👤 Robert M Haws

Bardet-Biedl syndrome (BBS) is a rare genetic disease associated with hyperphagia, a pathologic insatiable hunger, due to impaired signaling in the melanocortin-4 receptor (MC4R) pathway. The impact of hyperphagia on the lives of patients with BBS and their families has not been fully characterized. Patients with BBS or their caregivers who participated in clinical trials of the MC4R agonist setmelanotide (NCT03013543 and NCT03746522) were included in this qualitative study. Telephone interviews were conducted using a semistructured interview guide to explore patient experience and caregiver observations of hyperphagia before and during setmelanotide treatment. Nineteen interviews (8 patients, 11 caregivers) were conducted. The term "hunger" (rather than "hyperphagia") was used in interviews to ensure common terminology. Before setmelanotide treatment, all participants described their (or their child's) hunger as all-consuming, leading to an obsessive focus on food. Nine participants recalled intense, continuous hunger, and most participants (5 patients, 10 caregivers) reported lack of control with eating. Negative impacts on patients' lives included difficulties with concentration, emotional and physical manifestations, and impaired relationships. All participants experienced or observed improvements in hunger and health outcomes during treatment, the most meaningful of which included weight loss and decrease in obsessive focus on food and food-seeking behaviors. All participants reported improvements in either physical and/or emotional well-being and being satisfied with setmelanotide. Hyperphagia and resulting food-seeking behaviors have notable negative impacts on quality of life in patients with BBS and caregivers. Setmelanotide improved hyperphagia, reduced body weight and obsessive focus on food, and facilitated improvements in physical and emotional well-being for both patients and caregivers. NCT03013543 and NCT03746522. Show less

Impaired 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. This 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/m Between 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. Setmelanotide 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. Rhythm Pharmaceuticals. Show less

A phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related outcomes in participants with Bardet-Biedl syndrome (BBS) and Alström syndrome. Here, we present the study design of an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial to assess the long-term efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS or Alström syndrome (ClinicalTrials.gov identifier: NCT03746522). It was initially planned that ~30 participants aged ≥6 years with a clinical diagnosis of BBS or Alström syndrome would be enrolled. Participants with obesity as defined by a body mass index ≥30 kg/m This pivotal trial is designed to evaluate the efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS and Alström syndrome. Study Design, Statistical Design, Study Protocols. Show less