Setmelanotide

updated

Setmelanotide (IMCIVREE) is an FDA-approved MC4R agonist, first approved in 2020, for weight reduction in acquired hypothalamic obesity, Bardet-Biedl syndrome, and POMC, PCSK1 or LEPR deficiency confirmed by genetic testing. In TRANSCEND, BMI changed -16.5% versus +3.3% on placebo at 52 weeks in 120 people with acquired hypothalamic obesity. The label excludes general obesity, and a PubMed search on 10 October 2026 found no weight trial in it.

Melanocortin-4 receptor (MC4R) agonist peptide

  • FDA approved IMCIVREE under NDA 213793 (Rhythm) on 25 November 2020 as a Type 1 new molecular entity. An efficacy supplement approved on 19 March 2026 lines up with the label's 03/2026 revision that added acquired hypothalamic obesity.
  • The label covers patients 4 years and older with acquired hypothalamic obesity and patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency confirmed by genetic testing. It excludes general (polygenic) obesity.
  • In TRANSCEND (120 participants with acquired hypothalamic obesity, 52 weeks), BMI changed -16.5% on setmelanotide versus +3.3% on placebo. The label reports a placebo-corrected -18.40% for 142 analyzed patients in the same trial.
  • In two single-arm phase 3 trials, at least 10% weight loss at about 1 year occurred in 8 of 10 (80%) with POMC deficiency and 5 of 11 (45%) with LEPR deficiency.
  • A PubMed search on 10 October 2026 for setmelanotide in the title, limited to clinical or randomized trials, returned 12 records, and none tested weight loss in general obesity.
  • The label warns of spontaneous penile erections, depression and suicidal ideation, and skin darkening, and in TRANSCEND serious adverse events occurred in 28% versus 8% on placebo.

What is setmelanotide approved to do?

FDA labels IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity, and in patients 2 years and older with Bardet-Biedl syndrome or POMC, PCSK1 or LEPR deficiency confirmed by genetic testing. The label excludes general (polygenic) obesity, where it would not be expected to be effective.

IMCIVREE is labeled to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing. The variants may be read as pathogenic, likely pathogenic, or of uncertain significance. The limitations of use say it is not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. The label version used here took effect on 1 April 2026, and its Indications and Usage were revised in 03/2026.

FDA approved IMCIVREE under NDA 213793 (Rhythm) on 25 November 2020 as a Type 1 new molecular entity. The openFDA record lists efficacy supplements approved on 16 June 2022, 20 December 2024 and 19 March 2026, and does not name the indication for each supplement. The 19 March 2026 approval lines up with the label's 03/2026 indication revision that added acquired HO, so the 2026 hypothalamic obesity approval is confirmed by the FDA record together with the label.

Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt. PubChem lists CID 11993702, C49H68N18O9S2, molecular weight 1117.3, CAS 920014-72-8, with the synonyms RM-493 and BIM-22493. The label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base.

IMCIVREE label, version effective 1 April 2026: indications, limits of use, warnings, PK, hypothalamic obesity trial

FDA prescribing information

DailyMed, U.S. National Library of Medicine. IMCIVREE (setmelanotide) injection, multiple-dose vial, prescribing information, label version effective 1 April 2026 (Indications and Usage revised 03/2026). Set ID 70c3ccf7-4df0-4c75-ba07-fede9970c8d9.

The label approves IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing (variants read as pathogenic, likely pathogenic, or of uncertain significance). Limitations of use: not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. Warnings cover spontaneous penile erections in males and sexual adverse reactions in females; depression and suicidal ideation; serious hypersensitivity including anaphylaxis; generalized skin darkening, darkening of existing nevi and new nevi; and, in HO, acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%). The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt; the label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base. It has 20-fold less activity at MC3 and MC1 receptors than at MC4, protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. The label's account of the HO trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose, with about 61% versus 5% reaching at least 10% BMI reduction and drug discontinuation of 10.6% versus 12.5%.

Participants / model
Patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency; patients 4 years and older with acquired HO; label PK participants and label trial participants
Treatment
IMCIVREE subcutaneous injection, once daily, multiple-dose vial
Follow-up
Label version effective 1 April 2026; label HO trial of 52 weeks
Study design
FDA prescribing information
Funding
not stated in the source

The label's 142 participants in the HO trial differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. Melanoma and nevus incidence is not quantified beyond the label warning.

Read the original source
Drugs@FDA: IMCIVREE approved 25 November 2020; supplements 2022, 2024 and 19 March 2026

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record for NDA 213793 (IMCIVREE, Rhythm). Dates read from the openFDA Drugs@FDA record on 10 October 2026.

FDA approved IMCIVREE under NDA 213793 (Rhythm) on 25 November 2020 as a Type 1 new molecular entity. The openFDA record lists efficacy supplements approved on 16 June 2022, 20 December 2024 and 19 March 2026. It does not name the indication for each supplement. The 19 March 2026 approval lines up with the label's 03/2026 indication revision that added acquired HO.

Participants / model
Not a clinical population
Treatment
New drug application and supplements
Follow-up
Approved in 2020; supplements in 2022, 2024 and 2026
Study design
FDA application record
Funding
not stated in the source

openFDA does not tie the 19 March 2026 supplement to hypothalamic obesity by name. The link rests on the matching label revision date.

Read the original source
PubChem: setmelanotide identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 11993702 (setmelanotide).

PubChem lists setmelanotide as CID 11993702, C49H68N18O9S2, molecular weight 1117.3, CAS 920014-72-8, with the synonyms RM-493 and BIM-22493.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined cyclic peptide
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source

What did the trials in genetic obesity find?

In two single-arm phase 3 trials in 21 people, at least 10% weight loss at about 1 year occurred in 8 of 10 with POMC deficiency (80%) and 5 of 11 with LEPR deficiency (45%). In 38 patients with BBS or Alstrom syndrome, 32.3% of the BBS patients aged 12 and older reached at least 10% weight loss after 52 weeks. In 12 children aged 2 to 5, mean BMI change at week 52 was -18%.

Two single-arm, open-label phase 3 trials at ten hospitals treated 10 participants with POMC deficiency and 11 with LEPR deficiency, aged 6 and older, for about 1 year, with an 8-week blinded withdrawal for responders. At least 10% weight loss at about 1 year occurred in 8 (80%) with POMC deficiency and 5 (45%) with LEPR deficiency. Most-hunger scores fell 27.1% and 43.7% in the 7 assessed in each trial. Injection site reactions and hyperpigmentation were common, and there were no serious treatment-related events. Rhythm funded the trials, registered as NCT02896192 and NCT03287960. With no control group and 21 participants, this is a small evidence base.

In the BBS and Alstrom syndrome trial at 12 sites, 38 patients aged 6 and older were randomized 1:1 to setmelanotide or placebo for 14 weeks, then treated open-label for 52 weeks. Among BBS patients aged 12 and older, 32.3% (95% CI 16.7 to 51.4) reached at least 10% weight loss after 52 weeks on drug. Results in Alstrom syndrome were inconclusive. Rhythm funded the trial, registered as NCT03746522.

VENTURE was an open-label phase 3 trial in 12 children aged 2 to 5, seven with POMC or LEPR deficiency and five with BBS. Mean BMI change at week 52 was -18% overall, -26% in POMC or LEPR deficiency and -10% in BBS, with no serious adverse events. Rhythm funded the trial. It is the evidence behind the label's expansion to age 2.

POMC and LEPR deficiency: 21 people, about 1 year, at least 10% weight loss in 80% and 45%

Clinical trial

Clément K et al. Lancet Diabetes Endocrinol. 2020;8(12):960-970. PMID 33137293.

At least 10% weight loss at about 1 year occurred in 8 (80%) of 10 with POMC deficiency and 5 (45%) of 11 with LEPR deficiency. Most-hunger scores fell 27.1% and 43.7% in the 7 assessed in each trial. Injection site reactions and hyperpigmentation were common, and there were no serious treatment-related events.

Participants / model
21 people aged 6 and older with obesity from POMC deficiency (10) or LEPR deficiency (11), at ten hospitals
Treatment
Subcutaneous setmelanotide once daily, about 1 year, with an 8-week blinded withdrawal for responders
Follow-up
About 1 year
Study design
Two single-arm open-label phase 3 trials (NCT02896192 and NCT03287960)
Funding
Funded by Rhythm

Single-arm trials with no control group. The hunger figures come from 7 assessed participants in each trial.

Read the original source
BBS and Alstrom syndrome: 38 patients, 14 weeks randomized then 52 weeks open-label

Randomized controlled trial

Haqq AM et al. Lancet Diabetes Endocrinol. 2022;10(12):859-868. PMID 36356613.

Among BBS patients aged 12 and older, 32.3% (95% CI 16.7 to 51.4) reached at least 10% weight loss after 52 weeks on drug. Results in Alstrom syndrome were inconclusive. Hyperpigmentation occurred in 61% and injection site erythema in 48%.

Participants / model
38 patients aged 6 and older with BBS or Alstrom syndrome and obesity, at 12 sites
Treatment
Subcutaneous setmelanotide once daily or placebo for 14 weeks, then open-label for 52 weeks
Follow-up
14 weeks randomized, then 52 weeks open-label
Study design
Randomized phase 3 trial with an open-label period (NCT03746522)
Funding
Funded by Rhythm

The 52-week figure is from the open-label period, on drug, without a placebo comparison at that point.

Read the original source
VENTURE: 12 children aged 2 to 5, week 52 BMI change -18%, no serious adverse events

Clinical trial

Argente J et al. Lancet Diabetes Endocrinol. 2025;13(1):29-37. PMID 39549719.

Mean BMI change at week 52 was -18% overall, -26% in POMC or LEPR deficiency and -10% in BBS. There were no serious adverse events.

Participants / model
12 children aged 2 to 5: seven with POMC or LEPR deficiency and five with BBS
Treatment
Subcutaneous setmelanotide once daily
Follow-up
52 weeks
Study design
Open-label single-arm phase 3 trial
Funding
Funded by Rhythm

Twelve children and no control group. This trial is the evidence behind the label's expansion to age 2.

Read the original source

What did the hypothalamic obesity trial find?

In TRANSCEND, 120 participants aged 4 to 66 with acquired hypothalamic obesity were randomized 2:1 to setmelanotide or placebo for 52 weeks. BMI changed -16.5% versus +3.3% on placebo. The label's account of the same trial reports 142 patients and a placebo-corrected BMI change of -18.40%.

TRANSCEND (NCT05774756) randomized 120 participants aged 4 to 66 (mean adult BMI 41.2) with a history of hypothalamic tumor, lesion or injury, 2:1 to setmelanotide (81) or placebo (39) for 52 weeks after dose escalation. BMI changed -16.5% (95% CI -19.3 to -13.8) on setmelanotide versus +3.3% (95% CI -0.6 to 7.2) on placebo. These are each arm's percent change in BMI. Hunger scores fell more on drug (-2.73 versus -1.45). Serious adverse events occurred in 28% versus 8%. Rhythm funded the trial.

The label's account of the same trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose. About 61% versus 5% reached at least 10% BMI reduction, and drug discontinuation was 10.6% versus 12.5%. The label's -18.40% is placebo-corrected, unlike the paper's per-arm figures.

The label's 142 participants differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. A phase 2 trial in hypothalamic obesity was not reviewed here.

TRANSCEND: 120 participants, 52 weeks, BMI change -16.5% versus +3.3% on placebo

Randomized controlled trial

Miller JL et al. N Engl J Med. 2026;395(2):138-150. PMID 42418774.

BMI changed -16.5% (95% CI -19.3 to -13.8) on setmelanotide versus +3.3% (95% CI -0.6 to 7.2) on placebo. Hunger scores fell more on drug (-2.73 versus -1.45). Serious adverse events occurred in 28% versus 8%, and hyperpigmentation, nausea, vomiting and headache were most common.

Participants / model
120 participants aged 4 to 66 (mean adult BMI 41.2) with acquired hypothalamic obesity after a hypothalamic tumor, lesion or injury
Treatment
Subcutaneous setmelanotide (81) or placebo (39), randomized 2:1, for 52 weeks after dose escalation
Follow-up
52 weeks
Study design
Randomized placebo-controlled phase 3 trial (NCT05774756)
Funding
Funded by Rhythm

The figures are each arm's percent change in BMI. The label reports a placebo-corrected figure and 142 patients for the same trial, and neither source explains the difference from the paper's 120.

Read the original source
IMCIVREE label, version effective 1 April 2026: indications, limits of use, warnings, PK, hypothalamic obesity trial

FDA prescribing information

DailyMed, U.S. National Library of Medicine. IMCIVREE (setmelanotide) injection, multiple-dose vial, prescribing information, label version effective 1 April 2026 (Indications and Usage revised 03/2026). Set ID 70c3ccf7-4df0-4c75-ba07-fede9970c8d9.

The label approves IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing (variants read as pathogenic, likely pathogenic, or of uncertain significance). Limitations of use: not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. Warnings cover spontaneous penile erections in males and sexual adverse reactions in females; depression and suicidal ideation; serious hypersensitivity including anaphylaxis; generalized skin darkening, darkening of existing nevi and new nevi; and, in HO, acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%). The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt; the label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base. It has 20-fold less activity at MC3 and MC1 receptors than at MC4, protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. The label's account of the HO trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose, with about 61% versus 5% reaching at least 10% BMI reduction and drug discontinuation of 10.6% versus 12.5%.

Participants / model
Patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency; patients 4 years and older with acquired HO; label PK participants and label trial participants
Treatment
IMCIVREE subcutaneous injection, once daily, multiple-dose vial
Follow-up
Label version effective 1 April 2026; label HO trial of 52 weeks
Study design
FDA prescribing information
Funding
not stated in the source

The label's 142 participants in the HO trial differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. Melanoma and nevus incidence is not quantified beyond the label warning.

Read the original source

Is there data for obesity without these specific causes?

No weight trial in general obesity was found. A PubMed search on 10 October 2026 for setmelanotide in the title, limited to clinical or randomized trials, returned 12 records, none testing weight loss in general (polygenic) obesity. The label says it would not be expected to be effective there.

In 12 otherwise healthy obese adults (BMI 35.7), a 72-hour continuous infusion of RM-493 (1 mg per 24 hours) raised resting energy expenditure by 6.4% (about 111 kcal per day) versus placebo in a crossover trial, with no heart rate or blood pressure effect. This was a short mechanistic study, not a weight trial.

A 28-day phase 1b in MC4R variant carriers showed less weight loss than in POMC-pathway defects, and the authors said clinical benefit in MC4R deficiency still needed study. The label's limitations of use also exclude obesity with benign or likely benign variants in the labeled genes.

A PubMed search on 10 October 2026 for setmelanotide in the title, limited to clinical or randomized trials, returned 12 records, none testing weight loss in general (polygenic) obesity. The label says setmelanotide would not be expected to be effective in general obesity.

PubMed search, 10 October 2026: 12 records, none in general obesity; 72-hour infusion study

PubMed search record

Chen KY et al. J Clin Endocrinol Metab. 2015;100(4):1639-45. PMID 25675384.

In 12 otherwise healthy obese adults (BMI 35.7), a 72-hour continuous infusion of RM-493 (1 mg per 24 hours) raised resting energy expenditure by 6.4% (about 111 kcal per day) versus placebo in a crossover trial, with no heart rate or blood pressure effect. This is a short mechanistic study, not a weight trial. A 28-day phase 1b in MC4R variant carriers showed less weight loss than in POMC-pathway defects, and the authors said clinical benefit in MC4R deficiency still needed study. The PubMed search returned 12 records, none testing weight loss in general (polygenic) obesity, and the label says setmelanotide would not be expected to work there.

Participants / model
12 obese adults; obese MC4R variant carriers; records reviewed
Treatment
Subcutaneous infusion or injection of setmelanotide (RM-493)
Follow-up
72-hour infusion; 28-day phase 1b; search run on 10 October 2026
Study design
Dated literature search plus a short crossover study and a phase 1b
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source
IMCIVREE label, version effective 1 April 2026: indications, limits of use, warnings, PK, hypothalamic obesity trial

FDA prescribing information

DailyMed, U.S. National Library of Medicine. IMCIVREE (setmelanotide) injection, multiple-dose vial, prescribing information, label version effective 1 April 2026 (Indications and Usage revised 03/2026). Set ID 70c3ccf7-4df0-4c75-ba07-fede9970c8d9.

The label approves IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing (variants read as pathogenic, likely pathogenic, or of uncertain significance). Limitations of use: not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. Warnings cover spontaneous penile erections in males and sexual adverse reactions in females; depression and suicidal ideation; serious hypersensitivity including anaphylaxis; generalized skin darkening, darkening of existing nevi and new nevi; and, in HO, acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%). The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt; the label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base. It has 20-fold less activity at MC3 and MC1 receptors than at MC4, protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. The label's account of the HO trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose, with about 61% versus 5% reaching at least 10% BMI reduction and drug discontinuation of 10.6% versus 12.5%.

Participants / model
Patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency; patients 4 years and older with acquired HO; label PK participants and label trial participants
Treatment
IMCIVREE subcutaneous injection, once daily, multiple-dose vial
Follow-up
Label version effective 1 April 2026; label HO trial of 52 weeks
Study design
FDA prescribing information
Funding
not stated in the source

The label's 142 participants in the HO trial differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. Melanoma and nevus incidence is not quantified beyond the label warning.

Read the original source

Is the supplier description of setmelanotide accurate?

Yes. IMCIVREE is an FDA-approved MC4R agonist for specific genetic obesities, and the 2026 hypothalamic obesity approval is confirmed by a 19 March 2026 FDA efficacy supplement and the label's 03/2026 indication revision. Nothing supports use for ordinary weight loss.

The supplier description is of an FDA-approved MC4R agonist (IMCIVREE, Rhythm Pharmaceuticals) for specific genetic obesities, with a reported 2026 approval for hypothalamic obesity. It is accurate. The genetic-obesity indications are on the label, and the acquired hypothalamic obesity approval is confirmed by a 19 March 2026 FDA efficacy supplement and the label's 03/2026 indication revision. The openFDA record does not name the indication for the supplement, so the link rests on the matching label revision date.

Nothing supports use for ordinary weight loss. The label's limitations of use exclude general (polygenic) obesity, and a PubMed search on 10 October 2026 found no weight trial in it.

IMCIVREE label, version effective 1 April 2026: indications, limits of use, warnings, PK, hypothalamic obesity trial

FDA prescribing information

DailyMed, U.S. National Library of Medicine. IMCIVREE (setmelanotide) injection, multiple-dose vial, prescribing information, label version effective 1 April 2026 (Indications and Usage revised 03/2026). Set ID 70c3ccf7-4df0-4c75-ba07-fede9970c8d9.

The label approves IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing (variants read as pathogenic, likely pathogenic, or of uncertain significance). Limitations of use: not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. Warnings cover spontaneous penile erections in males and sexual adverse reactions in females; depression and suicidal ideation; serious hypersensitivity including anaphylaxis; generalized skin darkening, darkening of existing nevi and new nevi; and, in HO, acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%). The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt; the label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base. It has 20-fold less activity at MC3 and MC1 receptors than at MC4, protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. The label's account of the HO trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose, with about 61% versus 5% reaching at least 10% BMI reduction and drug discontinuation of 10.6% versus 12.5%.

Participants / model
Patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency; patients 4 years and older with acquired HO; label PK participants and label trial participants
Treatment
IMCIVREE subcutaneous injection, once daily, multiple-dose vial
Follow-up
Label version effective 1 April 2026; label HO trial of 52 weeks
Study design
FDA prescribing information
Funding
not stated in the source

The label's 142 participants in the HO trial differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. Melanoma and nevus incidence is not quantified beyond the label warning.

Read the original source
Drugs@FDA: IMCIVREE approved 25 November 2020; supplements 2022, 2024 and 19 March 2026

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record for NDA 213793 (IMCIVREE, Rhythm). Dates read from the openFDA Drugs@FDA record on 10 October 2026.

FDA approved IMCIVREE under NDA 213793 (Rhythm) on 25 November 2020 as a Type 1 new molecular entity. The openFDA record lists efficacy supplements approved on 16 June 2022, 20 December 2024 and 19 March 2026. It does not name the indication for each supplement. The 19 March 2026 approval lines up with the label's 03/2026 indication revision that added acquired HO.

Participants / model
Not a clinical population
Treatment
New drug application and supplements
Follow-up
Approved in 2020; supplements in 2022, 2024 and 2026
Study design
FDA application record
Funding
not stated in the source

openFDA does not tie the 19 March 2026 supplement to hypothalamic obesity by name. The link rests on the matching label revision date.

Read the original source
PubMed search, 10 October 2026: 12 records, none in general obesity; 72-hour infusion study

PubMed search record

Chen KY et al. J Clin Endocrinol Metab. 2015;100(4):1639-45. PMID 25675384.

In 12 otherwise healthy obese adults (BMI 35.7), a 72-hour continuous infusion of RM-493 (1 mg per 24 hours) raised resting energy expenditure by 6.4% (about 111 kcal per day) versus placebo in a crossover trial, with no heart rate or blood pressure effect. This is a short mechanistic study, not a weight trial. A 28-day phase 1b in MC4R variant carriers showed less weight loss than in POMC-pathway defects, and the authors said clinical benefit in MC4R deficiency still needed study. The PubMed search returned 12 records, none testing weight loss in general (polygenic) obesity, and the label says setmelanotide would not be expected to work there.

Participants / model
12 obese adults; obese MC4R variant carriers; records reviewed
Treatment
Subcutaneous infusion or injection of setmelanotide (RM-493)
Follow-up
72-hour infusion; 28-day phase 1b; search run on 10 October 2026
Study design
Dated literature search plus a short crossover study and a phase 1b
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source

How does setmelanotide work, and how long does it last in the body?

Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH that acts as an MC4R agonist, with 20-fold less activity at MC3 and MC1 receptors than at MC4. The effective half-life is about 11 hours.

Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH. The label says it has 20-fold less activity at MC3 and MC1 receptors than at MC4. In a short crossover study in 12 obese adults, a 72-hour infusion raised resting energy expenditure by 6.4% versus placebo, which is a mechanistic signal and not a weight result.

Protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. Tmax is not given in the sources reviewed.

IMCIVREE label, version effective 1 April 2026: indications, limits of use, warnings, PK, hypothalamic obesity trial

FDA prescribing information

DailyMed, U.S. National Library of Medicine. IMCIVREE (setmelanotide) injection, multiple-dose vial, prescribing information, label version effective 1 April 2026 (Indications and Usage revised 03/2026). Set ID 70c3ccf7-4df0-4c75-ba07-fede9970c8d9.

The label approves IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing (variants read as pathogenic, likely pathogenic, or of uncertain significance). Limitations of use: not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. Warnings cover spontaneous penile erections in males and sexual adverse reactions in females; depression and suicidal ideation; serious hypersensitivity including anaphylaxis; generalized skin darkening, darkening of existing nevi and new nevi; and, in HO, acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%). The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt; the label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base. It has 20-fold less activity at MC3 and MC1 receptors than at MC4, protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. The label's account of the HO trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose, with about 61% versus 5% reaching at least 10% BMI reduction and drug discontinuation of 10.6% versus 12.5%.

Participants / model
Patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency; patients 4 years and older with acquired HO; label PK participants and label trial participants
Treatment
IMCIVREE subcutaneous injection, once daily, multiple-dose vial
Follow-up
Label version effective 1 April 2026; label HO trial of 52 weeks
Study design
FDA prescribing information
Funding
not stated in the source

The label's 142 participants in the HO trial differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. Melanoma and nevus incidence is not quantified beyond the label warning.

Read the original source
PubChem: setmelanotide identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 11993702 (setmelanotide).

PubChem lists setmelanotide as CID 11993702, C49H68N18O9S2, molecular weight 1117.3, CAS 920014-72-8, with the synonyms RM-493 and BIM-22493.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined cyclic peptide
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
PubMed search, 10 October 2026: 12 records, none in general obesity; 72-hour infusion study

PubMed search record

Chen KY et al. J Clin Endocrinol Metab. 2015;100(4):1639-45. PMID 25675384.

In 12 otherwise healthy obese adults (BMI 35.7), a 72-hour continuous infusion of RM-493 (1 mg per 24 hours) raised resting energy expenditure by 6.4% (about 111 kcal per day) versus placebo in a crossover trial, with no heart rate or blood pressure effect. This is a short mechanistic study, not a weight trial. A 28-day phase 1b in MC4R variant carriers showed less weight loss than in POMC-pathway defects, and the authors said clinical benefit in MC4R deficiency still needed study. The PubMed search returned 12 records, none testing weight loss in general (polygenic) obesity, and the label says setmelanotide would not be expected to work there.

Participants / model
12 obese adults; obese MC4R variant carriers; records reviewed
Treatment
Subcutaneous infusion or injection of setmelanotide (RM-493)
Follow-up
72-hour infusion; 28-day phase 1b; search run on 10 October 2026
Study design
Dated literature search plus a short crossover study and a phase 1b
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source

What warnings and adverse reactions are reported?

The label warns of spontaneous penile erections in males and sexual adverse reactions in females, depression and suicidal ideation, serious hypersensitivity including anaphylaxis, and skin darkening and new nevi. In hypothalamic obesity it also warns of acute adrenal insufficiency and sodium imbalance. In TRANSCEND, serious adverse events occurred in 28% versus 8% on placebo.

The label warns of spontaneous penile erections in males and sexual adverse reactions in females, depression and suicidal ideation, serious hypersensitivity including anaphylaxis, and generalized skin darkening, darkening of existing nevi and new nevi, and it advises full skin examination. Melanoma and nevus incidence is not quantified beyond the label warning.

In hypothalamic obesity, the label warns of acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and of sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%).

The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection.

In the POMC and LEPR trials, injection site reactions and hyperpigmentation were common and there were no serious treatment-related events. In the BBS and Alstrom trial, hyperpigmentation occurred in 61% and injection site erythema in 48%. In TRANSCEND, serious adverse events occurred in 28% versus 8% on placebo, and hyperpigmentation, nausea, vomiting and headache were most common. In VENTURE, with 12 children, there were no serious adverse events.

IMCIVREE label, version effective 1 April 2026: indications, limits of use, warnings, PK, hypothalamic obesity trial

FDA prescribing information

DailyMed, U.S. National Library of Medicine. IMCIVREE (setmelanotide) injection, multiple-dose vial, prescribing information, label version effective 1 April 2026 (Indications and Usage revised 03/2026). Set ID 70c3ccf7-4df0-4c75-ba07-fede9970c8d9.

The label approves IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing (variants read as pathogenic, likely pathogenic, or of uncertain significance). Limitations of use: not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. Warnings cover spontaneous penile erections in males and sexual adverse reactions in females; depression and suicidal ideation; serious hypersensitivity including anaphylaxis; generalized skin darkening, darkening of existing nevi and new nevi; and, in HO, acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%). The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt; the label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base. It has 20-fold less activity at MC3 and MC1 receptors than at MC4, protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. The label's account of the HO trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose, with about 61% versus 5% reaching at least 10% BMI reduction and drug discontinuation of 10.6% versus 12.5%.

Participants / model
Patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency; patients 4 years and older with acquired HO; label PK participants and label trial participants
Treatment
IMCIVREE subcutaneous injection, once daily, multiple-dose vial
Follow-up
Label version effective 1 April 2026; label HO trial of 52 weeks
Study design
FDA prescribing information
Funding
not stated in the source

The label's 142 participants in the HO trial differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. Melanoma and nevus incidence is not quantified beyond the label warning.

Read the original source
POMC and LEPR deficiency: 21 people, about 1 year, at least 10% weight loss in 80% and 45%

Clinical trial

Clément K et al. Lancet Diabetes Endocrinol. 2020;8(12):960-970. PMID 33137293.

At least 10% weight loss at about 1 year occurred in 8 (80%) of 10 with POMC deficiency and 5 (45%) of 11 with LEPR deficiency. Most-hunger scores fell 27.1% and 43.7% in the 7 assessed in each trial. Injection site reactions and hyperpigmentation were common, and there were no serious treatment-related events.

Participants / model
21 people aged 6 and older with obesity from POMC deficiency (10) or LEPR deficiency (11), at ten hospitals
Treatment
Subcutaneous setmelanotide once daily, about 1 year, with an 8-week blinded withdrawal for responders
Follow-up
About 1 year
Study design
Two single-arm open-label phase 3 trials (NCT02896192 and NCT03287960)
Funding
Funded by Rhythm

Single-arm trials with no control group. The hunger figures come from 7 assessed participants in each trial.

Read the original source
BBS and Alstrom syndrome: 38 patients, 14 weeks randomized then 52 weeks open-label

Randomized controlled trial

Haqq AM et al. Lancet Diabetes Endocrinol. 2022;10(12):859-868. PMID 36356613.

Among BBS patients aged 12 and older, 32.3% (95% CI 16.7 to 51.4) reached at least 10% weight loss after 52 weeks on drug. Results in Alstrom syndrome were inconclusive. Hyperpigmentation occurred in 61% and injection site erythema in 48%.

Participants / model
38 patients aged 6 and older with BBS or Alstrom syndrome and obesity, at 12 sites
Treatment
Subcutaneous setmelanotide once daily or placebo for 14 weeks, then open-label for 52 weeks
Follow-up
14 weeks randomized, then 52 weeks open-label
Study design
Randomized phase 3 trial with an open-label period (NCT03746522)
Funding
Funded by Rhythm

The 52-week figure is from the open-label period, on drug, without a placebo comparison at that point.

Read the original source
TRANSCEND: 120 participants, 52 weeks, BMI change -16.5% versus +3.3% on placebo

Randomized controlled trial

Miller JL et al. N Engl J Med. 2026;395(2):138-150. PMID 42418774.

BMI changed -16.5% (95% CI -19.3 to -13.8) on setmelanotide versus +3.3% (95% CI -0.6 to 7.2) on placebo. Hunger scores fell more on drug (-2.73 versus -1.45). Serious adverse events occurred in 28% versus 8%, and hyperpigmentation, nausea, vomiting and headache were most common.

Participants / model
120 participants aged 4 to 66 (mean adult BMI 41.2) with acquired hypothalamic obesity after a hypothalamic tumor, lesion or injury
Treatment
Subcutaneous setmelanotide (81) or placebo (39), randomized 2:1, for 52 weeks after dose escalation
Follow-up
52 weeks
Study design
Randomized placebo-controlled phase 3 trial (NCT05774756)
Funding
Funded by Rhythm

The figures are each arm's percent change in BMI. The label reports a placebo-corrected figure and 142 patients for the same trial, and neither source explains the difference from the paper's 120.

Read the original source
VENTURE: 12 children aged 2 to 5, week 52 BMI change -18%, no serious adverse events

Clinical trial

Argente J et al. Lancet Diabetes Endocrinol. 2025;13(1):29-37. PMID 39549719.

Mean BMI change at week 52 was -18% overall, -26% in POMC or LEPR deficiency and -10% in BBS. There were no serious adverse events.

Participants / model
12 children aged 2 to 5: seven with POMC or LEPR deficiency and five with BBS
Treatment
Subcutaneous setmelanotide once daily
Follow-up
52 weeks
Study design
Open-label single-arm phase 3 trial
Funding
Funded by Rhythm

Twelve children and no control group. This trial is the evidence behind the label's expansion to age 2.

Read the original source

Why does setmelanotide sit in A tier?

IMCIVREE has been FDA-approved since 2020 with phase 3 evidence across three indications, including a 120-person randomized trial in hypothalamic obesity with a large BMI effect. The A does not extend to ordinary obesity: the label is narrow by design and excludes it.

A fits an approved drug whose narrow label is sometimes read more widely than written. The approval is real, and the hypothalamic obesity trial is randomized with a large BMI effect (-16.5% versus +3.3% on placebo at 52 weeks).

The label is narrow by design and excludes general (polygenic) obesity, where it would not be expected to be effective and where no weight trial was found. The POMC and LEPR evidence also rests on 21 people in single-arm trials.

IMCIVREE label, version effective 1 April 2026: indications, limits of use, warnings, PK, hypothalamic obesity trial

FDA prescribing information

DailyMed, U.S. National Library of Medicine. IMCIVREE (setmelanotide) injection, multiple-dose vial, prescribing information, label version effective 1 April 2026 (Indications and Usage revised 03/2026). Set ID 70c3ccf7-4df0-4c75-ba07-fede9970c8d9.

The label approves IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing (variants read as pathogenic, likely pathogenic, or of uncertain significance). Limitations of use: not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. Warnings cover spontaneous penile erections in males and sexual adverse reactions in females; depression and suicidal ideation; serious hypersensitivity including anaphylaxis; generalized skin darkening, darkening of existing nevi and new nevi; and, in HO, acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%). The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt; the label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base. It has 20-fold less activity at MC3 and MC1 receptors than at MC4, protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. The label's account of the HO trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose, with about 61% versus 5% reaching at least 10% BMI reduction and drug discontinuation of 10.6% versus 12.5%.

Participants / model
Patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency; patients 4 years and older with acquired HO; label PK participants and label trial participants
Treatment
IMCIVREE subcutaneous injection, once daily, multiple-dose vial
Follow-up
Label version effective 1 April 2026; label HO trial of 52 weeks
Study design
FDA prescribing information
Funding
not stated in the source

The label's 142 participants in the HO trial differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. Melanoma and nevus incidence is not quantified beyond the label warning.

Read the original source
Drugs@FDA: IMCIVREE approved 25 November 2020; supplements 2022, 2024 and 19 March 2026

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record for NDA 213793 (IMCIVREE, Rhythm). Dates read from the openFDA Drugs@FDA record on 10 October 2026.

FDA approved IMCIVREE under NDA 213793 (Rhythm) on 25 November 2020 as a Type 1 new molecular entity. The openFDA record lists efficacy supplements approved on 16 June 2022, 20 December 2024 and 19 March 2026. It does not name the indication for each supplement. The 19 March 2026 approval lines up with the label's 03/2026 indication revision that added acquired HO.

Participants / model
Not a clinical population
Treatment
New drug application and supplements
Follow-up
Approved in 2020; supplements in 2022, 2024 and 2026
Study design
FDA application record
Funding
not stated in the source

openFDA does not tie the 19 March 2026 supplement to hypothalamic obesity by name. The link rests on the matching label revision date.

Read the original source
TRANSCEND: 120 participants, 52 weeks, BMI change -16.5% versus +3.3% on placebo

Randomized controlled trial

Miller JL et al. N Engl J Med. 2026;395(2):138-150. PMID 42418774.

BMI changed -16.5% (95% CI -19.3 to -13.8) on setmelanotide versus +3.3% (95% CI -0.6 to 7.2) on placebo. Hunger scores fell more on drug (-2.73 versus -1.45). Serious adverse events occurred in 28% versus 8%, and hyperpigmentation, nausea, vomiting and headache were most common.

Participants / model
120 participants aged 4 to 66 (mean adult BMI 41.2) with acquired hypothalamic obesity after a hypothalamic tumor, lesion or injury
Treatment
Subcutaneous setmelanotide (81) or placebo (39), randomized 2:1, for 52 weeks after dose escalation
Follow-up
52 weeks
Study design
Randomized placebo-controlled phase 3 trial (NCT05774756)
Funding
Funded by Rhythm

The figures are each arm's percent change in BMI. The label reports a placebo-corrected figure and 142 patients for the same trial, and neither source explains the difference from the paper's 120.

Read the original source
POMC and LEPR deficiency: 21 people, about 1 year, at least 10% weight loss in 80% and 45%

Clinical trial

Clément K et al. Lancet Diabetes Endocrinol. 2020;8(12):960-970. PMID 33137293.

At least 10% weight loss at about 1 year occurred in 8 (80%) of 10 with POMC deficiency and 5 (45%) of 11 with LEPR deficiency. Most-hunger scores fell 27.1% and 43.7% in the 7 assessed in each trial. Injection site reactions and hyperpigmentation were common, and there were no serious treatment-related events.

Participants / model
21 people aged 6 and older with obesity from POMC deficiency (10) or LEPR deficiency (11), at ten hospitals
Treatment
Subcutaneous setmelanotide once daily, about 1 year, with an 8-week blinded withdrawal for responders
Follow-up
About 1 year
Study design
Two single-arm open-label phase 3 trials (NCT02896192 and NCT03287960)
Funding
Funded by Rhythm

Single-arm trials with no control group. The hunger figures come from 7 assessed participants in each trial.

Read the original source
PubMed search, 10 October 2026: 12 records, none in general obesity; 72-hour infusion study

PubMed search record

Chen KY et al. J Clin Endocrinol Metab. 2015;100(4):1639-45. PMID 25675384.

In 12 otherwise healthy obese adults (BMI 35.7), a 72-hour continuous infusion of RM-493 (1 mg per 24 hours) raised resting energy expenditure by 6.4% (about 111 kcal per day) versus placebo in a crossover trial, with no heart rate or blood pressure effect. This is a short mechanistic study, not a weight trial. A 28-day phase 1b in MC4R variant carriers showed less weight loss than in POMC-pathway defects, and the authors said clinical benefit in MC4R deficiency still needed study. The PubMed search returned 12 records, none testing weight loss in general (polygenic) obesity, and the label says setmelanotide would not be expected to work there.

Participants / model
12 obese adults; obese MC4R variant carriers; records reviewed
Treatment
Subcutaneous infusion or injection of setmelanotide (RM-493)
Follow-up
72-hour infusion; 28-day phase 1b; search run on 10 October 2026
Study design
Dated literature search plus a short crossover study and a phase 1b
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source

Studies and sources

IMCIVREE label, version effective 1 April 2026: indications, limits of use, warnings, PK, hypothalamic obesity trial

FDA prescribing information

DailyMed, U.S. National Library of Medicine. IMCIVREE (setmelanotide) injection, multiple-dose vial, prescribing information, label version effective 1 April 2026 (Indications and Usage revised 03/2026). Set ID 70c3ccf7-4df0-4c75-ba07-fede9970c8d9.

The label approves IMCIVREE to reduce excess body weight and maintain the reduction long term in patients 4 years and older with acquired hypothalamic obesity (HO), and in patients 2 years and older with Bardet-Biedl syndrome (BBS) or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing (variants read as pathogenic, likely pathogenic, or of uncertain significance). Limitations of use: not for obesity with benign or likely benign variants in those genes, other genetic syndromes, or general (polygenic) obesity, where it would not be expected to be effective. Warnings cover spontaneous penile erections in males and sexual adverse reactions in females; depression and suicidal ideation; serious hypersensitivity including anaphylaxis; generalized skin darkening, darkening of existing nevi and new nevi; and, in HO, acute adrenal insufficiency (serious events in 5% on setmelanotide versus none on placebo) and sodium imbalance in patients with central diabetes insipidus (hyponatremia 6% versus 2%). The most common adverse reactions (20% or more in at least one indication) were hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Setmelanotide is an 8-amino-acid cyclic peptide analog of alpha-MSH, supplied as the acetate salt; the label gives C49H68N18O9S2 and 1117.3 Da for the anhydrous free base. It has 20-fold less activity at MC3 and MC1 receptors than at MC4, protein binding is 79.1%, the effective half-life is about 11 hours, and about 39% of a dose is excreted unchanged in urine. The label's account of the HO trial (Trial 1, NCT05774756) reports 142 patients randomized and analyzed (47% adults, mean BMI 36) and a placebo-corrected BMI change of -18.40% after 52 weeks at the therapeutic dose, with about 61% versus 5% reaching at least 10% BMI reduction and drug discontinuation of 10.6% versus 12.5%.

Participants / model
Patients 2 years and older with BBS or POMC, PCSK1 or LEPR deficiency; patients 4 years and older with acquired HO; label PK participants and label trial participants
Treatment
IMCIVREE subcutaneous injection, once daily, multiple-dose vial
Follow-up
Label version effective 1 April 2026; label HO trial of 52 weeks
Study design
FDA prescribing information
Funding
not stated in the source

The label's 142 participants in the HO trial differ from the 120 in the New England Journal of Medicine paper, and neither source explains the difference. Melanoma and nevus incidence is not quantified beyond the label warning.

Read the original source
Drugs@FDA: IMCIVREE approved 25 November 2020; supplements 2022, 2024 and 19 March 2026

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record for NDA 213793 (IMCIVREE, Rhythm). Dates read from the openFDA Drugs@FDA record on 10 October 2026.

FDA approved IMCIVREE under NDA 213793 (Rhythm) on 25 November 2020 as a Type 1 new molecular entity. The openFDA record lists efficacy supplements approved on 16 June 2022, 20 December 2024 and 19 March 2026. It does not name the indication for each supplement. The 19 March 2026 approval lines up with the label's 03/2026 indication revision that added acquired HO.

Participants / model
Not a clinical population
Treatment
New drug application and supplements
Follow-up
Approved in 2020; supplements in 2022, 2024 and 2026
Study design
FDA application record
Funding
not stated in the source

openFDA does not tie the 19 March 2026 supplement to hypothalamic obesity by name. The link rests on the matching label revision date.

Read the original source
PubChem: setmelanotide identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 11993702 (setmelanotide).

PubChem lists setmelanotide as CID 11993702, C49H68N18O9S2, molecular weight 1117.3, CAS 920014-72-8, with the synonyms RM-493 and BIM-22493.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined cyclic peptide
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
POMC and LEPR deficiency: 21 people, about 1 year, at least 10% weight loss in 80% and 45%

Clinical trial

Clément K et al. Lancet Diabetes Endocrinol. 2020;8(12):960-970. PMID 33137293.

At least 10% weight loss at about 1 year occurred in 8 (80%) of 10 with POMC deficiency and 5 (45%) of 11 with LEPR deficiency. Most-hunger scores fell 27.1% and 43.7% in the 7 assessed in each trial. Injection site reactions and hyperpigmentation were common, and there were no serious treatment-related events.

Participants / model
21 people aged 6 and older with obesity from POMC deficiency (10) or LEPR deficiency (11), at ten hospitals
Treatment
Subcutaneous setmelanotide once daily, about 1 year, with an 8-week blinded withdrawal for responders
Follow-up
About 1 year
Study design
Two single-arm open-label phase 3 trials (NCT02896192 and NCT03287960)
Funding
Funded by Rhythm

Single-arm trials with no control group. The hunger figures come from 7 assessed participants in each trial.

Read the original source
BBS and Alstrom syndrome: 38 patients, 14 weeks randomized then 52 weeks open-label

Randomized controlled trial

Haqq AM et al. Lancet Diabetes Endocrinol. 2022;10(12):859-868. PMID 36356613.

Among BBS patients aged 12 and older, 32.3% (95% CI 16.7 to 51.4) reached at least 10% weight loss after 52 weeks on drug. Results in Alstrom syndrome were inconclusive. Hyperpigmentation occurred in 61% and injection site erythema in 48%.

Participants / model
38 patients aged 6 and older with BBS or Alstrom syndrome and obesity, at 12 sites
Treatment
Subcutaneous setmelanotide once daily or placebo for 14 weeks, then open-label for 52 weeks
Follow-up
14 weeks randomized, then 52 weeks open-label
Study design
Randomized phase 3 trial with an open-label period (NCT03746522)
Funding
Funded by Rhythm

The 52-week figure is from the open-label period, on drug, without a placebo comparison at that point.

Read the original source
TRANSCEND: 120 participants, 52 weeks, BMI change -16.5% versus +3.3% on placebo

Randomized controlled trial

Miller JL et al. N Engl J Med. 2026;395(2):138-150. PMID 42418774.

BMI changed -16.5% (95% CI -19.3 to -13.8) on setmelanotide versus +3.3% (95% CI -0.6 to 7.2) on placebo. Hunger scores fell more on drug (-2.73 versus -1.45). Serious adverse events occurred in 28% versus 8%, and hyperpigmentation, nausea, vomiting and headache were most common.

Participants / model
120 participants aged 4 to 66 (mean adult BMI 41.2) with acquired hypothalamic obesity after a hypothalamic tumor, lesion or injury
Treatment
Subcutaneous setmelanotide (81) or placebo (39), randomized 2:1, for 52 weeks after dose escalation
Follow-up
52 weeks
Study design
Randomized placebo-controlled phase 3 trial (NCT05774756)
Funding
Funded by Rhythm

The figures are each arm's percent change in BMI. The label reports a placebo-corrected figure and 142 patients for the same trial, and neither source explains the difference from the paper's 120.

Read the original source
VENTURE: 12 children aged 2 to 5, week 52 BMI change -18%, no serious adverse events

Clinical trial

Argente J et al. Lancet Diabetes Endocrinol. 2025;13(1):29-37. PMID 39549719.

Mean BMI change at week 52 was -18% overall, -26% in POMC or LEPR deficiency and -10% in BBS. There were no serious adverse events.

Participants / model
12 children aged 2 to 5: seven with POMC or LEPR deficiency and five with BBS
Treatment
Subcutaneous setmelanotide once daily
Follow-up
52 weeks
Study design
Open-label single-arm phase 3 trial
Funding
Funded by Rhythm

Twelve children and no control group. This trial is the evidence behind the label's expansion to age 2.

Read the original source

Why is Setmelanotide in A tier?

A fits an approved drug whose label is narrow by design. IMCIVREE has been FDA-approved since 2020 with phase 3 evidence across three indications, including a randomized hypothalamic obesity trial with a large BMI effect. The label excludes general obesity, where no weight trial was found, and the POMC and LEPR evidence rests on 21 people in single-arm trials.