Dataset Information

Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome.

ABSTRACT: Aim: To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS).

Materials and methods: Individuals aged 12?years and older with BBS received once-daily setmelanotide. The dose was titrated every 2?weeks to establish the individual therapeutic dose (?3?mg); treatment continued for an additional 10?weeks. Participants who lost 5 kg or more (or ?5% of body weight if <100?kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes.

Results: From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12?months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points.

Conclusions: Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.

SUBMITTER: Haws R

PROVIDER: S-EPMC7689750 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome.

Haws Robert R Brady Sheila S Davis Elisabeth E Fletty Kristina K Yuan Guojun G Gordon Gregory G Stewart Murray M Yanovski Jack J

Diabetes, obesity & metabolism 20200722 11

<h4>Aim</h4>To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS).<h4>Materials and methods</h4>Individuals aged 12 years and older with BBS received once-daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 ...[more]

PMID: 32627316

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Project description:Abstract Objective Bardet-Biedl syndrome (BBS) is a rare genetic disease characterized by hyperphagia (pathologic insatiable hunger) and early-onset, severe obesity believed to be driven by impaired signaling in the melanocortin-4 receptor (MC4R) pathway. In a Phase 2 and a pivotal Phase 3 trial, treatment with the MC4R agonist setmelanotide produced beneficial reductions in weight, body mass index (BMI), BMI Z score, and hunger in patients with BBS at ∼1 year. The current analysis is the first to assess the continued long-term efficacy of setmelanotide administration in patients with BBS over ∼2 years. Methods Patients with BBS aged ≥6 years were eligible for this observational long-term extension (LTE) trial (NCT03651765) if they completed an index trial in which they received setmelanotide and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received up to ∼12 months of setmelanotide as part of the index trial and began the LTE immediately following completion of the index trial. Study visits occurred approximately every 3 months in the LTE trial. Study objectives included evaluating changes in body weight and assessing safety and tolerability. The current analysis reports outcomes after ∼1 year of additional setmelanotide administration during the LTE trial, relative to index trial baseline. Results As of October 29, 2021, 54 patients with BBS enrolled the index trial, including 28 patients <18 years old and 26 patients ≥18 years old. Among patients who entered the LTE trial, 30 and 19 received at least 18 and 24 months of treatment, respectively. At their enrollment in their index trial, participants’ baseline mean (standard deviation [SD]) BMI was 42.2 (9.2) kg/m2, body weight in patients ≥18 years old was 132.3 (20.9) kg, and BMI Z score in patients <18 years old was 3.5 (0.76). Across age groups, after 18 and 24 months of treatment, mean (SD) percent change in BMI was −9.5% (10.5%; n=30) and −14.3% (11.6%; n=19), respectively. Mean (SD) percent change in body weight in those ≥18 years old after 18 and 24 months was −8.6% (10.3%; n=15) and −14.9% (10.4%; n=6), respectively. The mean (SD) change in BMI Z score in patients <18 years old after 18 and 24 months was −0.83 (0.50; n=13) and −0.72 (0.54; n=12), respectively. No new safety signals were observed during long-term setmelanotide administration. One patient discontinued because of an adverse event (hallucination; unlikely to be related to setmelanotide). Conclusions Clinically beneficial effects of setmelanotide on body weight-related measures continued to be observed in patients with BBS for up to 2 years. Only 1 patient discontinued the LTE trial due to an adverse event, suggesting setmelanotide continued to have clinical benefit and was generally well tolerated. These data support the long-term use of setmelanotide in patients with BBS. Presentation: No date and time listed

Project description:BackgroundImpaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients.MethodsThis multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m2 for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522.FindingsBetween Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment.InterpretationSetmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome.FundingRhythm Pharmaceuticals.

Dataset Information

Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome.

Publications

Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome.

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