A Randomized, Double-Blind Phase 2b Proof of Concept Clinical Trial in Early Alzheimer's Disease with BAN2401, an Anti-Aβ Protofibril Antibody

Background: BAN2401, an IgG1 monoclonal antibody, selectively targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils and insoluble fibrils. BAN2401-G000-201, a randomized double blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of BAN2401 versus placebo in early Alzheimer’s disease (EAD).Methods: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The Primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical slowing versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging.Findings: 854 randomized subjects were treated (BAN2401:609; placebo:245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome . At 18 months, 10-mg/kg biweekly BAN2401 reduced brain amyloid (-0.306 SUVr units) while slowing clinical decline by 27% and 30% on ADCOMS, 56% and 47% on ADAS-cog14 and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarker and HV results were supportive of treatment effect. BAN2401 was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10-mg/kg biweekly.Interpretation: BAN2401-G000-201 did not meet the 12-month Primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent slowing of clinical decline across several clinical and biomarker endpoints. A Phase 3 study (ClarityAD) in EAD is underway.Trial Registration: Clinical Trials.gov: NCT01767311.Funding Statement: This trial was funded by Eisai Inc.Declaration of Interests: CJS, YZ, SD, JW, JK, RYKL, HB, MR, AK, LR, RG, and LDK are employees of Eisai. LL is an employee of BioArctic. DAB and SB are employees of Berry Consultants.JLC provided consultation to the following pharmaceutical companies: Acadia, Accera, Actinogen, ADAMAS, Alkahest, Allergan, Alzheon, Avanir, Axovant, Axsome, BiOasis Technologies, Biogen, Eisai, Genentech, Grifols, Kyowa, Lilly, Lundbeck, Merck, Nutricia, Otsuka, QR Pharma, Resverlogix, Roche, Samus, Servier, Suven, Takeda, Toyoma, and United Neuroscience companiesEthics Approval Statement: The trial was approved by the institutional review board or independent ethics committee at each center and all patients provided informed consent.