Key considerations for combination therapy in Alzheimer's clinical trials: Perspectives from an expert advisory board convened by the Alzheimer's drug discovery foundation

Jeffrey Cummings¹, Michael Gold², Mark Mintun³, Michael Irizarry⁴, Andrew von Eschenbach⁵, Suzanne Hendrix⁶, Donald Berry⁷, Cristina Sampaio⁸, Kaycee Sink⁹, Jaren Landen¹⁰, Miia Kivipelto¹¹, Michael Grundman¹², Steven E Arnold¹³, Allan Green¹⁴, Katherine Partrick¹⁵, Laura Nisenbaum¹⁶, Aaron Burstein¹⁶, Howard Fillit¹⁷

Affiliations

¹ Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, Las Vegas, NV, USA.
² Compass Pathways, London, UK.
³ Eli Lilly and Company, Indianapolis, IN, USA.
⁴ Eisai Inc, Nutley, NJ, USA.
⁵ Samaritan Health Initiatives, Houston, TX, USA.
⁶ Pentara Corporation, Millcreek, UT, USA.
⁷ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Berry Consultants, LLC, Austin TX, USA.
⁸ CHDI Management, Inc. the company that manages the scientific activities of CHDI Foundation Princeton, NJ, USA, Faculdade Medicina University of Lisbon, Lisboa, Portugal.
⁹ Genentech Inc., South San Francisco, CA, USA.
¹⁰ Biogen, Cambridge, MA, USA at the time of advisory board.
¹¹ Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden, Ageing Epidemiology Research Unit (AGE), School of Public Health, Faculty of Medicine, Imperial College London, UK, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
¹² Global R&D Partners, LLC., San Diego, CA, USA and University of California, San Diego, San Diego, CA, USA.
¹³ Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ SDG, LLC, Cambridge, MA, USA.
¹⁵ Independent Researcher, Albuquerque, NM, USA.
¹⁶ Alzheimer's Drug Discovery Foundation, New York, NY, USA.
¹⁷ Alzheimer's Drug Discovery Foundation, New York, NY, USA. Electronic address: hfillit@alzdiscovery.org.

PMID: 39800453
PMCID: PMC12183988
DOI: 10.1016/j.tjpad.2024.100001

Key considerations for combination therapy in Alzheimer's clinical trials: Perspectives from an expert advisory board convened by the Alzheimer's drug discovery foundation

Jeffrey Cummings et al. J Prev Alzheimers Dis. 2025 Jan.

. 2025 Jan;12(1):100001.

doi: 10.1016/j.tjpad.2024.100001. Epub 2025 Jan 1.

Authors

Affiliations

¹ Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, Las Vegas, NV, USA.
² Compass Pathways, London, UK.
³ Eli Lilly and Company, Indianapolis, IN, USA.
⁴ Eisai Inc, Nutley, NJ, USA.
⁵ Samaritan Health Initiatives, Houston, TX, USA.
⁶ Pentara Corporation, Millcreek, UT, USA.
⁷ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Berry Consultants, LLC, Austin TX, USA.
⁸ CHDI Management, Inc. the company that manages the scientific activities of CHDI Foundation Princeton, NJ, USA, Faculdade Medicina University of Lisbon, Lisboa, Portugal.
⁹ Genentech Inc., South San Francisco, CA, USA.
¹⁰ Biogen, Cambridge, MA, USA at the time of advisory board.
¹¹ Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden, Ageing Epidemiology Research Unit (AGE), School of Public Health, Faculty of Medicine, Imperial College London, UK, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
¹² Global R&D Partners, LLC., San Diego, CA, USA and University of California, San Diego, San Diego, CA, USA.
¹³ Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ SDG, LLC, Cambridge, MA, USA.
¹⁵ Independent Researcher, Albuquerque, NM, USA.
¹⁶ Alzheimer's Drug Discovery Foundation, New York, NY, USA.
¹⁷ Alzheimer's Drug Discovery Foundation, New York, NY, USA. Electronic address: hfillit@alzdiscovery.org.

PMID: 39800453
PMCID: PMC12183988
DOI: 10.1016/j.tjpad.2024.100001

Abstract

There is growing consensus in the Alzheimer's community that combination therapy will be needed to maximize therapeutic benefits through the course of the disease. However, combination therapy raises complex questions and decisions for study sponsors, from preclinical research through clinical trial design to regulatory, statistical, and operational considerations. In January 2024, the Alzheimer's Drug Discovery Foundation convened an expert advisory board to discuss the key considerations in each of these areas. Experts agreed on the need to prioritize a combination therapy approach that encompasses a wide range of targets associated with aging and the underlying biology of Alzheimer's disease. Progress in combination therapy could be accelerated by leveraging preclinical research and Phase 1 and 2A trials to identify the most promising combinations for further development, exploring repurposed agents with available preclinical and clinical data, building collaborations across sectors to support operational challenges, and planning for the likely impact of anti-amyloid beta-protein monoclonal antibody therapies on future clinical trial designs.

Keywords: Alzheimer's disease; Biomarkers; Clinical trials; Combination therapy; Preclinical research.

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Conflict of interest statement

Declaration of interests JC has provided consultation to Acadia, Acumen, ALZpath, Annovis, Aprinoia, Artery, Biogen, Biohaven, BioXcel, Bristol-Myers Squib, Eisai, Fosun, GAP Foundation, Green Valley, Janssen, Karuna, Kinoxis, Lighthouse, Lilly, Lundbeck, LSP/eqt, Merck, MoCA Cognition, New Amsterdam, Novo Nordisk, Optoceutics, Otsuka, Oxford Brain Diagnostics, Praxis, Prothena, ReMYND, Roche, Scottish Brain Sciences, Signant Health, Simcere, sinaptica, TrueBinding, and Vaxxinity pharmaceutical, assessment, and investment companies. JC owns the copyright of the Neuropsychiatric Inventory. JC has stocks/options in Artery, Vaxxinity, Behrens, Alzheon, MedAvante-Prophase, Acumen. JC is supported by NIGMS grant P20GM109025; NIA grant R35AG71476; NIA R25 AG083721-01; Alzheimer's Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; Joy Chambers-Grundy Endowment. AG is external counsel for the ADDF and a member of the ADDF Board of Overseers; AG has no financial interest in the materials or related companies discussed in this manuscript. MG(b) is an employee of Global R&D Partners, LLC. JL was a Biogen colleague when this panel was conducted and is a shareholder. AE holds Board of Director positions on Bausch and Lomb, Trisalus Biosciences and the Reagan Udall Foundation. MCI is an employee of Eisai, Inc. KC is a full-time employee of Genentech, Inc., a member of the Roche Group, and a shareholder in F. Hoffmann-La Roche. CS has received consulting fees from Novartis, Biogen, and Eisai. MK is on the scientific advisory boards for Combinostics, BioArtic, Eisai, Eli Lilly, and Nestle, has served as a speaker for Eisai, Nestle, Nutricia, and Novo Nordisk, is the Director of R&D, Karolinska University Hospital, and receives grant support from Academy of Finland, Swedish Research Council, Alzheimer's Research and Prevention Foundation, EU 7th framework, CIMED, JPND, IMI, Wallenberg Clinical grant, FORTE, KI-Janssen Strategic Collaboration, Imperial College ITMAT, Innovative Health Initiative (IHI), Gates Ventures, ADDI, Alzheimer's Drug Discovery Foundation, Part the Cloud. DB is co-owner of Berry Consultants, LLC, a company that designs adaptive Bayesian clinical trials for pharmaceutic and medical device companies, NIH cooperative groups, patient advocacy groups, and international consortia. SH is owner of Pentara Corporation, who performs statistical consulting services for dozens of companies in the Neurodegenerative space. SEA has received grants or contracts from AbbVie, AC Immune, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Amylyx, Athira, Challenger Foundation, Chromadex, EIP Pharma, Ionis Pharmaceuticals, Janssen Pharmaceuticals, John Sperling Foundation, National Institutes of Health, Novartis, and Seer Biosciences, and has provided consultation to BioVie, Daewoong Pharmaceutical, EIP Pharma, and Risen Pharmaceutical Technology. SEA has received payment for testimony from Boyle Shaughnessy Law, is a co-inventor on a pending patent application related to assays for neurological biomarkers, and on advisory boards for Allyx Therapeutics, Bob's Last Marathon, Cortexyme/Quince, Jocasta Neuroscience, Sage Therapeutics, Sanofi, Vandria, and BioVie. HF has consulted with Alector, LifeWorx, Mediflix, Samus Therapeutics, Otsuka Pharmaceuticals, Pinteon Therapeutics and has served as an unpaid consultant for Eli Lilly. MG(a), KP, LN and AB have no conflicts of interest to disclose.

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Key considerations for combination therapy in Alzheimer's clinical trials: Perspectives from an expert advisory board convened by the Alzheimer's drug discovery foundation

Affiliations

Key considerations for combination therapy in Alzheimer's clinical trials: Perspectives from an expert advisory board convened by the Alzheimer's drug discovery foundation

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical