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A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Abstract

Dominantly inherited Alzheimer’s disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4–7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

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Fig. 1: Randomization, group assignment and follow-up.
Fig. 2: Cognitive and clinical results.
Fig. 3: Key biomarker results.

Data availability

Data access to the DIAN–TU trial data will follow the policies of the DIAN–TU data access policy55, which complies with the guidelines established by the Collaboration for Alzheimer’s Prevention. Patient-related data not included in the paper were generated as part of a clinical trial and may be subject to patient confidentiality. Any data and materials that can be shared will be released via a data/material sharing agreement. Requests to access the DIAN–TU-001 trial data can be made at https://dian.wustl.edu/our-research/for-investigators/diantu-investigator-resources/. All code for data cleaning and analysis associated with the current submission is available upon request to the corresponding author and is provided as part of the replication package.

Code availability

All code for data cleaning and analysis associated with the current submission is available upon request to the corresponding author and is provided as part of the replication package.

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Acknowledgements

We gratefully acknowledge the outstanding commitment of the participants, family members and caregivers whose participation was critical to the success of the DIAN–TU trial. We thank the DIAN–TU Funding and Study Team (https://dian.wustl.edu/our-research/clinical-trial/funding/) for their exceptional dedication and accomplishments, which ensured the success of the trial. We thank the DIAN–EXR and DIAN–OBS study teams for their support on recruitment and commitment to family members. We acknowledge the robust intellectual collaboration between the DIAN–TU investigators, participants and family members, F. Hoffmann-La Roche, Ltd/Genentech and Eli Lilly and Company, the DIAN–TU Pharma Consortium (https://dian.wustl.edu/our-research/the-pharma-consortium/), the NIH, and regulatory representatives who were critical in making this study possible. We thank the Alzheimer’s Association, GHR Foundation, an anonymous organization, other industry partners (Avid Radiopharmaceuticals, a wholly-owned subsidiary of Eli Lilly and Company, Signant Health and Cogstate) and regulatory representatives for their support. We also thank L. Ryan from the National Institute on Aging (NIA) for her key contributions in leadership and scientific guidance on this project. The research reported in this publication was supported by the NIA of the NIH under award nos. U01AG042791, U01AG042791-S1 (FNIH and Accelerating Medicines Partnership), R01AG046179 and R01AG053267-S1. This research was also supported by the Alzheimer’s Association, Eli Lilly and Company, F. Hoffman-LaRoche Ltd, Avid Radiopharmaceuticals GHR Foundation and an anonymous organization. Cogstate and Signant Health offered in-kind support. The DIAN–OBS was supported by the NIA of the NIH (DIAN, U19AG032438), the German Center for Neurodegenerative Diseases, Raúl Carrea Institute for Neurological Research, partial support by the Research and Development Grants for Dementia from the Japan Agency for Medical Research and Development (AMED) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute.

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R.J.B., S.S., M. Farlow, D.B.C., E.M., G.W., S.L.M., A.M.S., J.H., T.L.S.B., A.M.F., A.A.G., C.C., R.J.P., C.X., J.C.M., S.W.A., K.C.H., R.Y., J.R.S., M.B., P.D., R.S.D., P.F., C.G. and G.A.K. designed the study and wrote the study protocol. J.M.H., A.J.A., Y.L., J.J.L.G., B.A.G., S.M.B., R.K., P.J.S., P.S.A., R.G.T., M.A.M. and B.A.W. provided additional input to the study design. R.J.B., S.S., M. Farlow, D.B.C., E.M., S.L.M. and A.M.S. coordinated the trial. B.J.S., C.M., G.M.S., D.H., D.W., S.B.B., J.J.L., I.Z.J.V., E.D.R., C.H.V.D., L.S.H., R.S.V., W.S.B., S.G., D.R.G., C.L.M., J.R.B., G.R.H., S.J., M. Formaglio, M.M., R.C., J.P., B.D. and F.P. recruited and treated the patients and collected the data. G.W., Y.L., C.X., S.M.B., B.A.W., S.W.A. and P.D. performed the statistical analysis. S.L.M. and A.M.S. were responsible for central and local data management. A.F. and K.A.C. performed the analysis of the CSF biomarkers data. C.R.J.J., T.L.S.B. and B.A.G. performed the processing and analysis of the neuroimaging data. A.G. and C.C. were responsible for the sequencing and genetic analysis. Every author contributed to the initial draft of the manuscript and agreed on submission for publication. All authors interpreted the data, reviewed the manuscript and approved the final version.

Corresponding author

Correspondence to Randall J. Bateman.

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Competing interests

S.S. was the Project Arm Leader for the gantenerumab arm. He also receives research support and is a consultant to Eisai, Novartis, Genentech, F. Hoffmann-La Roche Ltd, GemVax, Avid Radiopharmaceuticals and Eli Lilly and Company. M. Farlow was the Project Arm Leader for the solanezumab arm. He receives research support and is consultant to Eli Lilly and Company, Eisai, Novartis, Green Valley, AbbVie, Biogen, Eisai, F. Hoffmann-La Roche Ltd, Suvan, vTv Therapeutics, Vaccinex, QR Pharma, Avanir Pharmaceuticals, AZTherapies, Cerecin, Cognition Therapeutics, Cortexyme, Longeveron, Otsuka Pharmaceutical, Samumed and Takeda. A.M.F. is the Biomarker Core Leader of DIAN–TU. She is a member of the scientific advisory boards (SABs) for Roche Diagnostics, Genentech and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR and Otsuka Pharmaceuticals. T.L.S.B. has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. She participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Janssen and F. Hoffmann-La Roche Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker’s Bureau for Biogen. 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. He is funded by NIH grant nos. P30 AG066444, P01AG003991, P01AG026276, U19 AG032438 and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. J.H. is an employee of Hitchcock Regulatory Consulting and has consulted for Acumen Pharmaceuticals, Axon Advisors, Critical Path Institute, Gerson Lehrman Group, H. Lundbeck, High Lantern Group, Regenera Pharma Ltd, UCB Biopharma SPRL, United Neuroscience, Vaccinex and Washington University. She is retired from Eli Lilly and Company and is an Eli Lilly and Company shareholder. E.M. is the Associate Director of the DIAN–TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and Alector. He is scientific consultant for Eisai and Eli Lilly and Company and has received institutional grant support from Eli Lilly and Company, F. Hoffmann-La Roche Ltd. and Janssen. D.B.C. is Medical Director of DIAN–TU and serves as scientific consultant to Biogen, Takeda, Millennium, Genzyme, Amgen, F. Hoffmann-La Roche Ltd/Genentech, GlaxoSmithKline, Serono, Inhibikase Therapeutics, Dr Reddy’s Laboratories, Bristol Myers Squibb, Atara, Mitsubishi Tanabe Pharma, Excision BioTherapeutics, UpToDate and Wolters Kluwer. He serves on the Data and Safety Monitoring Board (DSMB)/Data Monitoring Committees for F. Hoffmann-La Roche Ltd/Genentech, Wave, EMD Serono, Shire, Pfizer and Sanofi. He has carried out legal consulting for Cook County, State Farm, Wilke & Wilke PC, Shevlin Smith and Sal Indomenico & Associates PC. He receives research support from the NIH National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences and NIA. A.J.A. has served as a consultant for Biogen and H. Lundbeck. J.H. is a paid consultant for F. Hoffmann-La Roche Ltd, Takeda and H. Lundbeck and is on the Data Safety and Monitoring Board for Eisai. C.R.J. Jr serves on an independent data monitoring board for F. Hoffmann-La Roche Ltd, has consulted for and served as a speaker for Eisai and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from the NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. C.C. receives research support from Biogen, Eisai, Alector and Parabon. C.C. is a member of the advisory board of Vivid Genetics, Halia Therapeutics and ADx Healthcare. C.M. is a consultant for Biogen. L.S.H. is a consultant for Cortexyme, Eisai, Eli Lilly and Company, Medscape and Prevail. He receives research grant support from Abbvie, Alector, Biogen, Genentech, Eli Lilly and Company and F. Hoffmann-La Roche Ltd. J.P. is on the Speakers’ Bureau for Biogen. E.D.R. is a consultant for Biogen, Applied Genetic Technologies Corporation and AVROBIO, receives funding from Alector and is the owner of intellectual property related to tau. S.G. is a member of the SAB for Alzheon, Biogen, Eli Lilly and Company and TauRx and a member of the Data Safety Monitoring Board for Alzheimer’s Disease Cooperative Study, ATRI and Banner Health. C.H.V.D. has served as a consultant for F. Hoffmann-La Roche Ltd and Eisai and received grant support for clinical trials from F. Hoffmann-La Roche Ltd, Eli Lilly and Company, Biogen, Genetech, Merck, Janssen, Eisai, Novartis and Biohaven Pharmaceuticals. R.S.V. served on a SAB for Ionis Pharmaceuticals. B.D. receives research support from F. Hoffmann-La Roche Ltd. M.M. is a consultant to Arkuda Therapeutics, Ionis and Alector and receives research funding from F. Hoffmann-La Roche Ltd, Novartis and Alector. D.R.G. is a consultant to Biogen, Esai, Fujirebio and Amprion and is on the DSMB for Cognition Therapeutics. G.R.H. has received research support as a clinical trial site investigator for Anavax, Biogen and F. Hoffmann-La Roche Ltd. He has received research funding from the Canadian Institutes of Health Research, Alzheimer Society of Canada and the NIH. P.S.A. collaborates with Eli Lilly and Company and F. Hoffmann-La Roche Ltd on drug development in AD and has a research grant from Eli Lilly and Company. M.B., P.D., R.S.D., P.F., C.G. and G.A.K. are employees and shareholders of F. Hoffmann-La Roche Ltd. S.W.A., K.C.H., M.A.M., J.R.S. and R.Y. are employees and shareholders of Eli Lilly and Company. 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 partners (Eli Lilly and Company, F. Hoffman-La Roche Ltd and Avid Radiopharmaceuticals), Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN–TU Pharma Consortium (active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche Ltd/Genentech; previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience). He has been an invited speaker and consultant for AC Immune, F. Hoffman-La Roche Ltd and Janssen and a consultant for Amgen and Eisai. D.H., the Department Head of Neurology where the research is being conducted, is an inventor on patents for solanezumab, currently being tested in the DIAN–TU clinical trials. If solanezumab is approved as a treatment for AD or dominantly inherited AD, Washington University and D.H. will receive part of the net sales of solanezumab from Eli Lilly and Company, which has licensed patents related to solanezumab from Washington University. 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. S.B.B., S.M.B., W.S.B., K.A.C., D.H., B.A.G., J.J.L., J.J.L.G., M. Formaglio, S.J., R.C., Y.L., R.K., I.Z.J.V., S.L.M., G.M.S., C.X., D.W. and J.R.B. do not declare any competing interests.

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Peer review information Nature Medicine thanks Gil Rabinovici, Todd Golde and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jerome Staal was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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DIAN–TU Study Team, Supplementary Figs. 1–10 and Supplementary Tables 1–4.

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Salloway, S., Farlow, M., McDade, E. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med 27, 1187–1196 (2021). https://doi.org/10.1038/s41591-021-01369-8

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