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

40 Pages Posted: 29 Sep 2020

See all articles by Chad Swanson

Chad Swanson

Eisai, Inc. - Eisai, Inc. - United States

Yong Zhang

Eisai, Inc. - Eisai, Inc. - United States

Shobha Dhadda

Eisai, Inc. - Eisai, Inc. - United States

Jinping Wang

Eisai, Inc. - Eisai, Inc. - United States

June Kaplow

Eisai, Inc. - Eisai, Inc. - United States

Robert YK Lai

Eisai Ltd.

Lars Lannfelt

BioArctic AB; Uppsala University - Department of Public Health/Geriatrics

Heather Bradley

Eisai, Inc. - Eisai, Inc. - United States

Martin Rabe

Eisai, Inc. - Eisai, Inc. - United States

Akihiko Koyama

Eisai, Inc. - Eisai, Inc. - United States

Larisa Reyderman

Eisai, Inc. - Eisai, Inc. - United States

Donald A. Berry

Berry Consultants, LLC

Scott Berry

Berry Consultants, LLC

Robert Gordon

Eisai Ltd.

Lynn D. Kramer

Eisai, Inc. - Eisai, Inc. - United States

Jeffrey Cummings

Cleveland Clinic - Lou Ruvo Center for Brain Health; University of Nevada, Las Vegas - Chambers-Grundy Center for Transformative Neuroscience

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Abstract

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 companies

Ethics Approval Statement: The trial was approved by the institutional review board or independent ethics committee at each center and all patients provided informed consent.

Keywords: Alzheimer's disease, BAN2401, clinical trial, biomarker, ADCOMS, amyloid PET, neurofilament light, neurogranin, p-tau

Suggested Citation

Swanson, Chad and Zhang, Yong and Dhadda, Shobha and Wang, Jinping and Kaplow, June and Lai, Robert YK and Lannfelt, Lars and Bradley, Heather and Rabe, Martin and Koyama, Akihiko and Reyderman, Larisa and Berry, Donald A. and Berry, Scott and Gordon, Robert and Kramer, Lynn D. and Cummings, Jeffrey, A Randomized, Double-Blind Phase 2b Proof of Concept Clinical Trial in Early Alzheimer's Disease with BAN2401, an Anti-Aβ Protofibril Antibody. Available at SSRN: https://ssrn.com/abstract=3672342 or http://dx.doi.org/10.2139/ssrn.3672342

Chad Swanson

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Yong Zhang

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Shobha Dhadda

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Jinping Wang

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

June Kaplow

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Robert YK Lai

Eisai Ltd.

Hatfield
United Kingdom

Lars Lannfelt

BioArctic AB

Warfvinges väg 35
SE-112 51
Stockholm
Sweden

Uppsala University - Department of Public Health/Geriatrics

Uppsala
Sweden

Heather Bradley

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Martin Rabe

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Akihiko Koyama

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Larisa Reyderman

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Donald A. Berry

Berry Consultants, LLC

Austin, TX
United States

Scott Berry

Berry Consultants, LLC

Austin, TX
United States

Robert Gordon

Eisai Ltd.

Hatfield
United Kingdom

Lynn D. Kramer

Eisai, Inc. - Eisai, Inc. - United States

Woodcliff Lake, NJ
United States

Jeffrey Cummings (Contact Author)

Cleveland Clinic - Lou Ruvo Center for Brain Health ( email )

888 W Bonneville Ave.
Las Vegas, NV 89106
United States

University of Nevada, Las Vegas - Chambers-Grundy Center for Transformative Neuroscience ( email )

Las Vegas, NV
United States

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