Aims and Hypothesis: TRAILBLAZER-ALZ 6 (NCT05738486) assessed the effect of donanemab dosing regimens on amyloid-related imaging abnormalities edema (ARIA-E) and amyloid reduction.
Background: Donanemab is a monoclonal antibody specific for an insoluble form of amyloid beta present only in brain amyloid plaques. Donanemab has been approved by the FDA as a treatment to slow the progression of Alzheimer’s disease (AD). ARIA have been observed with amyloid-targeting therapies, including donanemab.
Methods: In a double-blind phase 3b study, adults with early symptomatic AD (n=843) were stratified by APOE genotype and baseline amyloid level and randomized in a 1:1:1:1 ratio into four arms (standard and three alternative dosing regimens). ARIA-E risk by week (W) 24 was evaluated by Bayesian logistic regression. Amyloid positron emission tomography (PET) and plasma P-tau217 levels were also assessed.
Results: By the W24 primary endpoint, ARIA-E frequency was numerically lower in all alternative dosing arms. The modified titration arm showed the lowest ARIA-E (13.7% compared to 23.7% in the standard dosing arm), achieving a 41% relative risk reduction. Radiographic severity of ARIA-E was also significantly reduced. Symptomatic ARIA-E was lower in the modified titration arm, with 2.8% symptomatic compared to 4.8% in the standard arm. Comparable amyloid reduction was observed between the standard and modified titration with mean changes of 58.8 and 56.3 Centiloids, respectively. Plasma P-tau217 reductions were similar in both dosing arms.
Conclusions: The modified titration approach significantly reduces ARIA-E frequency and severity while maintaining amyloid reduction. Updated results may follow.