Evaluation of dose-dependent treatment effects after mid-trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect. Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes. Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes. Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies.Dose-dependent treatment effects were observed in some biomarkers.No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.

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© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.

Déclaration de conflit d'intérêts

Guoqiao Wang, PhD, is the biostatistics core co‐leader for the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and as a statistical consultant for Alector. Eric McDade, DO, is the Associate Director of the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and Alector; as a scientific consultant for Eisai and Eli Lilly and Company; receiving institutional grant support from Eli Lilly and Company, F. Hoffmann‐La Roche, Ltd., and Janssen. Anne M. Fagan, PhD, is the Biomarker Core Leader of the DIAN‐TU. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and DiademRes and also consults for DiamiR and Siemens Healthcare Diagnostics, Inc. Tammie L.S. Benzinger, MD, PhD, has investigator‐initiated research funding from the NIH, the Alzheimer's Association, the Barnes‐Jewish Hospital Foundation, and Avid Radiopharmaceuticals. Dr. Benzinger participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen, 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. David B. Clifford, MD, is Medical Director of the DIAN‐TU and serves as scientific consultant to Biogen, Takeda, Millennium, Genzyme, Amgen, F. Hoffmann‐La Roche, Ltd./Genentech, Glaxo Smith Kline, Serono, Inhibikase, Dr Reddy's Lab, Bristol Myers Squibb, Atara, Mitsubishi Tanabe, Excision BioTherapeutics, Up to Date, and Wolters Kluwer; on DSMB/Data Monitoring Committees for Genentech/ F. Hoffmann‐La Roche, Ltd., Wave, EMD Serono, Shire, Pfizer, Sanofi; does legal consulting: Cook County, State Farm, Wilke & Wilke PC, Shevlin Smith, Sal Indomenico PC. He receives research support from NIH NINDS, NIMH, NIAID, NCATS, and NIA. Andrew J. Aschenbrenner, PhD, has served as a consultant for Biogen Inc, and H. Lundbeck HS. Jason Hassenstab, PhD, is a paid consultant for F. Hoffmann‐La Roche, Ltd., Takeda, and Lundbeck, and is on the Data Safety and Monitoring Board for Eisai. Catherine Mummery, MD, is a consultant for Biogen. Mario Masellis, MD, is a consultant to Arkuda Therapeutics, Ionis, and Alector and receives research funding from F. Hoffmann‐La Roche, Ltd., Novartis, and Alector. Serge Gauthier, MD, FRCPC, is a member of the Scientific Advisory Board for Alzheon, Biogen, Eli Lilly and Company, and TauRx and a member of the Data Safety Monitoring Board for ADCS, ATRI, and Banner Health. Scott Andersen, MS; Karen C. Holdridge, MPH; Saptarshi Chatterjee, PhD; John R. Sims, MD; and Roy Yaari, MD are employees and shareholders of Eli Lilly and Company. Randall J. Bateman, MD, is the Director of the DIAN‐TU and Principal Investigator of the DIAN‐TU‐001. He receives research support from the National Institute on Aging of the National Institutes of Health, 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 for Novartis and serves on the Advisory Board for F. Hoffman La Roche, Ltd. Barbara A. Wendelberger, PhD; Susan L. Mills BS; Anna M. Santacruz BS; Kelley A. Coalier, MS; Brian A. Gordon, PhD; Jorge J. Libre‐Guerra, MD; Austin McCullough; Nelly Joseph‐Mathurin, PhD; Charlie Chen; Yan Li, PhD; Chengji Xiong, PhD, have no conflicts of interest to disclose. Paul Delmar, Geoffrey A. Kerchner, Tobias Bittner, and Carsten Hofmann are full‐time employees of F. Hoffmann‐La Roche, Ltd. and own stock in F. Hoffmann‐La Roche, Ltd. David Holtzman, MD, the prior Department Head of Neurology where the research was conducted, is an inventor on patents for solanezumab, which was tested in the DIAN‐TU‐001 clinical trial. If solanezumab is approved as a treatment for AD or dominantly inherited AD, Washington University and Dr. Holtzman will receive part of the net sales of solanezumab from Eli Lilly and Company, which has licensed patents related to solanezumab from Washington University. All the other authors reported no conflicts of interest. Author disclosures are available in the supporting information.