Eli Lilly and Company has announced that donanemab met all primary and secondary endpoints for the 6-month primary outcome analysis in the Phase 3 TRAILBLAZER-ALZ 4 study, providing the first active comparator data on amyloid plaque clearance in patients with early symptomatic Alzheimer's disease treated with amyloid-targeting therapies. These data comparing donanemab to Aduhelm® * (aducanumab-avwa) to assess superiority on amyloid plaque reduction were shared at the 15th Clinical Trials on Alzheimer's Disease (CTAD) conference. Donanemab is an investigational antibody that targets a modified form of beta amyloid plaque called N3pG.

Through the FDA's accelerated approval pathway, the FDA has recognized that the reduction of amyloid beta plaque is a biomarker reasonably likely to predict clinical benefit in the treatment of early Alzheimer's disease. In the co-primary outcomes, brain amyloid plaque clearance, defined as achieving brain amyloid plaque levels of <24.1 Centiloids, was achieved in 37.9% of donanemab-treated participants (25 of 66) compared with 1.6% of Aduhelm-treated patients (1 of 64) at 6 months; in the intermediate tau subpopulation, 38.5% of donanemab-treated participants (10 of 26) reached brain amyloid clearance compared with 3.8% of Aduhelm-treated participants (1 of 26) by 6 months. In a key secondary outcome, donanemab reduced brain amyloid levels vs.

baseline by 65.2% compared with 17.0% for Aduhelm at 6 months. In an exploratory outcome, donanemab, but not aducanumab-avwa, treatment significantly reduced plasma P-tau217 at 6 months compared to baseline. The safety profile of both treatments was consistent with their previously published studies.

ARIA was the most common treatment emergent adverse event in both groups. In the aducanumab-avwa group, the incidence of total ARIA was 26.1% with 4.3% being symptomatic. In the donanemab group, the incidence of total ARIA was 25.4% with 2.8% being symptomatic.

For both treatments, all symptomatic cases were related to ARIA-E. TRAILBLAZER-ALZ 4 is ongoing and will have 12-month and 18-month secondary analyses. The study is one of five studies that comprise the clinical program to evaluate the efficacy and safety of donanemab. In August, Lilly announced that the FDA accepted the donanemab application for review, with Priority Review designation, for Alzheimer's disease under the accelerated approval pathway.