Positive results were announced from the TRAILBLAZER-ALZ 2 (NCT04437511) phase 3 study showing that donanemab (Eli Lilly and Company, Indianapolis, IN) significantly slowed cognitive and functional decline in people with early symptomatic Alzheimer disease (AD). Donanemab met the primary endpoint of change from baseline until 18 months on the integrated Alzheimer's Disease Rating Scale (iADRS). The primary endpoint of iADRS measures cognition and activities of daily living such as managing finances, driving, engaging in hobbies, and conversing about current events. All secondary endpoints of cognitive and functional decline also were met and showed highly statistically significant clinical benefits with similar magnitude. Based on these results, Lilly will proceed with global regulatory submissions as quickly as possible and anticipates making a submission to the Food and Drug Administration (FDA) in Q2 2023. Lilly will work with the FDA and other global regulators to achieve the fastest path to traditional approvals.
TRAILBLAZER-ALZ 2, a randomized, double-blind, placebo-controlled study, evaluated the safety and efficacy of donanemab, an investigational amyloid plaque targeting therapy. The study enrolled people with early symptomatic AD, which includes mild cognitive impairment (MCI) and the mild dementia stage of disease, with the confirmed presence of AD neuropathology Participants completed their course of treatment with donanemab once they reached a prespecified level of amyloid plaque clearance.
Participants in TRAILBLAZER-ALZ 2 were stratified by their level of the brain protein tau, a predictive biomarker for AD progression. The primary analysis population (n=1182) for which the study was powered was comprised of people with an intermediate level of tau and clinical symptoms of AD. In this population, the primary endpoint (iADRS) showed 35% slowing of decline (P<.0001), and an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36% slowing of decline (P<.0001) over 18 months. Additional prespecified secondary analyses showed:
The study also enrolled a smaller number of people with high levels of tau at baseline (n=552), representing a later stage of disease progression. Because these participants were predicted to progress more quickly and be less responsive to therapy, the target population for the study was the intermediate tau population. The high tau participants were combined with the intermediate tau population in an additional primary analysis of all participants enrolled (n=1736). In this combined population, donanemab also demonstrated meaningful positive results across all clinical endpoints (P<.001), with CDR-SB and iADRS showing 29% and 22% slowing of decline, respectively.
In addition to slowing cognitive and functional decline in TRAILBLAZER-ALZ 2, donanemab produced significant reductions in brain amyloid plaque levels as early as 6 months after initiating treatment, as observed using amyloid PET brain scan, with many patients reaching amyloid levels considered negative for pathology (34% of participants in the intermediate tau population achieved amyloid clearance at 6 months and 71% achieved clearance at 12 months).
Dr. Eric Reiman, CEO of Banner Research, one of the research sites for the TRAILBLAZER-ALZ 2 trial, commented: "This study's topline results provide compelling support for the relationship between amyloid plaque removal and a clinical benefit in people with this disease."