Amyloid Reduction and Dementia Progression in Dominantly Inherited Alzheimer's Diseaseafter Long-Term Gantenerumab Treatment: Results from the Dian-Tu Trial

Background: Amyloid-plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease (AD), however the potential for delaying the onset of clinical symptoms in asymptomatic people are unknown. We conducted a trial to evaluate whether amyloid-plaque removal delays AD progression in asymptomatic individuals with dominantly inherited AD (DIAD). Methods: This double-blind, phase 2/3 trial, followed by open-label extension (OLE), investigated increasing gantenerumab doses up to 1500 mg subcutaneous every 2 weeks [enrollment started June 30, 2020, reported under NCT01760005]. We report interim and final analyses of clinical, amyloid-plaque removal, and biomarker outcomes in asymptomatic mutation carriers treated for up to 10 years. The primary endpoint was the change from OLE baseline to year 3 in PiB-PET SUVR and the key secondary endpoints were the time to recurrent progression of the global Clinical Dementia Rating® (CDR) with the Cox proportional hazards model, compared to internal and external controls. Findings: The primary outcome was positive with amyloid removal of 0.71 SUVR (95% CI 0.53 to 0.88, p< 0.0001). Higher doses were associated with larger amounts of amyloid plaque removal and 30% of participants remained amyloid normal or converted to normal. For the clinical decline of CDR-SB, in the group with any gantenerumab exposure (n=53, average dosing 4.3 years), the hazard ratio was 0.77 (0.47, 1.27). In the longest-treated group (n=22, average 8.4 years), the hazard ratio was 0.55 (0.29, 1.04) for CDR-SB clinical decline. CSF amyloid-beta 42/40 and p-tau181/tau181 improved proportionally with amyloid reduction. Amyloid-related imaging abnormalities occurred in 53% of participants; 47% with microhemorrhages, 30% with edema, and 6% were associated with symptoms. There were no treatment-associated macrohemorrhages or deaths. Interpretation: While no significant clinical effect was observed in the overall group treated, results suggest potential delayed symptom onset and dementia progression in asymptomatic DIAD mutation carriers with long-term, high-dose gantenerumab exposure. Because this study design included an OLE and external controls, firm conclusions are limited. Funding: National Institutes on Aging, Alzheimer’s Association, GHR, F. Hoffmann-La Roche, Ltd/Genentech Declaration of Interest: R.J.B. is Director of DIAN–TU and Principal Investigator of DIAN–TU-001. He receives research support from the NIA of the NIH, DIAN–TU trial pharmaceutical partner (Hoffman-La Roche Ltd), Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN–TU Pharma Consortium (Active: AbbVie, Biogen, BMS, Eisai, Eli Lilly & Co., Ionis, Janssen, Prothena, Roche/Genentech. Previous: Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience ). He has been a scientific advisor for NAPA Advisory Council Biogen, F. Hoffman-La Roche/Genentech Ltd, 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, CTAD, FBRI, Beeson, Adler Symposium and Fondazione Prada. R.J.B. and D.M.H. 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. R.J.B. and D.M.H. are co-inventors of the stable isotope labeling kinetics and blood plasma assay technology licensed by Washington University to C2N Diagnostics. Through these relationships, Washington University, R.J.B. and D.M.H. are entitled to receive royalties and/or equity from the license agreement with C2N. E.M.M. is the Co-Director of the DIAN-TU. He receives research support from the NIA of the NIH, DIAN-TU002 Trial pharmaceutical partner (Eli Lilly and Company), Alzheimer’s Association, and GHR Foundation. He has been a consultant to Astra Zeneca, 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 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. J.J.G.L. is Co-Medical Director of DIANTU. He receives research support from the NIA of the NIH and the Alzheimer’s Association. D.B.C. is Co-Medical Director of DIAN–TU. He receives royalties from Wolters Kluwer. He serves as scientific consultant to F. Hoffmann-La Roche Ltd/Genentech, Wave Life Sciences, Excision BioTherapeutics, Atara Biotherapeutics Inc, Sanofi Genzyme, Cellevolve Bio, Inc., Seagen Inc. 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 Inc, Sanofi Genzyme, Atara Biotherapeutics Inc, Cellevolve Bio, Inc. G.W. serves as a consultant for Alector and Pharmapace. He serves on the data safety monitoring board for Eli Lilly and Co. T.L.S.B. 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 ASNR Alzheimer’s, RSNA Quantitative Imaging Committee, American College of Radiology/ALZ NET and NIH CNN Study Section Chair. B.A.G. receives research support from the NIA of the NIH. G.K., M.B.K., R.S.D., P.D., G.A.K., T.B., A.B., P.F., C.H. and L.K. are employees of F. Hoffmann La Roche. J.H. is a consultant to Parabon Nanolabs, Prothena and AlzPath. He serves on the data safety monitoring board for Caring Bridge and Wall-E. A.J.A. receives research support from the NIA of the NIH and he is a consultant to Albert Einstein College of Medicine. R.J.P. and A.E.R. receives research support from the NIA of the NIH. C.C. receives research support from the NIA of the NIH and the Michael J. Fox Foundation. He is a consultant for Circular Genomics and Alector. C.X. receives research support from the NIH and he is a consultant for Diadem. He serves of the FDA Advisory Committee on Imaging Medical Products. A.A.G. is a consultant for Genentech and Muna Therapeutics. J.C.M. 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 center in Minority Aging Research. He has been an invited speaker for the AAIM Longer Life Foundation and the International Brain Health Symposium. He serves on the data safety monitoring board for Cure Alzheimer’s Fund and LEADS Advisory Board. D.M.H. receives research support from the NIH. He serves as a consultant for Genentech, Denali, and Cajal Neurosciences. He is a co-inventor of the stable isotope labeling kinetics and blood plasma assay technology licensed by Washington University to C2N Diagnostics. Through these relationships, Washington University, D.M.H. is entitled to receive royalties and/or equity from the license agreement with C2N. B.J.S. 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 and Altheneum, Slingshot. She received honoraria from the AAN and the ANA. She receives royalties from Elsevier. C.M. 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 and F. Hoffman La Roche/Genentech, Eisai and Immunobrain. E.R. receives research support from the NIH, ADDF and Bluefield Projectx. He receives royalties from Genentech. He is a consultant for AGTC. He serves on the data safety monitoring board for Eli Lilly and serves as fiduciary for the Society for Neuroscience. C.H.V.D. has served as a consultant for F. Hoffmann-La Roche Ltd, Cervel, Ono and Eisai and received grant support for clinical trials from F. Hoffmann-La Roche Ltd, Eli Lilly and Company, Biogen, Genetech, Janssen, Eisaiand Cerevel. R.S.V. receives grant support from ISCIII. 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. W.S.B. received financial support from Roche to attend an educational meeting about management of Alzheimer’s disease. S.G. 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. D.R.G. is a consultant for Eisai, Biogen and Fujirebio, Inc. He has received honoraria from GE Healthcare and he serves on the data safety committee for Artery Therapeutics, Inc. G.S.H. receives research support from the NIH, 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. M.M. receives research support from the Ontario Brain Institute, Women’s Brain Health Initiative, Brain Canada, Roche, Canadian Institutes of Health Research, 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. B.D. is a consultant for Fondation Recherche Alzheimer, Qynapse and Eisai and is an unpaid board member for the Foundation Claude Pompidou. J.P. serves on the data safety committee for Biogen and Borhinger. L.S.H. receives research support from the NIH, Acumen, Alector, Biogen, Cognition, EIP, Eisai, Ferrer, Genentech, Janssen/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. J.C. receives research support from the NIH and the Doris Duke Charitable Foundation. He is a consultant for MedaCorp. G.D. receives research support from NIH, Alzheimer’s Association, 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, Inc. He served as an unpaid clinical director for Anti-NMDA Receptor Encephalitis Foundation. He reports owning stocks in ANI Pharmaceuticals and Parabon Nanolabs. N.C.F. 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. A.I.L. 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. T.I. 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. J.L. 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. F.L. receives research support from the NIH, Banner Institute and Roche. He is a consultant for Biogen and Technoquimicas. He has received honoraria from Tecnofarma. P.R.N. is a consultant for Novodisk, Eli Lilly and Biogen. P.R.S. receives research support from the NIH, NHMRC, MRFF and Roth Charitable Foundation. He is a consultant for Outside Opinion Pty Ltd, Moira Clay Consulting Pty Ltd and Neuroscience Research Australia. He is the director of the Australian Dementia Network Ltd, Neuroscience Research Australia, Health Science Alliance, Schizophrenia Research Institute, StandingTall Pty Ltd and Australian Association of Medical Research Institutes. He is president of the Australasian Neuroscience Society. L.T. participates on the data safety monitoring board of Denali and has received research support from the NIH and Alzheimer’s Association. Y.L., S.L.M., A.M.S., C.S., L.I., D.W., S.B.B., C.L.M., S.J., J.K., C.R.J., A.D., R.A., B.G., E.D.H., M.J., J.H.L., J.H.R. and A.L.S. do not declare any competing interests. Ethical Approval: Ethics approval was obtained through a central Institutional Review Board (Advarra) for US sites. Ethics committee approval was obtained at all other participating sites.