Building a roadmap for developing combination therapies for Alzheimer’s disease

Abstract

Combination therapy has proven to be an effective strategy for treating many of the world’s most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer’s disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer’s Disease Coalition, the Critical Path Institute and the Alzheimer’s Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality.

Keywords:

• Alzheimer’ disease
• combination therapy
• collaboration
• co-development
• novel therapy

Financial & competing interests disclosure

JQ Trojanowski may accrue revenue on patents submitted by the University of Pennsylvania on methods and diagnostics that he invented. F Owen Fields is employed by Pfizer and has stock options in Pfizer. R Sperling has served as a consultant to Roche, Isis, Genentech, Janssen and has received research support from Eli Lilly, Eisai, Avid and Janssen. J Luthman is an employee of Eisai and owns shares in AstraZeneca and Merck. S Salloway has received research support from Biogen Idec, Merck Lilly, Roche and Genentech. J McKew was an employee of aTyr pharma at the time of publication. V Gribkoff was an employee of Elan at the time of the meeting. S Potkin has received grant support, funding, honoraria, consultancy fees from the following companies; Alkermes, Eli Lilly, Forest, FORUM Pharmaceuticals, Genentech, Janssen, Lundbeck, Merck, Novartis, Otsuka, Roche, Sunovion, Takeda, Toyama and Vanda. E Liu is an employee of Janssen. C Bountra is funded by the Wellcome Trust, IMI, Abbvie, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novartis, Pfizer and Takeda. M Krams is employed by J&J. D Berry is co-owner of Berry Consultants, LLC. JA Ware is a full time employee of Eli Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer’s Disease Coalition, the Critical Path Institute and the Alzheimer’s Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality.

• Research over the past 30 years has broadened the view of the multifactorial nature and heterogeneity of AD. A scientific rationale is emerging for the use of more than one drug to treat this disease.

• In addition to Aβ and tau, classes of targets discussed that currently seem most viable to begin exploiting in combination include targets related to lipid metabolism, such as APOEϵ4, TDP-43, α-synuclein and targets related to inflammation. Other targets mentioned include growth factors, receptor modulators insulin, mitochondrial agents, calcium-channel modulators and neuroprotective agents.

• Modeling and simulation will be necessary to help identify subgroups of patients that show disease progression on a clinically meaningful endpoint. An inventory of existing tools, a plan on how to use them in combination trials for early AD and the identification of data will be needed for optimal modeling.

• Collaboration and data sharing are a critical aspect of any trial that incorporates assets from multiple sources. Collaboration must be structured to build knowledge, avoid duplication of efforts and learn from mistakes.

• Financial support for building a collaboration on combination therapy for AD is essential. Questions remain as to whether a new consortium should be created or if existing entities have the bandwidth and motivation to pursue combination therapy.

• Incentives that could foster collaboration to test multiple drugs in combination include the possibility of seeing enhanced signals that could suggest alliances; access to animal models; an available cohort of well-characterized, ready-to-enroll subjects in whom biomarker and genetic status is known; access to cutting edge tools for assessments; modeling, simulation, and statistical expertise; and cost savings and faster completion of early stage drug development efforts.

• Existing guidance from regulatory authorities and their participation in discussions on combination therapy to date demonstrate the regulators’ interest in ensuring that trials of combination therapies are designed to be as effective and efficient as possible.