ESPE Abstracts

Background: The MC4R pathway is the principal regulator of mammalian energy balance through its modulation of energy intake and energy expenditure. Variants in genes associated with the MC4R pathway can result in rare genetic diseases of obesity. Clinical data in patients with genetic defects in the MC4R pathway indicate that setmelanotide, an MC4R agonist, can effectively reduce weight and hunger in scientifically rationalized obese subpopulations in which MC4R-pathway deficit is a contributing factor to obesity. Here we introduce an evidence-based framework designed to evaluate various genes’ relevance to the MC4R pathway to identify those genetic patient populations most likely to benefit from long-term setmelanotide therapy.

Methods and Results: This framework utilizes a set of clinical (human genetics) and non-clinical experimental evidence to evaluate MC4R pathway relevance and is based on the core principles of the NIH ClinGen Gene-disease Clinical Validation approach which is the industry standard for assessing gene-disease relationships. Human genetic evidence helps define the contribution of the gene to human obesity, while experimental evidence assesses involvement of the gene in the function of MC4R pathway. The cumulative burden of this evidence is used to classify MC4R pathway genes into four strength-based tiers: very strong, strong, moderate, weak. The nature, quantity, and quality of evidence required for each tier builds upon that of the previous tier, with higher ranked genes being most likely to define patient populations potentially responsive to long-term setmelanotide treatment. Based on a comprehensive literature review, 118 MC4R pathway genes were identified and rank ordered: 8 “very strong”, 29 “strong”, 22 “moderate”, 59 “weak”. Importantly, clinically meaningful weight and hunger score reductions following treatment with setmelanotide have been previously demonstrated in patients with obesity due to variants in 6 genes, all initially classified as “very strong” or “strong”, lending credence to this framework for the selection of patient populations most likely to benefit from long-term setmelanotide therapy.

Conclusion: This framework provides robust means of selecting MC4R pathway relevant genes and supports clinical investigation of setmelanotide responsiveness in an additional 31 “very strong/strong” genes including LEP, SIM1, MRAP2, and KSR2. A clinical trial in patients with these 31 gene variants will commence before the end of 2021.