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.
Original language | English |
---|---|
Pages (from-to) | 1187-1196 |
Number of pages | 10 |
Journal | Nature medicine |
Volume | 27 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2021 |
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In: Nature medicine, Vol. 27, No. 7, 07.2021, p. 1187-1196.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease
AU - the Dominantly Inherited Alzheimer Network–Trials Unit
AU - Salloway, Stephen
AU - Farlow, Martin
AU - McDade, Eric
AU - Clifford, David B.
AU - Wang, Guoqiao
AU - Llibre-Guerra, Jorge J.
AU - Hitchcock, Janice M.
AU - Mills, Susan L.
AU - Santacruz, Anna M.
AU - Aschenbrenner, Andrew J.
AU - Hassenstab, Jason
AU - Benzinger, Tammie L.S.
AU - Gordon, Brian A.
AU - Fagan, Anne M.
AU - Coalier, Kelley A.
AU - Cruchaga, Carlos
AU - Goate, Alison A.
AU - Perrin, Richard J.
AU - Xiong, Chengjie
AU - Li, Yan
AU - Morris, John C.
AU - Snider, B. Joy
AU - Mummery, Catherine
AU - Surti, G. Mustafa
AU - Hannequin, Didier
AU - Wallon, David
AU - Berman, Sarah B.
AU - Lah, James J.
AU - Jimenez-Velazquez, Ivonne Z.
AU - Roberson, Erik D.
AU - van Dyck, Christopher H.
AU - Honig, Lawrence S.
AU - Sánchez-Valle, Raquel
AU - Brooks, William S.
AU - Gauthier, Serge
AU - Galasko, Douglas R.
AU - Masters, Colin L.
AU - Brosch, Jared R.
AU - Hsiung, Ging Yuek Robin
AU - Jayadev, Suman
AU - Formaglio, Maité
AU - Masellis, Mario
AU - Clarnette, Roger
AU - Pariente, Jérémie
AU - Dubois, Bruno
AU - Pasquier, Florence
AU - Jack, Clifford R.
AU - Koeppe, Robert
AU - Snyder, Peter J.
AU - Bateman, Randall J.
N1 - Funding Information: 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/ourresearch/clinicaltrial/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. HoffmannLa Roche, Ltd/Genentech and Eli Lilly and Company, the DIAN–TU Pharma Consortium (https://dian.wustl. edu/ourresearch/thepharmaconsortium/), 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 whollyowned 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, U01AG042791S1 (FNIH and Accelerating Medicines Partnership), R01AG046179 and R01AG053267S1. This research was also supported by the Alzheimer’s Association, Eli Lilly and Company, F. HoffmanLaRoche Ltd, Avid Radiopharmaceuticals GHR Foundation and an anonymous organization. Cogstate and Signant Health offered inkind 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. Funding Information: DIAN–TU001 is the first global treatment trial in DIAD and the first AD prevention trial to test amyloidtargeting drugs. The trial had excellent recruitment and retention due to the dedication of the DIAD participants and families, researchers and medical providers. This adaptive multidrug multiarm platform trial was supported by a strong publicprivate partnership of the National Institutes of Health (NIH), industry, advocacy groups and philanthropic organizations. The success of the DIAN–TU platform in completing the first drug arms and continuing ongoing arms demonstrates the potential for informative global platform trials, even with rare diseases (Supplementary Fig. 9)39. Finally, since several prevention trials in sporadic AD are now underway or planned, the results from the DIAN–TU001 study have provided critical insight regarding the need for better and more sensitive cognitive measures in asymptomatic populations and the use of higher doses for longer periods to maximize target engagement. Although no cognitive or clinical benefit was observed, improvements in downstream biomarkers in participants treated with gantenerumab support the possibility of preventing or slowing the biological progression of AD via amyloid lowering, especially at the earlier stages of the disease. Funding Information: 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. HoffmannLa 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. HoffmannLa 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 investigatorinitiated research funding from the NIH, the Alzheimer’s Association, the BarnesJewish 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. HoffmannLa 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. HoffmannLa 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. HoffmannLa 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. HoffmannLa 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. HoffmannLa 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. HoffmannLa 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. HoffmannLa 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. HoffmannLa Roche Ltd and Eisai and received grant support for clinical trials from F. HoffmannLa 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. HoffmannLa Roche Ltd. M.M. is a consultant to Arkuda Therapeutics, Ionis and Alector and receives research funding from F. HoffmannLa 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. HoffmannLa 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. HoffmannLa 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. HoffmannLa 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–TU001. He receives research support from the NIA of the NIH, DIAN–TU trial pharmaceutical partners (Eli Lilly and Company, F. HoffmanLa 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. HoffmannLa 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. HoffmanLa 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108993807&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01369-8
DO - 10.1038/s41591-021-01369-8
M3 - Article
C2 - 34155411
AN - SCOPUS:85108993807
SN - 1078-8956
VL - 27
SP - 1187
EP - 1196
JO - Nature medicine
JF - Nature medicine
IS - 7
ER -