Setmelanotide

Research overview

Key studies

1. Clément et al., Lancet Diabetes Endocrinol (2020)

   Two single-arm, open-label, multicentre phase 3 trials with withdrawal period
   Model: Humans (10 with POMC/PCSK1 deficiency, 11 with LEPR deficiency)

   80% (POMC) and 45% (LEPR) reached at least 10% body-weight reduction at about 1 year; no serious treatment-related adverse events ^3.

2. Haqq et al., Lancet Diabetes Endocrinol (2022)

   Randomized, double-blind, placebo-controlled phase 3 with open-label period
   Model: Humans (38 with Bardet-Biedl or Alström syndrome)

   32.3% of patients aged 12 or older with Bardet-Biedl syndrome reached at least 10% body-weight reduction at 52 weeks; hyperpigmentation in 61% ^4.

3. Miller et al., N Engl J Med (TRANSCEND, NCT05774756) (2026)

   Randomized 2:1, placebo-controlled phase 3, 52 weeks after dose escalation
   Model: Humans (120 aged 4-66 with acquired hypothalamic obesity)

   BMI change -16.5% versus +3.3% with placebo; hunger scores fell more; serious adverse events 28% versus 8% ^5.

Dosing as stated on the FDA label

Quoted from the prescribing information for reference. Prescribing decisions belong to a licensed clinician; this is not a recommendation or instruction for use.

• Acquired hypothalamic obesity, age 4 and older (IMCIVREE): starting dosage 0.5 mg subcutaneously once daily for 2 weeks, then titrated per the label's tables ^1.
• BBS or POMC, PCSK1 or LEPR deficiency: starting dosage 2 mg once daily for 2 weeks (age 12 and older), 1 mg (age 6 to under 12) or 0.5 mg (age 2 to under 6) ^1.
• Recommended maintenance dosage for adults and children aged 6 and older for all indications is 3 mg subcutaneously once daily; for younger children the maintenance dosage is based on body weight ^1.
• The label specifies dose reductions if starting or escalated dosages are not tolerated, dosing in renal impairment, and patient selection by clinical or genetic diagnosis; those details are in the prescribing information and not reproduced here ^1.

Published adverse-event data

Reported in the cited trials or product labels. Frequencies apply to the stated population and do not transfer to other settings.

• Skin hyperpigmentation
  Majority of treated patients; 67% versus 0% placebo in the 14-week BBS placebo period
  Label clinical trials ¹ · Reversible on discontinuation per label
• Spontaneous or increased penile erections
  7% versus 4% placebo (acquired HO trial); 8% (BBS trial)
  Males in label trials ¹ · Seek emergency care for erections over 4 hours
• Acute adrenal insufficiency (serious)
  5% versus 0% placebo
  Acquired HO with secondary adrenal insufficiency ¹ · Serious
• Hyponatremia / hypernatremia
  6% versus 2% / 5% versus 4%
  Acquired HO with central diabetes insipidus ¹ · Monitor sodium
• Vomiting
  11% versus 0% placebo
  BBS trial, 14-week placebo period ¹ · Not graded
• Serious adverse events (any)
  28% versus 8% placebo
  TRANSCEND, acquired hypothalamic obesity ⁵ · As reported

What is not known: Long-term effects of chronic MC4 and MC1 receptor activation, including on nevi, are not established in the sources reviewed ^1. The label states it is not expected to work in general obesity or obesity from other genetic syndromes, and evidence in the genetic indications comes from small trials ^1,3.

Regulatory status

Status

FDA-approved as IMCIVREE (NDA 213793, original approval November 25, 2020) ^2. The April 2, 2026 label covers people aged 4 years and older with acquired hypothalamic obesity and aged 2 years and older with Bardet-Biedl syndrome or POMC, PCSK1 or LEPR deficiency; it is not indicated for other genetic syndromes or general (polygenic) obesity ^1.

United States (FDA)

FDA-approved under NDA 213793 (IMCIVREE, Rhythm), original approval November 25, 2020 per Drugs@FDA ^2; indications per the April 2, 2026 DailyMed label include acquired hypothalamic obesity, Bardet-Biedl syndrome and POMC, PCSK1 or LEPR deficiency ^1.

Sport (WADA)

Setmelanotide is not named in the 2026 Prohibited List text reviewed; as an approved drug it falls outside S0, so status should be confirmed with the relevant anti-doping organization ^6.

Status varies by country and changes over time. How we describe regulatory status.

References

1. IMCIVREE (setmelanotide) injection, prescribing information (DailyMed SPL version 14, published Apr 02, 2026) FDA label (DailyMed). 2026
2. Drugs@FDA application NDA 213793 (IMCIVREE, Rhythm; original approval 2020-11-25) via openFDA FDA (openFDA Drugs@FDA). 2026
3. 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
4. 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
5. Setmelanotide for the Treatment of Acquired Hypothalamic Obesity N Engl J Med. 2026
6. Tractatenblad 2026 Nr. 25: Anti-doping convention (ETS No. 135), amendment to the appendix - The 2026 Prohibited List, World Anti-Doping Code (English text; entry into force 1 January 2026) Tractatenblad van het Koninkrijk der Nederlanden (official government publication). 2026
7. PubChem compound record for setmelanotide (CID 11993702) PubChem. 2026