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Clinical Trial
. 2025 Apr;24(4):316-330.
doi: 10.1016/S1474-4422(25)00024-9.

Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open-label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU trial

Randall J Bateman  1 , Yan Li  2 , Eric M McDade  3 , Jorge J Llibre-Guerra  3 , David B Clifford  3 , Alireza Atri  4 , Susan L Mills  3 , Anna M Santacruz  3 , Guoqiao Wang  3 , Charlene Supnet  3 , Tammie L S Benzinger  3 , Brian A Gordon  3 , Laura Ibanez  3 , Gregory Klein  5 , Monika Baudler  5 , Rachelle S Doody  5 , Paul Delmar  5 , Geoffrey A Kerchner  5 , Tobias Bittner  5 , Jakub Wojtowicz  5 , Azad Bonni  5 , Paulo Fontoura  5 , Carsten Hofmann  5 , Luka Kulic  5 , Jason Hassenstab  3 , Andrew J Aschenbrenner  3 , Richard J Perrin  3 , Carlos Cruchaga  3 , Alan E Renton  6 , Chengjie Xiong  3 , Alison A Goate  7 , John C Morris  3 , David M Holtzman  3 , B Joy Snider  3 , Catherine Mummery  8 , William S Brooks  9 , David Wallon  10 , Sarah B Berman  11 , Erik Roberson  12 , Colin L Masters  13 , Douglas R Galasko  14 , Suman Jayadev  15 , Rachel Sanchez-Valle  16 , Jeremie Pariente  17 , Justin Kinsella  18 , Christopher H van Dyck  19 , Serge Gauthier  20 , Ging-Yuek Robin Hsiung  21 , Mario Masellis  22 , Bruno Dubois  23 , Lawrence S Honig  24 , Clifford R Jack  25 , Alisha Daniels  3 , David Aguillón  26 , Ricardo Allegri  27 , Jasmeer Chhatwal  28 , Gregory Day  29 , Nick C Fox  8 , Edward Huey  30 , Takeshi Ikeuchi  31 , Mathias Jucker  32 , Jae-Hong Lee  33 , Allan I Levey  34 , Johannes Levin  35 , Francisco Lopera  36 , JeeHoon Roh  37 , Pedro Rosa-Neto  20 , Peter R Schofield  9 ; Dominantly Inherited Alzheimer's Disease–Trials Unit
Affiliations
Clinical Trial

Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open-label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU trial

Randall J Bateman et al. Lancet Neurol. 2025 Apr.

Erratum in

Abstract

Background: Amyloid plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease; however, the potential for delaying the onset of clinical symptoms in asymptomatic people is unknown. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD). Based on findings of amyloid removal and downstream biological effects from the gantenerumab group of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab.

Methods: The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before and 10 years after their estimated years to symptom onset and who had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and the USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of subcutaneous gantenerumab up to 1500 mg every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a prespecified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-Sum of Boxes (CDR-SB). The primary outcome for the final analysis was the amyloid plaque measure 11C-Pittsburgh compound-B positron emission tomography (PiB-PET) standardised uptake value ratio (SUVR [PiB-PET SUVR]) at 3 years, assessed in the modified intention-to-treat group (mITT; defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment before gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. DIAN-TU-001 (NCT01760005) and the OLE (NCT06424236) are registered with ClinicalTrials.gov.

Findings: Of 74 participants who were recruited into the OLE study between June 3, 2020, and April 22, 2021, 73 were enrolled and received gantenerumab treatment. 47 (64%) stopped dosing due to early termination of the study by the sponsor, and 13 (18%) prematurely discontinued the study for other reasons; 13 people completed 3 years of treatment. The mITT group for the primary analysis comprised 55 participants. At the interim analysis, the hazard ratio for clinical decline of CDR-SB in asymptomatic mutation carriers was 0·79 (n=53 [95% CI 0·47 to 1·32]) for participants who were treated with gantenerumab in either the double-blind or OLE period (Any Gant), and 0·53 (n=22 [0·27 to 1·03]) for participants who were treated with gantenerumab the longest (Longest Gant). At the final analysis, the adjusted mean change from OLE baseline to year 3 in PiB-PET SUVR was -0·71 SUVR (95% CI -0·88 to -0·53, p<0·0001). Amyloid-related imaging abnormalities occurred in 53% (39 of 73) of participants: 47% (34 of 73) with microhaemorrhages, 30% (22 of 73) with oedema, and 6% (five of 73) were associated with superficial siderosis. No treatment-associated macrohaemorrhages or deaths occurred.

Interpretation: Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression. Our conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long-term trials.

Funding: National Institute on Aging, Alzheimer's Association, GHR Foundation, and F Hoffmann-La Roche/Genentech.

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Conflict of interest statement

Declaration of interests RJB is director of DIAN–TU and Principal Investigator of DIAN-TU-001. He receives research support from the National Institute on Aging (NIA) of the National Institutes of Health (NIH), DIAN–TU trial pharmaceutical partner (Hoffman-La Roche), Alzheimer's Association, GHR Foundation, an anonymous donor, and the DIAN-TU Pharma Consortium (Active: AbbVie, Biogen, BMS, Eisai, Eli Lilly, Ionis, Janssen, Prothena, and Roche/Genentech. Previous: Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience). He has been a scientific advisor for the National Alzheimer's Project Act (NAPA) Advisory Council, Biogen, F Hoffman-La Roche/Genentech, and the UK Dementia Research Institute at University College London and Stanford University. He has been an invited speaker for Alzheimer's Association, Duke Margolis Alzheimer's Roundtable, BrightFocus Foundation, Tau Consortium, NAPA Advisory Council on Alzheimer's Research, Clinical Trials on Alzheimer's Disease, Fralin Biomedical Research Institute, Beeson, Adler Symposium, and Fondazione Prada. RJB and DMH are co-founders of C2N Diagnostics and receive income from C2N Diagnostics for serving on the scientific advisory board. Washington University has equity ownership interest in C2N Diagnostics. They are also co-inventors of the stable isotope labelling kinetics and blood plasma assay technology licensed by Washington University to C2N Diagnostics. Through these relationships, Washington University, RJB. and DMH are entitled to receive royalties, equity, or both from the license agreement with C2N. EMM is the co-director of the DIAN-TU. He receives research support from the NIA of the NIH, the DIAN-TU-002 Trial pharmaceutical partner (Eli Lilly), Alzheimer's Association, and GHR Foundation. He has been a consultant to AstraZeneca, F Hoffman-LaRoche Ltd, Sanofi, and Merck. He has been an invited speaker for Alzheimer's Association, Projects in Knowledge (Kaplan), Neurology Live, American Academy of Neurology, and the University of Maryland. He has received support to attend meetings at Fondation Alzheimer, McGill University, University of Massachusetts, and Australian and New Zealand Association of Neurologists. He reports serving on a Data Safety Committee for Alnylam and Alector. JJGL is co-medical director of DIAN–TU. He receives research support from the NIA of the NIH and the Alzheimer's Association. DBC is co-medical director of DIAN–TU. He receives royalties from Wolters Kluwer. He serves as scientific consultant to F Hoffmann-La Roche/Genentech, Wave Life Sciences, Excision BioTherapeutics, Atara Biotherapeutics, Sanofi Genzyme, Cellevolve Bio, Seagen, and ICON (Teva). He has carried out legal consulting for Lewis, Thomason, King, Krieg and Waldrop (PML), and Loughren, Loughren, Loughren Powell Gilbert LLP. He serves on the Data Safety Monitoring Board for Wave Life Sciences, Excision Biotherapeutics, Sanofi Genzyme, Atara Biotherapeutics, and Cellevolve Bio. GW serves as a consultant for Alector and Pharmapace. He serves on the data safety monitoring board for Eli Lilly. TLSB has investigator-initiated research funding from the NIH, Avid Radiopharmaceuticals, Siemens, and Hyperfine. She is a consultant to Biogen, Eisai, Eli Lilly, Bristol Myers Squibb, and Janssen and Janssen. She is on the Speaker's Bureau for Medscape and Peerview. She serves on the data safety monitoring board for Eisai and Siemens. She provides unpaid leadership to the American Society of Neuroradiology Alzheimer's, Radiological Society of North America Quantitative Imaging Committee, American College of Radiology Alzheimer's Network for Treatment & Diagnosis, and NIH Clinical Neuroscience and Neurodegeneration Study Section Chair. BAG receives research support from the NIA of the NIH. GK, MBK, RSD, PD, GAK, TB, AB, PF, CH and LK are employees of F Hoffmann La Roche. JH is a consultant to Parabon Nanolabs, Prothena, and AlzPath. He serves on the data safety monitoring board for Caring Bridge and Wall-E. AJA receives research support from the NIA of the NIH and he is a consultant to Albert Einstein College of Medicine. RJP and AER receive research support from the NIA of the NIH. CC receives research support from the NIA of the NIH and the Michael J Fox Foundation. He is a consultant for Circular Genomics and Alector. CX receives research support from the NIH and he is a consultant for Diadem. He serves of the FDA Advisory Committee on Imaging Medical Products. AAG is a consultant for Genentech and Muna Therapeutics. JCM is the Friedman Distinguished Professor of Neurology, Director of the Charles F and Joanne Knight Alzheimer's Disease Research Center, Associate Director of DIAN and Founding Principal Investigator of DIAN. His research is funded by NIH and his is a consultant for Barcelona Brain Research Center and the Native Alzheimer Disease-related resource centre in Minority Aging Research. He has been an invited speaker for the Alliance for Academic Internal Medicine Longer Life Foundation and the International Brain Health Symposium. He serves on the data safety monitoring board for Cure Alzheimer's Fund and the Longitudinal Early-Onset Alzheimer's Disease Study Advisory Board. DMH receives research support from the NIH. He serves as a consultant for Genentech, Denali, and Cajal Neurosciences. BJS receives research clinical trial support from NIH, Biogen, Eisai, Eli Lilly, F Hoffmann La Roche, Janssen, and Alzheimer's Association. She is a consultant for Eisai, Roche, Altheneum, and Slingshot. She received honoraria from the American Nurses Association and the American Academy of Nursing. She receives royalties from Elsevier. CM receives research support from Biogen and the NIHR. She is a consultant for Eli Lilly, Biogen, and Eisai. She has received honoraria from Eli Lilly and Eisai. She serves on the data safety monitoring board for Eli Lilly, Novartis, F Hoffman La Roche/Genentech, Eisai, and Immunobrain. ER receives research support from the NIH, Alzheimer's Drug Discovery Foundation, and Bluefield Project. He receives royalties from Genentech. He is a consultant for Applied Genetic Technologies Corporation. He serves on the data safety monitoring board for Eli Lilly and serves as fiduciary for the Society for Neuroscience. CHVD has served as a consultant for F Hoffmann-La Roche, Cervel, Ono, and Eisai and received grant support for clinical trials from F Hoffmann-La Roche, Eli Lilly and Company, Biogen, Genetech, Janssen, Eisai, and Cerevel. RSV receives grant support from Instituto de Salud Carlos III. She is a consultant for UCB, Pfizer, and Lilly. She has received honoraria from Neuraxpharm and Roche. She serves on the data safety monitoring board of Wave Pharmaceuticals. WSB received financial support from Roche to attend an educational meeting about management of Alzheimer's disease. SG received honoraria from Lundbeck and Biogen, and travel support from TauRx. He serves on the data safety monitoring board for Alzheon, AmyriAD, Eisai, ENIGMA, Lilly, Okutsa, Nordisk, TauRx, and AbbVie. He serves on the board of the Francis Foundation. DRG is a consultant for Eisai, Biogen and Fujirebio. He has received honoraria from GE Healthcare, and he serves on the data safety committee for Artery Therapeutics. GSH receives research support from the NIH, Canadian Institutes of Health Research (CIHR), Biogen, Roche, Cassava, and Eisai. He is a consultant for Biogen, Roche, Novonordisk, Eisai, and Eli Lilly. He also serves unpaid as the president of the Consortium of Canadian Centres for Clinical Cognitive Research. MM receives research support from the Ontario Brain Institute, Women's Brain Health Initiative, Brain Canada, Roche, CIHR, Alector, and Weston Brain Institute. He reports receiving royalties from Henry Stewart Talks. He is a consultant for Eli Lilly, Alector, Biogen, Wave Life Sciences, Eisai, and Novo-Nordisk. He has received honoraria from MINT Memory Clinics and ECHO Dementia Series. He serves unpaid on committees for Alzheimer Society Canada and Parkinson Canada. BD is a consultant for Fondation Recherche Alzheimer, Qynapse, and Eisai and is an unpaid board member for the Foundation Claude Pompidou. JP serves on the data safety committee for Biogen and Borhinger. LSH receives research support from the NIH, Acumen, Alector, Biogen, Cognition, EIP, Eisai, Ferrer, Genentech, Janssen and J&J, Roche, Transposon, UCB, and Vaccinex. He is a consultant for Biogen, Corium, Eisai, New Amsterdam, and Roche. He has received honoraria from Medscape and serves on the data safety committee for Cortexyme and Eli Lilly. JC receives research support from the NIH and the Doris Duke Charitable Foundation. He is a consultant for MedaCorp. GD receives research support from NIH, Alzheimer's Association, and Chan Zuckerberg Association. He is a consultant for Parabon Nanolabs, Arialys Therapeutics, and Ionis. He has received honoraria from PeerView Media, Eli Lilly, DynaMed, and Continuing Medical Education. He served as an unpaid clinical director for Anti-NMDA Receptor Encephalitis Foundation. He reports owning stocks in ANI Pharmaceuticals and Parabon Nanolabs. NCF is a consultant for Eisai, F Hoffmann La Roche, Eli Lilly, Ionis, Biogen, and Siemens. He has received honoraria from F Hoffmann La Roche and serves on the Alzheimer's Association Research Strategy Council. AIL receives research support from the NIH. He reports royalties from Linus Health and Emtherapro. He is a consultant for MEPSGEN and Emtherapro. He serves on the data safety monitoring board for NextSense, Karuna, and Cognito Therapeutics. He reports stock relationships with Emtherapro and NextSense. TI received research support from AMED JP23dk02027066. He is a consultant for Eli Lilly and Novo Nordisk. He received honoraria from Eisa, Fuji Rubio, and Eli Lilly. JL receives research support from the German Center for Neurodegenerative Diseases. He is a consultant for Eisai and Biogen. He has received honoraria from Bayer Vital, Biogen, Eisai, Teva, Roche, Esteve, and Zambon. He serves on the data safety committee for Axon Neuroscience, and he is an unpaid board member for ERN-RND Management, ERN-RND Atypical Parkinson Disease Coordinator, and the Deutsches Netzwerk Gedachtnisambulanzen. FL receives research support from the NIH, Banner Institute, and Roche. He is a consultant for Biogen and Technoquimicas. He has received honoraria from Tecnofarma. PRN is a consultant for Novodisk, Eli Lilly and Biogen. PRS receives research support from the NIH, National Health and Medical Research Council, Medical Research Future Fund, and Roth Charitable Foundation. He is a consultant for Outside Opinion Pty, Moira Clay Consulting, and Neuroscience Research Australia. He is the director of the Australian Dementia Network, Neuroscience Research Australia, Health Science Alliance, Schizophrenia Research Institute, StandingTall, and Australian Association of Medical Research Institutes. He is president of the Australasian Neuroscience Society. LT participates on the data safety monitoring board of Denali and has received research support from the NIH and Alzheimer's Association. YL, SLM, AMS, CS, LI, DW, SBB, CLM, SJ, JK, CRJ, AD, RA, BG, EDH, MJ, JHL, JHR and ALS have no interests to declare. The funders of the study had no role in the collection, analysis or interpretation of the data, the writing of the report or in the decision to submit the paper for publication.

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