The anti-inflammatory efficacy of melanocortin drugs is influenced by genetic variation at MC1R.

The melanocortin 1 receptor (MC1R) is a pro-resolving anti-inflammatory target under clinical development for scleroderma, arthritis, light intolerance or melanoma prevention. Genetic diversity at MC1R is high in certain populations, with some variants associated with loss-of function (LoF) resulting in red hair and poor tanning response. However, how these variants influence the anti-inflammatory efficacy of drug candidates targeting MC1R is unknown. We analysed the impact of 30 variants on receptor signalling (cAMP and phospho-ERK) and the anti-inflammatory response to nine agonists on the whole-blood assay on healthy volunteers. LoF presents as a continuum rather than as a binary characteristic (benign/pathogenic) and differentially affects each signalling pathway, undermining the usefulness of in silico tools to predict variants pathogenicity. Moreover, variants affected compounds differently, even causing LoF, no effect or gain-of-function depending on the compound tested. We identified responders and non-responders to melanocortin compounds, and the efficacy of most compounds (determined as reduction of cytokine release) was diminished by the presence of variants at MC1R. Carrying red-hair variants (RHC) also associated with reduced efficacy but not having light skin phototype. These data encourage the incorporation of pharmacogenetics strategies during melanocortin drug development programs to ensure targeted interventions for maximal efficacy and safety.