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Setmelanotide research

What published studies found for Setmelanotide: 10 papers, 9 in humans, with sample sizes and key results, plus 26 registered clinical trials.

B
Some human evidence
Why: Approved for rare genetic obesity on small trials: one 120-person phase 3 RCT, one 38-person RCT and open-label studies, all positive; under several hundred randomized.

Setmelanotide (an MC4R agonist) has human evidence only in rare genetic or hypothalamic forms of obesity: one 120-person phase 3 RCT in acquired hypothalamic obesity, one small RCT in Bardet-Biedl/Alström syndrome, and several small open-label trials, all showing meaningful BMI and hunger reductions; it has not been shown to work in common obesity, and skin darkening, nausea and injection-site reactions are frequent. Added real-world and registry-comparison data in Bardet-Biedl syndrome and related conditions (small, uncontrolled or externally controlled) are consistent with the trials.

✓ 7 positive~ 3 mixed

Studied only in small rare-disease populations; no evidence for use in common obesity.

US compounding: FDA-approved drug. FDA-approved (Imcivree) for specific genetic obesity syndromes. Status for every peptide.

Browse and filter these papersSetmelanotide prices and vendors

Reported side effects

Registered clinical trials

26 trials of Setmelanotide on ClinicalTrials.gov: 5 active, 19 completed, 14 with posted results. Registered trials include ones that haven't published yet.

TrialStatusPhasePeopleSponsor
Real-World Effects of MC4R Agonist Therapy in BBS and Severe Genetic ObesityNCT07674290 · started 2023-01-01RecruitingPhase 4200Tom Hühne
A Trial of Setmelanotide in Acquired Hypothalamic ObesityNCT05774756 · started 2023-04-26 · results postedActive, not recruitingPhase 3143Rhythm Pharmaceuticals, Inc.
A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)NCT06760546 · started 2025-09-23RecruitingPhase 339Rhythm Pharmaceuticals, Inc.
A Study of Setmelanotide in Patients With Prader-Willi SyndromeNCT06772597 · started 2025-03-04Active, not recruitingPhase 218Rhythm Pharmaceuticals, Inc.
Setmelanotide to Treat Obesity in a Patient With Pseudohypoparathyroidism Type 1a (PHP1a)NCT07496463 · started 2026-07-21Enrolling by invitationPhase 21Massachusetts General Hospital
Setmelanotide Phase 2 Treatment Trial in Participants With Rare Genetic Disorders of ObesityNCT03013543 · started 2017-02-10 · results postedCompletedPhase 2213Rhythm Pharmaceuticals, Inc.
Long Term Extension Trial of SetmelanotideNCT03651765 · started 2018-07-15 · results postedCompletedPhase 2, Phase 3205Rhythm Pharmaceuticals, Inc.
DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) PathwayNCT04963231 · started 2021-11-30 · results postedCompletedPhase 2164Rhythm Pharmaceuticals, Inc.
Phase 1b/2a Study to Evaluate Safety and Efficacy of Setmelanotide in Obese PatientsNCT02041195 · started 2014-01 · results postedCompletedPhase 1, Phase 299Rhythm Pharmaceuticals, Inc.
Study of Setmelanotide Effects on QTc (Corrected QT) Interval in Healthy ParticipantsNCT05046132 · started 2021-08-05 · results postedCompletedPhase 477Rhythm Pharmaceuticals, Inc.
Phase 2 Study to Evaluate Safety and Efficacy of RM-493 in Obese ParticipantsNCT01749137 · started 2013-01-14 · results postedCompletedPhase 274Rhythm Pharmaceuticals, Inc.
Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe ObesityNCT03746522 · started 2018-11-23 · results postedCompletedPhase 352Rhythm Pharmaceuticals, Inc.

All 26 Setmelanotide trials, with countries and recruiting status

Human studies

✓ Positivehuman RCTN Engl J Med · 2026

Setmelanotide for the Treatment of Acquired Hypothalamic Obesity.

n = 120 humansPhase 3 randomized (2:1) placebo-controlled trial (TRANSCEND)52 weeks

In 120 people aged 4-66 with acquired hypothalamic obesity, 52 weeks of setmelanotide changed BMI by -16.5% vs +3.3% with placebo and reduced hunger; serious adverse events 28% vs 8%.

Key resultLSM BMI change -16.5% (95% CI -19.3 to -13.8) with setmelanotide vs 3.3% (95% CI -0.6 to 7.2) with placebo (P<0.001); serious adverse events 28% vs 8%
Studied
People aged 4 to 66 with acquired hypothalamic obesity
Compared with
Placebo
Main outcome
Mean percent change in BMI at 52 weeks
Sample
120 participants (81 setmelanotide, 39 placebo)
Authors' conclusion
Setmelanotide significantly reduced BMI and hunger versus placebo at 52 weeks in participants aged 4 to 66 with acquired hypothalamic obesity.
Limitations
Adverse events in 100% of setmelanotide vs 90% of placebo participants.
PubMed 42418774DOI
~ Mixedhuman RCTLancet Diabetes Endocrinol · 2022

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.

n = 38 humansMulticentre randomised double-blind placebo-controlled phase 3 trial with open-label period14 weeks double-blind plus 52 weeks open-label

In 38 patients, 32.3% of those 12+ with Bardet-Biedl syndrome lost at least 10% of body weight after 52 weeks, but results in Alström syndrome were inconclusive; skin hyperpigmentation in 61%.

Key result32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight
Studied
Patients aged 6 or older with Bardet-Biedl or Alström syndrome and obesity
Compared with
Placebo
Main outcome
Proportion aged 12+ achieving at least 10% bodyweight reduction at 52 weeks
Sample
38 patients (19 setmelanotide, 19 placebo)
Authors' conclusion
Setmelanotide significantly reduced bodyweight in Bardet-Biedl syndrome; results were inconclusive in Alström syndrome.
Limitations
Small sample; inconclusive in Alström syndrome.
PubMed 36356613DOIFree full text
✓ Positivehuman trialLancet Diabetes Endocrinol · 2024

Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial.

n = 18 humansPhase 2 open-label multicentre trial16 weeks

In 18 patients with hypothalamic obesity, 89% reduced BMI by at least 5% at 16 weeks (mean -15%); nausea 61%, vomiting 33%, hyperpigmentation 33%.

Key result16 (89%) of 18 patients met the primary endpoint (p<0·0001); mean BMI reduction 15% (SD 10)
Studied
Patients aged 6 to 40 with obesity after hypothalamic injury or tumour
Compared with
Historic control rate (<5% reaching the BMI target)
Main outcome
Proportion with at least 5% BMI reduction
Sample
18 patients enrolled
Authors' conclusion
Findings support setmelanotide as an effective treatment of hypothalamic obesity.
Limitations
Open-label, single-arm, small.
PubMed 38697184DOI
✓ Positivehuman trialLancet Diabetes Endocrinol · 2025

Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial.

n = 12 humansPhase 3 open-label multicentre trial (VENTURE)52 weeks

In 12 children aged 2-5 with POMC/LEPR deficiency or Bardet-Biedl syndrome, BMI fell by 18% on average at 52 weeks with no serious adverse events.

Key resultTen (83%) of 12 reached a 0·2-point or greater BMI Z score reduction (95% CI 58·7-99·8); mean BMI change -18% (SD 13)
Studied
Children aged 2-5 with obesity and hyperphagia from POMC/LEPR deficiency or Bardet-Biedl syndrome
Compared with
None
Main outcome
BMI Z score reduction and percent BMI change
Sample
12 children aged 2-5 enrolled
Authors' conclusion
First trial under age 6; results support setmelanotide as early intervention for obesity in this population.
Limitations
Open-label, 12 patients, no control group.
PubMed 39549719DOI
✓ Positivehuman trialLancet Diabetes Endocrinol · 2020

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.

21 participants: 10 in POMC trial and 11 in LEPR trialSingle-arm open-label multicentre phase 3 trials with placebo-controlled withdrawalAbout 1 year

In 21 people with POMC or LEPR deficiency, 80% and 45% respectively lost at least 10% of body weight at about 1 year, with large falls in hunger; injection-site reactions and hyperpigmentation were near-universal.

Key resultEight (80%) POMC and five (45%) LEPR participants achieved at least 10% weight loss; most hunger score change -27·1% (p=0·0005) POMC and -43·7% (p<0·0001) LEPR
Studied
Individuals aged 6 or older with severe obesity from POMC or LEPR deficiency
Compared with
None (single-arm; 4-week placebo withdrawal)
Main outcome
Proportion with at least 10% weight loss at about 1 year
Authors' conclusion
Results support setmelanotide for obesity and hyperphagia caused by POMC or LEPR deficiency.
Limitations
Single-arm open-label design, very small trials.
PubMed 33137293DOI
~ Mixedhuman trialMol Metab · 2017

Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.

Cell, rodent and a 28-day Phase 1b human study; 369 MC4R variants annotatedCombined in vitro, rodent and phase 1b human study28 days (human trial)

In cells, rodents and a 28-day phase 1b trial, setmelanotide caused weight loss in MC4R variant carriers, but less than in POMC-deficient patients; MC4R knockout mice did not respond.

Studied
MC4R mutant cells, rodents, and obese MC4R variant carriers
Compared with
Obese controls and POMC-deficient patients
Main outcome
MC4R signaling and weight loss
Authors' conclusion
Setmelanotide led to weight loss in obese people with MC4R deficiency, but further studies are needed to see whether the weight loss is clinically meaningful in a subset.
Limitations
Short 28-day phase 1b human study; human sample size not given in abstract.
PubMed 29031731DOIFree full text
Figure 3: Effect of Setmelanotide administration in mice lacking Mc4r.Mc4r+/+, +/−, and −/− mice were infused with 1200 nmol/kg/day of Setmelanotide,
Figure 3. From PMC5641599, CC BY (terms); resized.
✓ Positivehuman trialObesity (Silver Spring) · 2026

Setmelanotide in Bardet-Biedl Syndrome: A 52-Week Comparison of Phase 3 Trial Participants With a Matched Registry Cohort.

29 treated phase 3 patients and 58 propensity-matched registry controlsIndirect comparison of phase 3 trial participants with matched external registry cohort52 weeks

Bardet-Biedl syndrome: 29 phase 3 patients on setmelanotide for 52 weeks were far more likely to be weight responders than 58 matched registry controls (58.6% vs 6.9%); external, not randomized, control.

Key result58.6% vs 6.9% met the primary endpoint.
Studied
Patients with Bardet-Biedl syndrome aged 6 years or older
Compared with
Matched CRIBBS registry cohort
Main outcome
Responder rate (>=0.3 BMI z-score fall or >=10% weight loss)
Authors' conclusion
This indirect comparison provides additional strong evidence that setmelanotide improves weight outcomes in BBS over 52 weeks.
Limitations
Non-randomized external control.
PubMed 41703984DOIFree full text
FIGURE 2: Primary endpoint responder rates in the (A) combined adult and pediatric populations, (B) pediatric population, and (C) adult population. Th
FIGURE 2. From PMC12933228, CC BY (terms); resized.
✓ Positivehuman observationalObesity (Silver Spring) · 2025

Real-World Efficacy and Safety of Setmelanotide in Adults With Monogenic or Syndromic Obesity: A Prospective Cohort Study.

n = 17 humansProspective single-center cohort, routine care or early accessAverage follow-up 14.4 months

Real-world cohort of 17 adults and children with BBS, LEPR or POMC obesity: about 20% weight loss from pre-treatment maximum in year one and hunger down 62%, safety consistent with trials.

Key result20% weight reduction within the first year; hunger -62%, food craving -41%.
Studied
Patients with obesity due to Bardet-Biedl syndrome or biallelic LEPR or POMC variants
Main outcome
Weight, eating behaviour, safety
Sample
17 patients (11 BBS, 4 LEPR, 2 POMC)
Authors' conclusion
Findings confirm long-term clinical benefit and a safety profile consistent with phase 3 data, with no new safety signals.
Limitations
Small uncontrolled single-center cohort.
PubMed 40897637DOI
✓ Positivehuman observationalJ Clin Endocrinol Metab · 2026

Impact of the Melanocortin-4 Receptor Agonist Setmelanotide on MASLD and Kidney Function in Bardet-Biedl Syndrome.

26 patients with BBS (mean age 19.2 years)Prospective monocentric observational cohort6 months

26 patients with BBS followed 6 months on setmelanotide: BMI z-score fell 0.5, hyperphagia scores improved and 85% had resolved or stabilized liver steatosis; eGFR rose about 10 mL/min; uncontrolled.

Key resulteGFR increased up to 10.1 mL/min/1.73 m2 (95% CI 4.3-15.9); BMI z-score -0.5 (95% CI -0.6 to -0.3).
Studied
Patients over 6 years with genetically confirmed BBS and obesity
Main outcome
Liver steatosis (MASLD), kidney function, BMI z-score, hyperphagia
Authors' conclusion
Setmelanotide was associated with improvement in MASLD independent of BMI reduction and with increased glomerular filtration rate in BBS.
Limitations
No control group; short follow-up.
PubMed 40903014DOI
~ Mixedcase reportJ Endocrinol Invest · 2026

Safety and effectiveness of setmelanotide in young patients with severe obesity due to craniopharyngioma: a real world monocentric experience.

3 young adultsRetrospective single-center case series6-9 months

Three young adults with post-craniopharyngioma hypothalamic obesity: variable response, with two losing weight over 6-9 months and one stopping after continued weight gain; adverse effects mild.

Studied
Young adults with hypothalamic obesity after craniopharyngioma surgery
Main outcome
Weight, BMI, waist circumference, metabolic measures
Authors' conclusion
Setmelanotide may benefit selected patients with treatment-refractory hypothalamic obesity; small sample size supports further investigation.
Limitations
Three patients, retrospective, no control.
PubMed 42329358DOI

Verdicts are judged on each paper's own main outcome; grades run from A (strong human evidence) to D (little or none). Details are read from the abstracts, and figures are reproduced only from openly licensed full texts. Not medical advice.