Advancing drug development for systemic sclerosis by prioritising findings from human genetic association studies

OBJECTIVES: Systemic sclerosis (SSc) is a rare rheumatological disease associated with significant morbidity and mortality. Despite significant recent international clinical trial activity, the yield of approved compounds has been disappointingly low. Our aim was to identify and prioritise potential 'druggable' targets with insights from human genetics, by integrating the available evidence with publicly available bioinformatics sources relevant for SSc drug development. METHODS: Genetic variants for SSc were identified through a search of the GWAS catalog, and the associated-mapped genes were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured literature searches and review of the evidence on MEDLINE and ClinialTrials.gov for each individual drug and its association with SSc. RESULTS: We identified 89 unique drugs, none of which are included in existing SSc guidelines/recommendations. Amlitelimab (anti-OX40L monoclonal antibody) is currently being explored in CONQUEST, a multicentre randomised controlled platform trial for SSc-ILD. Key groupings of drug therapies were 1) female sex hormones and function, 2) neurotransmitter-targeting therapies, and 3) inflammatory-fibrotic pathways. The Janus kinase (JAK)/STAT pathway is an attractive therapeutic target in SSc, targeting known pathobiology. CONCLUSION: Our systematic approach, combining evidence from different bioinformatics platforms, has identified drug opportunities for repurposing/druggable targets for SSc. A novel and unexpected finding was the identification of multiple neurotransmitter-targeting drug therapies, particularly relevant to SSc-related Raynaud's phenomenon and gastrointestinal involvement. Future studies of these candidates for SSc drug repurposing are indicated; many of which are widely available and often inexpensive.