Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer's disease.

Kaj Blennow, Randall J Bateman, Jeffrey Cummings, Scott Schobel, Stephen Salloway, Bruno Vellas, Mercè Boada, Sandra E Black, Paulo Fontoura, Gregory Klein, Sheila Seleri Assunção, Janice Smith, Rachelle S Doody

Journal: Alzheimer's research & therapy 2022;14(1):178

PMID: 36447240

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Abstract

BACKGROUND

This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration's approval of aducanumab, an anti-amyloid monoclonal antibody as the first potential disease-modifying therapy for AD, signaled the value of more than 20 years of drug development, adding to the available therapies the first nominal success since cholinesterase inhibitors and memantine were approved. BODY: Here, we review over 2 decades of gantenerumab development in the context of scientific discoveries in the broader AD field. Key learnings from the field were incorporated into the gantenerumab phase 3 program, including confirmed amyloid positivity as an entry criterion, an enriched clinical trial population to ensure measurable clinical decline, data-driven exposure-response models to inform a safe and efficacious dosing regimen, and the use of several blood-based biomarkers. Subcutaneous formulation for more pragmatic implementation was prioritized as a key feature from the beginning of the gantenerumab development program.

CONCLUSION

The results from the gantenerumab phase 3 programs are expected by the end of 2022 and will add critical information to the collective knowledge on the search for effective AD treatments.

Address: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. [email protected].; Dominantly Inherited Alzheimer's Network (DIAN) and The Knight Family DIAN Trials Unit (DIAN-TU), St. Louis, MO, USA. [email protected].; Department of Brain Health, Chambers-Grundy Center for Transformative Neuroscience, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.; Product Development, F. Hoffmann-La Roche, Basel, Switzerland.; Departments of Psychiatry, Human Behavior, and Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.; Department of Neurology, Butler Hospital, Providence, RI, USA.; Brown University Center for Alzheimer's Disease Research, Robert J. and Nancy D. Carney Institute for Brain Science, Providence, RI, USA.; Department of Geriatric Internal Medicine, UMR 1295 Mixed Unit INSERM - Université Toulouse III Paul Sabatier, Toulouse University Hospital, Toulouse, France.; Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya, Barcelona, Spain.; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.; LC Campbell Cognitive Neurology Research Unit, Dr Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Roche Pharma Research and Early Development, F. Hoffmann-La Roche, Basel, Switzerland.; US Medical Affairs, Genentech Inc., a member of the Roche Group, South San Francisco, CA, USA.; Product Development, Roche Products Ltd., Welwyn Garden City, UK.; Product Development, Genentech Inc., a member of the Roche Group, South San Francisco, CA, USA.

DOI: 10.1186/s13195-022-01110-8

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MeSH Terms: United States, Humans, Alzheimer Disease, Amyloidogenic Proteins, Amyloidosis, Plaque, Amyloid, Asymptomatic Diseases