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Cited by 109Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

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

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Bateman, Randall J., Cummings, Jeffrey, Schobel, Scott, Salloway, Stephen, Vellas, Bruno, Boada, Mercè, Black, Sandra E., Blennow, Kaj, Fontoura, Paulo, Klein, Gregory, Assunção, Sheila Seleri, Smith, Janice, Doody, Rachelle S.·2022·Alzheimer's Research & Therapy
DOI 10.1186/s13195-022-01110-8PMC PMC9707418
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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.

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Fig. 1 Gantenerumab development and key scientific advancements in AD. Key events and decisions that informed the gantenerumab clinical development program, ultimately leading to the GRADUATE I and II studies—2 ongoing phase 3, global, randomized, parallel-group, placebo-controlled clinical trials evaluating the efficacy and safety of subcutaneous gantenerumab in early AD (i.e., mild cognitive impairment due to AD to mild AD dementia), the launch of secondary prevention trials designed to remove amyloid plaques before symptom onset, and a primary prevention trial designed to prevent formation of amyloid plaques
Fig. 1 Gantenerumab development and key scientific advancements in AD. Key events and decisions that informed the gantenerumab clinical development program, ultimately leading to the GRADUATE I and II studies—2 ongoing phase 3, global, randomized, parallel-group, placebo-controlled clinical trials evaluating the efficacy and safety of subcutaneous gantenerumab in early AD (i.e., mild cognitive impairment due to AD to mild AD dementia), the launch of secondary prevention trials designed to remove amyloid plaques before symptom onset, and a primary prevention trial designed to prevent formation of amyloid plaquesCC BY · PubMed Central
Fig. 2 Amyloid aggregation in AD and the mechanism of action of gantenerumab. A The amyloid hypothesis of AD involves the accumulation of Aβ-soluble monomers and oligomers that aggregate into insoluble fibrils and amyloid plaques. Aggregated species of Aβ damages neurons and can increase oxidative stress, inflammation, mitochondrial dysfunction, and neuronal loss. B Based on the findings from in vitro studies, the mechanism of action of gantenerumab is thought to stem from the clearance of Aβ plaques by antibody-induced cell-mediated phagocytosis, dissociation of Aβ peptide aggregates by direct resolution, and neutralization of neurotoxic Aβ oligomers. Gantenerumab binds to all types of aggregated neurotoxic Aβ species, with the highest affinity to the fibrillar forms and plaques. After binding to aggregated amyloid (1), the Fc gamma receptor on microglia binds to the human immunoglobulin G1 backbone of gantenerumab, engulfing Aβ plaques (2), and, then, phagocytosis by microglia and removal of aggregated Aβ (3). A Adapted with permission from Panza F, et al. Nat Rev Neurol. 2019;15(2):73-88
Fig. 2 Amyloid aggregation in AD and the mechanism of action of gantenerumab. A The amyloid hypothesis of AD involves the accumulation of Aβ-soluble monomers and oligomers that aggregate into insoluble fibrils and amyloid plaques. Aggregated species of Aβ damages neurons and can increase oxidative stress, inflammation, mitochondrial dysfunction, and neuronal loss. B Based on the findings from in vitro studies, the mechanism of action of gantenerumab is thought to stem from the clearance of Aβ plaques by antibody-induced cell-mediated phagocytosis, dissociation of Aβ peptide aggregates by direct resolution, and neutralization of neurotoxic Aβ oligomers. Gantenerumab binds to all types of aggregated neurotoxic Aβ species, with the highest affinity to the fibrillar forms and plaques. After binding to aggregated amyloid (1), the Fc gamma receptor on microglia binds to the human immunoglobulin G1 backbone of gantenerumab, engulfing Aβ plaques (2), and, then, phagocytosis by microglia and removal of aggregated Aβ (3). A Adapted with permission from Panza F, et al. Nat Rev Neurol. 2019;15(2):73-88CC BY · PubMed Central
Fig. 3 A SCarlet RoAD (prodromal AD, CDR 0.5, ClinicalTrials.gov identifier: NCT10224106) study design: conversion from a gantenerumab phase 2/3 study in prodromal AD to an open-label extension and rollover into the Open RoAD open-label study. B Marguerite RoAD (mild AD, CDR 1.0, ClinicalTrials.gov identifier: NCT02051608) study design: conversion from a gantenerumab phase 3 study in mild AD to an open-label extension and rollover into the Open RoAD open-label study. C The Knight Family DIAN-TU dominantly inherited autosomal Alzheimer’s disease (prevention, prodromal or mild AD; ClinicalTrials.gov identifier: NCT01760005) study design: conversion from a gantenerumab phase 2/3 study to an exploratory open-label extension with dose escalation in asymptomatic or mild AD from DIAN-TU. D GRADUATE I and II (ClinicalTrials.gov identifiers: NCT03444870 and NCT03443973) phase 3 studies: two global, parallel, multicenter, randomized, double-blind, placebo-controlled studies of gantenerumab in patients with early AD (prodromal or MCI-AD to mild AD), and the post-GRADUATE (ClinicalTrials.gov identifier: NCT04374253) open-label extension study. E GRADUATION (ClinicalTrials.gov identifier: NCT04592341) study design: a multicenter, phase 2, open-label, single-arm, pharmacodynamic study to evaluate once-weekly subcutaneous gantenerumab dosing. After titration, at-home administration by care partners or home nurses is possible, allowing flexibility for patients. F SKYLINE (ClinicalTrials.gov identifier: NCT05256134) study design: a phase 3, randomized, double-blind, placebo-controlled secondary prevention trial of gantenerumab in participants at risk or at the earliest stages of AD. C Adapted with permission from “As DIAN wraps up anti-aβ drug arms, it sprouts tau, primary prevention arms.” 2019. Available from AlzForum at https://www.alzforum.org/news/conference-coverage/dian-wraps-anti-av-drug-arms-it-sprouts-tau-primary-prevention-arms
Fig. 3 A SCarlet RoAD (prodromal AD, CDR 0.5, ClinicalTrials.gov identifier: NCT10224106) study design: conversion from a gantenerumab phase 2/3 study in prodromal AD to an open-label extension and rollover into the Open RoAD open-label study. B Marguerite RoAD (mild AD, CDR 1.0, ClinicalTrials.gov identifier: NCT02051608) study design: conversion from a gantenerumab phase 3 study in mild AD to an open-label extension and rollover into the Open RoAD open-label study. C The Knight Family DIAN-TU dominantly inherited autosomal Alzheimer’s disease (prevention, prodromal or mild AD; ClinicalTrials.gov identifier: NCT01760005) study design: conversion from a gantenerumab phase 2/3 study to an exploratory open-label extension with dose escalation in asymptomatic or mild AD from DIAN-TU. D GRADUATE I and II (ClinicalTrials.gov identifiers: NCT03444870 and NCT03443973) phase 3 studies: two global, parallel, multicenter, randomized, double-blind, placebo-controlled studies of gantenerumab in patients with early AD (prodromal or MCI-AD to mild AD), and the post-GRADUATE (ClinicalTrials.gov identifier: NCT04374253) open-label extension study. E GRADUATION (ClinicalTrials.gov identifier: NCT04592341) study design: a multicenter, phase 2, open-label, single-arm, pharmacodynamic study to evaluate once-weekly subcutaneous gantenerumab dosing. After titration, at-home administration by care partners or home nurses is possible, allowing flexibility for patients. F SKYLINE (ClinicalTrials.gov identifier: NCT05256134) study design: a phase 3, randomized, double-blind, placebo-controlled secondary prevention trial of gantenerumab in participants at risk or at the earliest stages of AD. C Adapted with permission from “As DIAN wraps up anti-aβ drug arms, it sprouts tau, primary prevention arms.” 2019. Available from AlzForum at https://www.alzforum.org/news/conference-coverage/dian-wraps-anti-av-drug-arms-it-sprouts-tau-primary-prevention-armsCC BY · PubMed Central
Fig. 4 Scientific lessons that informed the updated dosing strategy of gantenerumab
Fig. 4 Scientific lessons that informed the updated dosing strategy of gantenerumabCC BY · PubMed Central
Fig. 5 Aβ plaque reduction with gantenerumab in basal ganglia before and up to 36 months after treatment, and reduction of amyloid burden toward zero centiloids after 36 months of open-label therapy. A Axial florbetapir brain PET images from 3 patients displaying different rates of reduction of Aβ plaques from OLE baseline to OLE week 52 and OLE week 104. Axial slices are at the level of the basal ganglia. PET images were obtained 50 min post-injection, standardized uptake value data with the cerebellar cortex as the reference region. a18F-Florbetapir amyloid PET. bLS mean (SE) analyzed using a mixed model for repeated measures; 1200 mg subcutaneous gantenerumab was administered every 4 weeks during the OLE studies. B Marked and consistent reduction of amyloid load in patients receiving high-dose gantenerumab. Marked reduction of amyloid-β plaques in patients receiving high-dose gantenerumab, and consistent reduction of amyloid-β plaques in all patient groups. B adapted from Klein G, et al. J Prev Alzheimers Dis. 2021;8(1):3-6, licensed under CC BY 4.0
Fig. 5 Aβ plaque reduction with gantenerumab in basal ganglia before and up to 36 months after treatment, and reduction of amyloid burden toward zero centiloids after 36 months of open-label therapy. A Axial florbetapir brain PET images from 3 patients displaying different rates of reduction of Aβ plaques from OLE baseline to OLE week 52 and OLE week 104. Axial slices are at the level of the basal ganglia. PET images were obtained 50 min post-injection, standardized uptake value data with the cerebellar cortex as the reference region. a18F-Florbetapir amyloid PET. bLS mean (SE) analyzed using a mixed model for repeated measures; 1200 mg subcutaneous gantenerumab was administered every 4 weeks during the OLE studies. B Marked and consistent reduction of amyloid load in patients receiving high-dose gantenerumab. Marked reduction of amyloid-β plaques in patients receiving high-dose gantenerumab, and consistent reduction of amyloid-β plaques in all patient groups. B adapted from Klein G, et al. J Prev Alzheimers Dis. 2021;8(1):3-6, licensed under CC BY 4.0CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Bateman RJ, Smith J, Fox NC, Black SE, Shij Turner RS, et al. The clinical development history of gantenerumab, a subcutaneous anti-Aβ monoclonal antibody for early Alzheimer’s disease: building on lessons from the past and paving a path for the future. San Diego: Presented at: Alzheimer’s Association International Conference Annual Meeting; 2022.
  2. Lane C, Bullain S, Thanasopoulou A, Delmar P, Searle A, Boada M, et al. ROC12- baseline characteristics of the GRADUATE studies: phase III randomized, placebo-controlled studies investigating subcutaneous gantenerumab in participants with early Alzheimer’s disease. J Prev Alzheimers Dis. 2021;8:S1-72.
  3. Sink K, Djakovic S, Smith JW, Smith J, Hu N, Mackey H, et al. FCSRT inclusion criteria support recruitment of a population with early Alzheimer’s disease likely to progress over 24 months: results from the CREAD trial. J Prev Alzheimers Dis. 2019;6:S19–20.

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Authors
Bateman, R. J., Cummings, J., Schobel, S., Salloway, S., Vellas, B., Boada, M., Black, S. E., Blennow, K., Fontoura, P., Klein, G., Assunção, S. S., Smith, J., & Doody, R. S.
Affiliations
  • Washington University in St. Louis (US)
  • University of Nevada, Las Vegas (US)
  • F. Hoffmann-La Roche AG (CH)
  • Brown University (US)
  • Université Toulouse III - Paul Sabatier (FR)
  • Sunnybrook Health Science Centre (CA)
  • Sahlgrenska University Hospital (SE)
  • Roche (United States) (US)
  • Roche (United Kingdom) (GB)
Corresponding author
Bateman, Randall J.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-11-29
Volume
14
Issue
1
Pages
178-178
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-022-01110-8
PMC
PMC9707418
OpenAlex
W4310985942
Cited by
109
References
39
Citations by year
2026: 20 · 2025: 19 · 2024: 40 · 2023: 29
FWCI
3.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Alzheimer's Association
  • F. Hoffmann-La Roche
  • Genentech
  • National Institute on Aging (R21AG067559, R01AG053798, P20AG068053, U01AG042791, U19AG032438, R01AG046179, RF1AG061900, R01AG053267, U01AG059798, P30AG072959, R35AG071476, R01AG068319)
  • National Institute of General Medical Sciences (P20GM109025)
  • National Institute of Neurological Disorders and Stroke (R01NS095773, U01NS093334)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
Keywords
gantenerumab, Alzheimer's disease, anti-amyloid monoclonal antibodies, amyloid plaques, disease-modifying therapy, aducanumab, amyloid positivity, exposure-response modeling, blood-based biomarkers, subcutaneous formulation, drug development
MeSH terms
Alzheimer Disease, Amyloidosis, Humans, United States, Asymptomatic Diseases, Plaque, Amyloid, Amyloidogenic Proteins, Antibodies, Monoclonal, Humanized

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