Innovative Therapeutic Development Programme for the Treatment of Early Alzheimer's Disease: Lecanemab (BAN2401)

Abstract

Lecanemab (BAN2401) is an amyloid-targeting monoclonal antibody with relative selectivity for the protofibrillar species of amyloidbeta protein. The murine equivalent of lecanemab, mAb158, reduced amyloid in transgenic mice bearing the Arctic mutation that overproduces protofibrillar amyloid and improved performance on spatial memory tasks. Phase I single and multiple-ascending dose studies established the safety and pharmacokinetic profile of lecanemab. An innovative phase II trial involved patients with early Alzheimer’s disease (AD) with confirmed brain amyloid. A Bayesian design dose-finding trial involving 854 participants was the largest phase II trial conducted in AD, and identified 10 mg/kg biweekly as the optimal dose as measured on the AD Composite Score (ADCOMS). The criterion for stopping the trial at 12 months was not met, due to an 80% probability of 25% greater slowing of decline than placebo, and the trial was continued for an additional 6 months. Prespecified frequentist analyses at trial end showed statistically significant differences in favour of lecanemab on the ADCOMS and the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog) subscale and a trend in favour of lecanemab on the Clinical Dementia Rating (sum of boxes). Marked amyloid lowering was observed on amyloid positron emission tomography. Lecanemab has been advanced to phase III trials in early AD (Clarity AD) and preclinical AD (AHEAD 3-45)