ESPE Abstracts (2015) 84 FC12.4

RM-493, a Melanocortin-4 Receptor (MC4R) Agonist, is Being Therapeutically Evaluated in Patients with Deficiencies in the Leptin - Proopiomelanocortin (POMC) - MC4R Hypothalamic Pathway, Including Prader-Willi Syndrome (PWS)

Peter Kühnena, Heiko Krudea, Susanna Wieganda, Lex van der Ploegb, Fred Fiedorekb, Michelle Hylanb & Keith Gottesdienerb

aInstitute for Paediatric Endocrinology, Charité Universitätsmedizin Berlin, Berlin, Germany; bRhythm Pharmaceuticals, Boston, Massachusetts, USA

Background: The hypothalamic leptin–melanocortin signalling pathway is a critical regulator of human appetite and weight regulation. Monogenetic defects in the POMC gene, the MSH ligand generating PC1 gene and the MSH receptor gene MC4R lead to severe early onset and leptin-resistant obesity. In PWS, where the function of genes such as MAGEL2 are impaired, the Magel2-/- mouse model revealed decreased POMC neuronal functioning as one critical mechanism of severe obesity in PWS. Magel2-/- mice were responsive to pharmacological treatment with an MC4R agonist that by-passes this defect.

Objective and hypotheses: Together, all leptin-resistant monogenetic obesity, including the more prevalent PWS, might be potentially treatable by MC4R agonists.

Method: More than 15 years after the initial description of MSH-deficient monogenetic human obesity, the synthetic MC4R agonist peptide RM-493 is ideally positioned for the experimental treatment of PWS patients and other monogenetic defects of the POMC signaling pathway. Several Phase 1 and Phase 2 studies were conducted to assess RM-493 safety, efficacy, and pharmacokinetics.

Results: RM-493 showed 13% weight loss in obese rhesus over 8 weeks of RM-493 treatment. Phase 1b studies in normal obese patients demonstrated ~1 kg/week weight loss vs. placebo. Extensive analysis of blood pressure showed little, if any of the increases seen with previous MC4R agonists.

Conclusion: RM-493 is a first in class well-tolerated efficacious MC4R agonist that may be a treatment for MSH deficient severe obesity. As a consequence we initiated several studies, including a double-blind, placebo controlled, randomized, Phase 2 study in overweight to obese adult patients (>16 years) with PWS, and a non-randomized, Phase 2 open-label pilot-study to treat homozygous or compound heterozygous POMC-deficient patients. Preliminary results show very promising weight loss in the first treated POMC null patient. RM-493 represents a new treatment option for PWS and other monogenetic obesity forms in which POMC function is affected.