Background: Bardet-Biedl syndrome (BBS) causes early-onset extreme obesity and hyperphagia that is hypothesized to arise from leptin receptor dysfunction. Setmelanotide, a melanocortin-4 receptor (MC4R) peptide agonist, has been shown to induce weight loss in individuals affected by other rare genetic obesity disorders resulting from leptin-melanocortin pathway dysfunction upstream of MC4R.
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 BBS.
Methods: Individuals 12 years of age and older with a confirmed diagnosis of BBS are eligible for enrollment in this ongoing study. Setmelanotide was administered daily by subcutaneous (SC) injection with dose titration every 2 weeks (maximum 3.0 mg). Adults losing ≥5 kg and adolescents losing ≥4 kg during the titration period and maintenance period continued treatment for a maximum of 52 weeks. Body weight, hunger or hyperphagia scores, blood pressure (BP) and heart rate (HR) were assessed at each visit. Skin and physical examination along with metabolic, endocrine, hematologic and pharmacokinetic testing were also conducted.
Results: As of 2 April 2018, six individuals (aged 1261 years, 4 females, baseline weight 124.8±10.6 kg; BMI 45.2±1.1 kg/m2; both mean ± S.E.M) diagnosed with BBS (including individuals with bi-allelic mutations in BBS1, BBS2, BBS10 and BBS12 genes) received setmelanotide. Four of six have been treated between 26-45 weeks. Four individuals demonstrated a mean body weight reduction of 17.7% (range 11.7% to 23.1%) after treatment with setmelanotide, while two patients with BBS did not meet criteria for continuing treatment. Five of six individuals reported greater than 50 percent reductions from baseline in either hunger or hyperphagia scores. Metabolic improvement in either lipids, liver transaminases, and/or glycemic indices was observed in 5 of 6 BBS subjects treated. Overall, setmelanotide was well tolerated; adverse events included mild injection site reactions and increased pigmentation of the skin/nevi. No adverse changes in BP or HR were observed with treatment with setmelanotide.
Conclusions: In this updated preliminary data set in individuals affected by BBS who were treated with setmelanotide, marked reductions in body weight and hunger/hyperphagia scores and the safety profile are consistent with other studies in rare genetic obesity disorders. These findings support the continued evaluation of MC4R agonist therapy in BBS and other rare genetic obesity disorders.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology