Donanemab for early symptomatic AD in the UK-indicated population: safety and efficacy in those who are non-carriers or heterozygous for APOE ε4

Background Licensing of donanemab in the United Kingdom (UK) for the treatment of early symptomatic Alzheimer’s disease is limited to adults who are Apolipoprotein E (APOE) ε4 non-carriers or heterozygotes.Aim To assess safety and efficacy of donanemab in the UK-indicated population.Methods Post-hoc analysis of APOE ε4 non-carriers or heterozygotes from a pooled TRAILBLAZER-ALZ and TRAILBLAZER-ALZ 2 population and the TRAILBLAZER-ALZ 2 population assessed safety and efficacy, respectively.Results By 76 weeks, 13/825 (1.6%) and 170/816 (20.8%) participants in the placebo and donanemab arms experienced amyloid-related imaging abnormalities (ARIA)-edema/effusion, 96/825 (11.6%) and 218/816 (26.7%) participants experienced ARIA-microhemorrhages/superficial siderosis and 3/825 (0.4%) and 67/816 (8.2%) participants experienced infusion-related reactions, respectively. Donanemab significantly slowed disease progression versus placebo across multiple clinical scales, including a 40.3% (p < 0.0001) lower risk of progression to the next stage as measured by the Clinical Dementia Rating-Global score. Amyloid clearance occurred in 80.8% of donanemab-treated participants.Conclusions In the UK-indicated population, excluding APOE ε4 homozygotes reduced, but did not eliminate, ARIA risk with donanemab. Treatment slowed disease progression and reduced brain amyloid plaque by 76 weeks. Therefore, donanemab treatment requires structured risk-benefit discussion and appropriate monitoring.Clinical trial registration ClinicalTrials.gov, NCT03367403, https://clinicaltrials.gov/study/NCT03367403 (TRAILBLAZER-ALZ) and NCT04437511, https://clinicaltrials.gov/study/NCT04437511 (TRAILBLAZER-ALZ 2).