Donanemab outperformed Aducanumab and Lecanemab on cognitive, but not on biomarker and safety outcomes: systematic review, frequentist and Bayesian network meta-analyses

INTRODUCTIONQuestions remain regarding safety and clinical relevance of anti-amyloid antibodies in Alzheimers disease (AD), with no scientific basis for choosing between different therapies. METHODSSystematic review, frequentist and Bayesian network meta-analyses of phase III randomized placebo-controlled trials were performed to comparatively evaluate cognitive, functional and biomarker efficacy and safety of anti-amyloid antibodies in sporadic AD. Treatments were ranked with P- and SUCRA scores, with rank robustness measured by Cohens kappa, and uncertainty in ranking probabilities estimated with Shannons normalized entropy. RESULTSBased on data from 16,971 patients (16 studies), we found Donanemab the best-ranked antibody on cognitive measures. Lecanemab was the most effective at reducing amyloid burden. Caution is needed concerning brain edema and microbleeding, with clinically important risks for Donanemab, Aducanumab and Lecanemab. DISCUSSIONRisk/benefit profile of anti-amyloid antibodies remains unfavorable. Patients in Donanemab study were stratified by tau load, with greater effects observed in low/medium tau population. HighlightsO_LINo single therapy ranked the best among all outcomes. C_LIO_LIDonanemab was the most effective antibody at reducing cognitive decline across all primary outcomes, while Lecanemab ranked the highest on amyloid PET removal. C_LIO_LIConsistently greater cognitive, functional and biomarker effects of Donanemab were observed in patients with low/medium tau load, suggesting more promising effects in earlier AD stages. C_LIO_LIAll antibodies, except Solanezumab, were significantly less tolerable than Placebo. C_LIO_LIThe risk of cerebral edema and microbleeding may outweigh the benefits, independently of APOE status. C_LI