year end.
Alzheimer Europe welcomes the encouraging data presented at AAIC, where Executive Director Jean Georges was in attendance at the Lilly symposium, alongside Project Officer Cindy Birck. Read the study in JAMA, here: https://jamanetwork.com/journals/jama/fullarticle/2807533
Read the Lilly press release, here: https://investor.lilly.com/news-releases/news-release-details/results-lillys-landmark-phase-3-trial-donanemab-presented