GRADUATE I AND II: Findings of Two Phase III Randomized Placebo-controlled Studies Assessing the Efficacy and Safety of Subcutaneous Gantenerumab in Early Alzheimer’s Disease (AD)
Janice Smith1, Michael C Donohue2, Elisabeth Gruendl3, Timo Grimmer4, Richard J Perry5, Sandra E Black6, Stephen Salloway7, Marco Lyons1, Loes Rutten-Jacobs3, Tobias Bittner8, Kaj Blennow9, Chris Pelentrides3, Frederik Barkhof10, Matteo Tonietto3, Monika Baudler-Klein3, Paulo Fontoura3, Rachelle S Doody3
1Roche Products Ltd, Welwyn Garden City, UK, 2Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego, CA, USA, 3F. Hoffmann-La Roche Ltd, Basel, Switzerland, 4Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany, 5Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK, 6Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, LC Campbell Cognitive Neurology Research Unit, Dr. Sandra Black Centre for Brain Resilience & Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada, 7Butler Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA, 8F. Hoffmann-La Roche Ltd, Basel, Switzerland, Genentech, Inc., South San Francisco, CA, USA, 9Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden, 10Department of Radiology & Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Netherlands, Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK
Objective:
GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27-month, global, Phase III, randomized, placebo-controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia).
Background:
Gantenerumab is a subcutaneous fully-human monoclonal antibody that binds to aggregated amyloid-beta species, including oligomers, fibrils, and plaques.
Design/Methods:
Eligible participants (50–90 years) with early AD were randomized 1:1 to receive subcutaneous gantenerumab or placebo, administered at the study site or at home. A universal titration scheme for all participants receiving gantenerumab, irrespective of apolipoprotein E ε4 (APOEε4) genotype, allowed participants to reach a target dose of 510 mg gantenerumab every 2 weeks. This titration maximizes gantenerumab exposure while balancing amyloid removal and amyloid-related imaging abnormalities (ARIA) risk for all individuals. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR-SB; higher scores indicate greater impairment). Secondary confirmatory and exploratory efficacy endpoints, tau and amyloid positron emission tomography, cerebrospinal fluid and plasma biomarkers, were also assessed.
Results:
GRADUATE I and II enrolled 985 and 980 participants, respectively. Change from baseline in CDR-SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% CI –0.66 to 0.05) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17). The difference between gantenerumab and placebo groups in amyloid reduction at Week 116 was –66.57 (standard error [SE] 4.13) centiloids for GRADUATE I and –56.52 (SE 3.96) centiloids for GRADUATE II. ARIA-edema (ARIA-E) occurred with gantenerumab; ARIA-E were manageable and mostly asymptomatic.
Conclusions:
Gantenerumab did not slow decline in participants with early AD. Clinical benefit may require sufficient amyloid plaque removal; however, the parameters remain to be defined.