Setmelanotide for treating obesity caused by LEPR or POMC deficiency

• setmelanotide is a melanocortin-4 receptor (MC4R) agonist recommended as an option for treating obesity and controlling hyperphagia in genetically confirmed Bardet-Biedl syndrome (BBS) in people aged 6 years and over (1, 3)
• updated NICE guidance (HST36, replacing HST31) expanded NHS funding to include adults who initiate treatment at age 18 years and over, as well as children (3)
• setmelanotide is also recommended for treating obesity and controlling hunger in pro-opiomelanocortin (POMC) deficiency, proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency in people aged 6 years and over (1)

Clinical Background and Efficacy

• disease impact: BBS is a rare genetic disorder leading to MC4R neuroendocrine pathway disruption, causing early-onset severe obesity, chronic hyperphagia, and multimorbidity (including renal and cardiovascular complications) (3)
• pivotal clinical trial evidence: a phase 3 trial (n=44) demonstrated significant weight loss and BMI reductions, with 32.3% of BBS patients achieving at least a 10% reduction in body weight at 52 weeks (2)
• long-term extension data: updated trial and registry data suggest weight loss and BMI improvements are maintained over long-term follow-up (up to 5 years) (3)
• Alström syndrome contrast: trial results were inconclusive regarding weight reduction efficacy in patients with Alström syndrome (2)

Adverse Effects and Tolerability

• common adverse events: most frequently reported treatment-emergent adverse events include skin hyperpigmentation (61%) and injection site erythema (48%) (2)
• daily administration: routinely administered as a daily subcutaneous injection, with weekly prefilled injector formulations under development to reduce administration burden (3)

NICE Guidance Recommendations (HST36 Update)

• universal age criteria: setmelanotide is recommended across the NHS for both children and adults aged 6 years and over with genetically confirmed BBS (3)
• commercial arrangement: recommendation is contingent on the manufacturer supplying setmelanotide under the agreed NHS commercial discount (3)
• baseline supportive care comparison: setmelanotide provides cost-effective clinical benefit compared to best supportive care (dietary restrictions and exercise modification) (3)

Reference:

1. National Institute for Health and Care Excellence (NICE). Setmelanotide for treating obesity caused by LEPR or POMC deficiency. Technology Appraisal Guidance [TA808]. Published 13 July 2022.
2. Haqq AM et al. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022;10(12):859-868.
3. National Institute for Health and Care Excellence (NICE). Setmelanotide for treating obesity and hyperphagia in Bardet-Biedl syndrome in people 6 years and over. Highly Specialised Technologies Guidance [HST36]. Published 4 November 2026.