ESPE Abstracts

Background: Alström syndrome (AS) is a rare genetic ciliopathy characterized by severe early-onset obesity, hyperphagia, retinal dystrophy, hearing loss, and cardiomyopathy. Rodent studies suggest that cilia play an important role in the leptin-MC4R pathway, which regulates energy balance and body weight. Setmelanotide, a peptide agonist of the MC4R, has led to weight loss in individuals affected by other rare genetic obesity disorders resulting from dysfunction in this pathway.

Objective: Report preliminary data on body weight, hunger scores, and safety from a Phase 2 proof of concept study of setmelanotide in individuals affected by AS.

Methods: Individuals age ≥12 years with a confirmed diagnosis of AS are eligible to enroll in this ongoing study. Setmelanotide is administered daily by subcutaneous injection with dose titration every 2 weeks up to 3.0 mg. Adults losing ≥5 kg and adolescents losing ≥4 kg during the titration and maintenance periods are eligible to continue treatment for a total of 52 weeks. Body weight, hunger assessments, BP and HR are assessed at each visit. Skin and physical examination plus metabolic, endocrine, hematologic and pharmacokinetic testing are also conducted.

Results: As of 31 March 2018, one 12-year-old male AS patient received setmelanotide at 0.5 mg and titrated up to 2.0 mg after 6 weeks in the study. At baseline, weight was 78.6 kg, BMI was 27.8 kg/m² (98th percentile for age and sex), mean daily highest hunger rating was 5.5 out of 10. At a dose of 0.5 mg, hunger rating dropped to 3.7, and at a dose of 1.5 mg, hunger rating dropped to 3.0 and remained stable through week 26. After 26 weeks of treatment, body weight was 62.5 kg (20.5% reduction), BMI was 21.8 kg/m² (85^th percentile). Clinical assessment of Dykens hyperphagia score was 31 (out of 55) at baseline and 11 after 26 weeks. Setmelanotide was well tolerated by this individual. Adverse events included mild injection site reactions and increased pigmentation of the skin/nevi. There were no clinically significant changes in blood pressure, vital signs or laboratory evaluations.

Conclusions: In this preliminary data set for one individual affected by AS treated with setmelanotide, marked reductions in body weight and hunger score were observed. The safety profile is consistent with other studies in rare genetic obesity disorders, including the related genetic ciliopathy disorder, Bardet-Biedl syndrome. These findings support continued evaluation of setmelanotide in AS and other rare genetic obesity disorders.