ESPE Abstracts (2016) 86 FC13.6

Treatment for Early Onset and Extreme Obesity in Two POMC Deficient Patients: Successful Weight Loss with the Melanocortin-4 Receptor Agonist Setmelanotide

Peter Kühnena, Karine Clementb, Keith Gottesdienerc, Fred Fiedorekc, Lex van der Ploegc, Susanna Wiegandd, Oliver Blankensteina, Annette Grütersd & Heiko Krudea

aInstitute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Berlin, Germany; bNutrition Department, Institute of Cardiometabolism and Nutrition, ICAN, Assistance-Publique Hôpitaux de Paris, Paris, France; cRhythm Pharmaceuticals, Boston, USA; dDepartment for Pediatric Endocrinology and Diabetes, Charité Universitätsmedizin Berlin, Berlin, Germany

Background: POMC deficiency is an extremely rare monogenetic obesity syndrome generally characterized by early onset hyperphagia, red hair and adrenal insufficiency. So far treatment of obesity and hyperphagia with MSH substitution failed, either due to ineffectiveness or side effects of available MC4R agonists.

Objective and hypotheses: We hypothesized that the new MC-4R agonist setmelanotide might be a treatment option in POMC deficient patients.

Method: A Phase 2, non-randomized, open label pilot study with the new MC4R agonist setmelanotide was conducted in two POMC deficient adult patients (EudraCT No. 2014-002392-28; identifier No. NCT02507492). Setmelanotide was injected subcutaneously once per day with a single dose of 0.5 up to 1.5 mg.

Results: Treatment resulted in 51 kg body weight loss after 42 weeks in patient 1 (32.9% of initial body weight) and 20.5 kg after three months in patient 2 (13.4% of the initial body weight). During a short, 3-week off-treatment phase patient 1 suffered from an immediate recurrence of hyperphagia and weight regain. Parallel to the weight loss, in both patients hyperinsulinemia improved significantly and led to a normalization of the initial insulin resistance. No serious adverse events were observed during the study period and setmelanotide treatment did not elicit the cardiovascular adverse effects described earlier with other MC4R agonists.

Conclusion: This is the first report showing successful treatment of extreme obesity in POMC deficient patients. We propose that weight loss by setmelanotide is the result of substitution at the hypothalamic weight regulatory POMC pathway, for the missing POMC derivative MSH thus restoring MC4R activation. We conclude that other syndromes of MSH deficient obesity including Leptin receptor defects and PCSK1 deficiency might also benefit from treatment with setmelanotide.