A pharmacogenetic framework for disease-modifying clinical trials in Parkinson’s disease

The biological heterogeneity of Parkinson’s disease impedes disease-modifying trials and demands stratified approaches. We present a framework applying pharmacogenetics across three domains: mechanistic stratification, drug-host interactions, and prognostic enrichment. Genetic heterogeneity operates from polygenic scores to single variants, and mechanistic and prognostic effects may conflict with direct consequences for trial power.

Realising this potential requires larger stratified trials, sensitive endpoints and collaborative infrastructure to detect genotype-by-treatment interactions with adequate power. The authors thank the EJS ACT-PD trial team and the wider Parkinson’s disease research community whose work is reviewed here. R.G. is supported by grant funding from the National Institute for Health and Care Research (NIHR) Clinical Research, the Edmond J.

Safra Foundation and Cure Parkinson’s. No specific funding was received for this review. UCL Queen Square Institute of Neurology, Department of Clinical and Movement Neurosciences, London, UK Rowan Gurney, Huw Morris & Thomas Foltynie R.G. declares no competing interests.

H.M. has received funding from Michael J Fox Foundation, Cure Parkinson’s, Progressive Supranuclear Palsy Association, Corticobasal Degeneration Solutions, Drake Foundation, Parkinson’s UK, and the Medical Research Council; has received consulting fees from Roche, Amylyx, and Aprinoia; and has received honoraria for speaking at meetings supported by Kyowa Kirin, The British Medical Journal, and Movement Disorders Society. T.F. has received grants from the National Institute of Health Research, Edmond J Safra Foundation, Michael J Fox Foundation, John Black Charitable Foundation, Cure Parkinson’s, Innovate UK, Janet Owens Research Fellowship, Rosetrees Trust, Van Andel Research Institute, and Defeat MSA; has served on advisory boards for Peptron, AC Immune, Eli Lilly, Voyager Therapeutics, Handl Therapeutics, Gain Therapeutics, Living Cell Technologies, AbbVie, Bluerock, Bayer, and Bial; and has received honoraria for talks sponsored by Bayer, Bial, Profile Pharma, Boston Scientific, and Novo Nordisk. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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