Efficacy And Safety Of Donanemab, A Novel Amyloid-Targeting Therapy

Objective: To characterize the efficacy and safety associated with donanemab, a novel amyloid-targeting therapy (ATT).

Methods: TRAILBLAZER-ALZ (phase-2) and TRAILBLAZER-ALZ 2 (phase-3) were multicenter, randomized, double-blind, placebo-controlled, 18-month trials that assessed the safety and efficacy of donanemab in patients with early Alzheimer’s disease. The primary outcome in both studies was change from baseline on the Integrated Alzheimer’s Disease Rating Scale (iADRS). Secondary outcomes included change from baseline on CDR-SB, ADAS-Cog13, ADCS-iADL, and MMSE. Amyloid-related imaging abnormalities of edema/effusion (ARIA-E), amyloid-related imaging abnormalities of microhemorrhages and hemosiderin deposits (ARIA-H), and infusion-related reactions were adverse events of special interest.

Results: TRAILBLAZER-ALZ 2 demonstrated a slowing of clinical progression at 76-weeks and had a safety profile consistent with TRAILBLAZER-ALZ. In the low/medium-tau population in TRAILBLAZER-ALZ 2, change in iADRS score demonstrated a 35% slowing of disease progression, and change in CDR-SB demonstrated a 36% slowing. Participants with low/medium-tau who received donanemab experienced a 39% lower risk of progressing to the next disease stage versus placebo over 76w (CDR-Global score, Hazard Ratio=0.61; P < 0.001). Significant, positive results across all clinical endpoints were also observed in the combined (low/medium and high tau) population. Adverse events with donanemab in TRAILBLAZER-ALZ 2 included ARIA-E (24.0%, 6.1% symptomatic); ARIA-H (31.4%); and infusion-related reactions (8.7%).

Conclusions: TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2 trials demonstrated that donanemab significantly slowed cognitive and functional decline in amyloid-positive early symptomatic AD participants and lowered their risk of disease progression while adverse events were consistent with donanemab’s well-characterized safety profile and known class risks.