• Randall J Bateman, Janice Smith, Michael C Donohue, Paul Delmar, Rachid Abbas, Stephen Salloway, Jakub Wojtowicz, Kaj Blennow, Tobias Bittner, Sandra E Black, Gregory Klein, Mercè Boada, Timo Grimmer, Akira Tamaoka, Richard J Perry, R Scott Turner, David Watson, Michael Woodward, Angeliki Thanasopoulou, Christopher Lane, Monika Baudler, Nick C Fox, Jeffrey L Cummings, Paulo Fontoura, Rachelle S Doody, and GRADUATE I and II Investigators and the Gantenerumab Study Group.
• From the Department of Neurology, Washington University School of Medicine, St. Louis (R.J.B.); Roche Products, Welwyn Garden City (J.S., C.L.), and the Department of Brain Sciences, Faculty of Medicine, Imperial College London (R.J.P.), and the Dementia Research Centre, Department of Neurodegenerative Disease, and the U.K. Dementia Research Institute, Queen Square Institute of Neurology, University College London (N.C.F.), London - all in the United Kingdom; the Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego (M.C.D.), and Genentech, South San Francisco (T.B., R.S.D.) - both in California; F. Hoffmann-La Roche, Basel, Switzerland (P.D., R.A., J.W., T.B., G.K., A. Thanasopoulou, M. Baudler, P.F., R.S.D.); Butler Hospital and Warren Alpert Medical School, Brown University, Providence, RI (S.S.); the Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, and the Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital - both in Mölndal, Sweden (K.B.); the Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, and the L.C. 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 - both in Toronto (S.E.B.); the Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, and the Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid - both in Spain (M. Boada); the Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany (T.G.); the Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan (A. Tamaoka); the Department of Neurology, Georgetown University School of Medicine, Washington, DC (R.S.T.); the Alzheimer's Research and Treatment Center, Wellington, FL (D.W.); the Medical and Cognitive Research Unit, Heidelberg Repatriation Hospital, Austin Health, Melbourne, VIC, Australia (M.W.); and the Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, Las Vegas (J.L.C.).
• N. Engl. J. Med. 2023 Nov 16; 389 (20): 186218761862-1876.

BackgroundMonoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease.MethodsWe conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116.ResultsA total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%.ConclusionsAmong persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).Copyright © 2023 Massachusetts Medical Society.

18 keywords...

hide…