FDA Approved Metabolic & Weight Loss

Setmelanotide

also known as: Imcivree, RM-493, BIM-22493

Rhythm Pharmaceuticals' Imcivree — the first and only FDA-approved MC4R agonist. Indicated for obesity due to POMC, PCSK1, or LEPR deficiency (2020) and Bardet-Biedl syndrome (2022). Restores downstream MC4R signaling when upstream leptin-melanocortin pathway components are genetically deficient.

A cyclic octapeptide MC4R agonist (Rhythm Pharmaceuticals, Imcivree) engineered to selectively activate the melanocortin-4 receptor — the terminal signaling node of the hypothalamic leptin-melanocortin satiety pathway. FDA-approved 2020 for obesity from biallelic POMC, PCSK1, or LEPR deficiency, and 2022 for obesity in Bardet-Biedl syndrome; the first precision-medicine approach to monogenic obesity.

Mechanism of action

Selective MC4R agonist (EC50 ~0.27 nM). In the leptin-melanocortin pathway, leptin activates POMC neurons in the arcuate nucleus of the hypothalamus; POMC is cleaved by PCSK1 into α-MSH, which activates MC4R on downstream paraventricular neurons to reduce hunger and increase energy expenditure. Loss-of-function in POMC, PCSK1, or LEPR disrupts this signal; BBS causes primary ciliary dysfunction impairing MC4R trafficking. Setmelanotide bypasses the upstream defect by directly agonizing MC4R, restoring satiety signaling and producing clinically meaningful weight loss. Note: not effective for common polygenic obesity, which is why setmelanotide labeling requires confirmed genetic diagnosis.

Primary uses

  • Obesity due to biallelic POMC deficiency (FDA-approved)
  • Obesity due to biallelic PCSK1 deficiency (FDA-approved)
  • Obesity due to biallelic LEPR deficiency (FDA-approved)
  • Obesity in Bardet-Biedl syndrome (FDA-approved)

Typical dosing

1–3 mg once daily (subcutaneous)

Adults ≥18 years: start 2 mg SC once daily × 2 weeks, then 3 mg once daily (max). Pediatric 6–17 years: start 1 mg × 2 weeks, then titrate to 2 mg, then 3 mg (max) based on tolerability and weight response. Pediatric 2–5 years: lower start. Skin hyperpigmentation and spontaneous penile erections are class effects of melanocortin receptor agonism; prior to initiation, a full-body skin exam is recommended to document pre-existing melanocytic lesions.

Regulatory status

FDA-approved November 25, 2020 for chronic weight management in adults and pediatric patients ≥6 years with obesity due to biallelic POMC, PCSK1, or LEPR deficiency confirmed by genetic testing (Rhythm Pharmaceuticals, Imcivree). Label expanded June 16, 2022 to include obesity in Bardet-Biedl syndrome (BBS) patients ≥6 years. Pediatric indication further extended to ages ≥2 years (December 2022) for BBS and POMC/PCSK1/LEPR deficiency. EMA authorization July 2021 (Rhythm Pharmaceuticals Netherlands). Prior to setmelanotide there was no approved pharmacotherapy for these monogenic obesity syndromes.

References

  1. [fda-label] Imcivree (setmelanotide) Prescribing Information. Rhythm Pharmaceuticals, Inc. Initial U.S. Approval: 2020.
  2. [pubmed] Clément K, et al. "Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials." Lancet Diabetes Endocrinol, 2020;8:960-970.
  3. [pubmed] 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;10:859-868.

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Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.