Setmelanotide

An FDA-approved synthetic cyclic octapeptide (8-amino-acid) analogue of alpha-melanocyte-stimulating hormone (α-MSH) with selective agonist activity at the melanocortin-4 receptor (MC4R). Marketed as Imcivree (Rhythm Pharmaceuticals). Approved 2020 for monogenic obesity due to POMC, PCSK1, or LEPR deficiency; indication expanded 2022 to Bardet-Biedl Syndrome (BBS). Aging-context relevance is speculative: MC4R agonism for sarcopenia or cachexia in older adults has not been evaluated in clinical trials.

Identity

• PubChem CID: 11993702
• ChEMBL ID: CHEMBL3301624 (free base); CHEMBL4650273 (acetate salt, marketed form)
• InChIKey: HDHDTKMUACZDAA-PHNIDTBTSA-N
• Molecular formula: C₄₉H₆₈N₁₈O₉S₂
• Molecular weight: 1117.3 Da
• Class: synthetic cyclic octapeptide; α-MSH analogue
• Route: subcutaneous injection daily; 10 mg/mL solution
• WHO INN: setmelanotide

Mechanism of action

Setmelanotide is a conformationally constrained cyclic peptide (disulfide bridge between Cys² and Cys⁷ residues) that acts as a selective, high-potency agonist at MC4R, a class-A GPCR coupled to Gs protein. MC4R is expressed in paraventricular hypothalamic neurons and mediates the anorexigenic arm of the melanocortin energy-homeostasis pathway: activation increases adenylyl cyclase → cAMP → reduced appetite and increased energy expenditure ¹.

Receptor selectivity profile (relative to non-selective parent α-MSH / Melanotan-II):

Receptor	Role	Setmelanotide activity
MC4R	Hypothalamic anorexigenic circuit	Primary target — full agonist, high potency
MC1R	Melanocyte melanogenesis; skin	Cross-reactivity — causes hyperpigmentation AE
MC3R	Hypothalamus; energy regulation	Partial cross-reactivity
MC2R	Adrenocortical ACTH receptor	Minimal binding
MC5R	Exocrine glands	Minimal binding

In POMC-deficient patients, endogenous α-MSH production is absent, leaving hypothalamic MC4R constitutively understimulated — the molecular basis for hyperphagia and severe early-onset obesity. Setmelanotide bypasses the upstream POMC → α-MSH → MC4R axis by directly activating MC4R ².

In LEPR-deficient patients, leptin signalling fails to upregulate POMC/α-MSH production, similarly creating functional MC4R understimulation; setmelanotide also rescues this phenotype, though with lower response rate than POMC deficiency ².

FDA approval history

Two approved indications as of 2026-05-09:

Approval	Date	NDA	Indication	Population
ORIG-1	2020-11-25	NDA213793	Obesity due to POMC, PCSK1, or LEPR deficiency	Age ≥6 years
SUPPL-1	2022-06-16	NDA213793/S-001	Obesity due to Bardet-Biedl Syndrome (BBS)	Age ≥6 years

Important classification note: Both approved indications are for rare monogenic or syndromic obesity — not for common polygenic obesity, age-related weight gain, sarcopenia, or any aging indication. The clinical-stage: fda-approved field reflects the maximal regulatory status; the translation-gap: phase-3-rct-needed field reflects that no aging-relevant indication has been evaluated ¹.

Phase 3 clinical trial evidence

Clément 2020 — POMC and LEPR deficiency ²

Phase 3 single-arm open-label multicentre trials (two parallel cohorts). Enrolled n=10 POMC/PCSK1-deficient and n=11 LEPR-deficient participants. Primary endpoint: ≥10% body weight loss at 52 weeks.

Cohort	n	≥10% weight loss (primary EP)	Hunger score reduction
POMC/PCSK1 deficiency	10	80%	−27.1%
LEPR deficiency	11	45%	−43.7%

Most common adverse events: injection site reactions, skin hyperpigmentation (MC1R cross-reactivity), nausea. No drug-related serious adverse events. No weight loss observed in placebo run-in period prior to treatment.

Haqq 2022 — Bardet-Biedl and Alström syndrome ³

Phase 3 multicentre randomised double-blind placebo-controlled trial (14-week DB period) with subsequent 52-week open-label phase. Enrolled n=32 BBS + n=6 Alström = 38 total. Primary endpoint: ≥10% body weight reduction at end of 52-week open-label period in BBS participants ≥12 years.

• Primary endpoint met: 32.3% of BBS participants achieved ≥10% weight loss (95% CI 16.7–51.4%, p=0.0006 vs pre-defined null hypothesis of ≤5%)
• None of the 6 Alström patients met the weight-loss threshold (Alström syndrome differs from BBS in MC4R pathway involvement)
• Most common AEs: hyperpigmentation 61%, injection site erythema 48%, nausea

Collet 2017 — MC4R deficiency (Phase 1b) ⁴

Phase 1b randomised double-blind placebo-controlled study (NOT a case series). Total enrolled n=49 (41 males + 8 females, ages 19–53, BMI 26.2–40.3 kg/m²) across 5 cohorts, of whom n=8 were heterozygous MC4R carriers (n=6 setmelanotide + n=2 placebo) and n=41 were obese controls without MC4R variants (n=5 setmelanotide + n=3 placebo shown in Table 1 comparison; remainder in other cohorts). Dose: 0.01 mg/kg/24h subcutaneous continuous infusion for 28 days. Primary weight-change results at Day 29:

• MC4R heterozygous carrier arm (n=6 setmelanotide): −3.48 kg from baseline (95% CI −4.99 to −1.96), p<0.0001; waist circumference −5.83 cm (95% CI −9.70 to −1.96), p=0.005
• Obese control arm (n=5 setmelanotide): −3.07 kg from baseline (95% CI −4.11 to −2.04), p<0.0001

Identified MC4R loss-of-function as a non-responsive context — setmelanotide cannot rescue complete loss-of-function MC4R mutations (in contrast to POMC/LEPR deficiency where the receptor is intact); heterozygous partial-LOF MC4R carriers did respond. This pharmacological distinction guided the Phase 3 indication selection. No increase in HR or BP observed at any dose in either obese controls or MC4R mutation carriers.

VENTURE trial (Lancet DE 2025) — pediatric extension ⁵

Phase 3 open-label multicentre trial in children aged 2–5 years with POMC/LEPR deficiency or BBS. Published Lancet Diabetes Endocrinol 2025;13(1):29–37 (doi:10.1016/S2213-8587(24)00273-0; PMID 39549719). Enrolled n=12 (7 POMC/LEPR + 5 BBS; 1 BBS patient later excluded for not meeting BMI threshold); 11 completed. Mean age 3.6 years (SD 0.9). Co-primary endpoints at 52 weeks: ≥0.2-point BMI Z-score decrease (WHO) and mean % BMI change.

• 10/12 (83%, 95% CI 58.7–99.8%) achieved ≥0.2-point BMI Z-score reduction at 52 weeks
• Mean BMI change: −18% (SD 13) overall; −26% (SD 11) in POMC/LEPR; −10% (SD 9) in BBS
• 91% of caregivers reported less hunger at baseline vs Week 52
• AEs: all mild or moderate; hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infections, injection site reactions; no serious AEs, no discontinuations, no deaths

Active clinical trials (ClinicalTrials.gov, 2026-05-09)

4 RECRUITING / ACTIVE_NOT_RECRUITING / ENROLLING_BY_INVITATION:

NCT	Phase	Status	Condition
NCT05774756	Phase 3	Active, not recruiting	Acquired hypothalamic obesity
NCT06760546	Phase 3	Recruiting	Congenital hypothalamic obesity (sub-study)
NCT06596135	Phase 3	Enrolling by invitation	MC4R pathway obesity disorders (broad)
NCT06772597	Phase 2	Active, not recruiting	Prader-Willi syndrome

No trial registered for sarcopenia, cachexia, frailty, or any aging-primary endpoint as of 2026-05-09. needs-human-replication

Pharmacokinetics

• Route: subcutaneous injection, once daily
• Concentration: 10 mg/mL solution; doses titrated 1–3 mg/day
• Half-life: approximately 11 hours (terminal); supports once-daily dosing (contrast with short-lived endogenous α-MSH)
• Cyclic structure advantage: the disulfide bridge confers conformational stability that markedly extends plasma half-life relative to linear α-MSH (~minutes) ¹
• Metabolism: proteolytic degradation; renal and hepatic pathways; no CYP450-mediated metabolism anticipated for peptides

Adverse effects

Adverse effect	Frequency	Mechanism
Skin hyperpigmentation	Very common (~50–70%)	MC1R cross-reactivity in melanocytes → melanogenesis
Injection site reactions	Very common (~48%)	Local peptide injection response
Nausea	Common	MC4R/central appetite axis
Spontaneous penile erections	~5% of males	MC4R CNS pleiotropic effect (BBB-crossing peptide)
Blood pressure increase	Observed	MC4R cardiovascular axis; concerning in older patients

The hyperpigmentation signal is a class-level effect of MC-receptor agonists. The melanoma risk signal documented for non-selective agonists (Melanotan II) should be tracked in long-term setmelanotide registries; per the class note in frameworks/intervention-classes.md, all melanocortin-receptor-agonist compound pages must disclose this. No confirmed melanoma causal link for setmelanotide exists as of 2026-05-09. long-term-unknown

Aging-context assessment

Potential relevance

MC4R agonism could theoretically address two contexts in aging:

1. Sarcopenia / cachexia: Anorexia of aging and disease-associated cachexia involve dysregulated appetite and accelerated muscle wasting. MC4R is a potent appetite driver — agonism suppresses appetite, however, making it contraindicated for anorexia-of-aging. MC4R antagonism has been proposed for cachexia, but that is a different pharmacological approach from setmelanotide.

2. Hypothalamic obesity in older adults: Acquired hypothalamic dysfunction (post-cranial radiation, craniopharyngioma, traumatic brain injury) phenocopies congenital MC4R pathway deficiency. NCT05774756 targets this acquired form.

Key aging-context caveats

• Appetite suppression exacerbates sarcopenia risk: In older adults with low caloric intake or pre-existing sarcopenia, further appetite suppression from MC4R agonism could worsen lean mass loss unless paired with supervised resistance training and protein supplementation. The compound’s effect on lean-to-fat mass ratio in older adults is not established.
• Cardiovascular concern: MC4R agonism raises blood pressure modestly. Older patients with hypertension or cardiovascular comorbidity represent a higher-risk population.
• MC4R agonism ≠ energy-sensing intervention: Despite mechanistic adjacency to the POMC/leptin/MC4R nutrient-sensing axis (placed under [[../../hallmarks/deregulated-nutrient-sensing]]), setmelanotide does not directly modulate mTOR, AMPK, insulin signaling, or sirtuins. The hallmark assignment reflects the upstream pathway, not a demonstrated aging-biology effect.
• No DrugAge entry: No lifespan-extension data for setmelanotide or MC4R agonists in any model organism. needs-human-replication

Dimension	Status
MC4R pathway conserved in humans?	Yes — all Phase 3 data is human
Aging-hallmark phenotype conserved?	Unknown — no aging-indication trial
Replicated in aging context?	Not tested

Classification

• Mechanism class: melanocortin-receptor-agonism (see frameworks/intervention-classes.md § melanocortin-receptor-agonist) — class already defined; no new class needed
• Hallmark target: deregulated-nutrient-sensing (MC4R/POMC/leptin nutrient-sensing axis)
• Related intervention class: peptide-therapeutics
• SENS category: none directly applicable

Cross-references

• mc4r — primary target; see R35-Stage2 page
• mc1r — cross-reactive receptor (hyperpigmentation mechanism)
• mc3r — partial cross-reactivity
• alpha-msh — endogenous parent peptide; see stub
• pomc — upstream precursor; deficiency is primary approved indication
• leptin — LEPR deficiency is the second approved indication context
• sarcopenia — potential adverse interaction (appetite suppression in older adults); no beneficial evidence established
• deregulated-nutrient-sensing — hallmark via MC4R/POMC axis

Limitations and gaps

• No aging-indication data. All Phase 3 evidence is in rare monogenic/syndromic pediatric and young-adult obesity. Extrapolation to aging biology is speculative. needs-human-replication
• Appetite suppression may be harmful in older adults without structured nutritional support and exercise; sarcopenic obesity is a plausible adverse outcome.
• Melanoma risk monitoring: long-term MC1R cross-reactivity safety data in aging populations with accumulated UV exposure is absent. long-term-unknown
• Lean mass effects unknown: no body-composition (DXA) endpoint has been reported for setmelanotide trials vs. a comparator in older adults.
• DrugBank ID not confirmed. PubChem and ChEMBL IDs are confirmed; DrugBank ID left null pending manual lookup. needs-canonical-id

Footnotes

Footnotes

1. doi:10.1007/s40265-021-01470-9 · Markham A · Drugs 2021;81(3):397–403 · drug review / first-approval summary · n/a · model: review; FDA approval documentation · archive: not_oa ↩ ↩² ↩³

2. doi:10.1016/S2213-8587(20)30364-8 · Clément K, van den Akker E, Argente J, Bahm A, Chung WK, et al. · Lancet Diabetes Endocrinol 2020;8(12):960–970 · n=10 (POMC/PCSK1) + n=11 (LEPR) · single-arm open-label Phase 3 · primary endpoint ≥10% weight loss at 52 weeks: 80% (POMC), 45% (LEPR) · model: human; monogenic obesity · archive: not_oa ↩ ↩² ↩³

3. doi:10.1016/S2213-8587(22)00277-7 · Haqq AM, Chung WK, Dollfus H, Haws RM, Martos-Moreno GÁ, Poitou C, Yanovski JA, Mittleman RS, Yuan G, Forsythe E, Clément K, Argente J · Lancet Diabetes Endocrinol 2022;10(12):859–868 · n=38 (32 BBS + 6 Alström) · randomised double-blind placebo-controlled Phase 3 + 52-week open-label · primary endpoint 32.3% of BBS patients ≥10% weight loss (p=0.0006) · model: human; BBS/Alström syndrome · archive: OA via PMC9847480 (download failed; use PMC) ↩

4. doi:10.1016/j.molmet.2017.06.015 · Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, et al. · Mol Metab 2017;6(10):1321–1329 · n=49 total (n=8 MC4R heterozygous carriers: 6 setmelanotide + 2 placebo; n=41 obese controls without MC4R variants) · Phase 1b randomised double-blind placebo-controlled · dose 0.01 mg/kg/24h SC for 28 days · MC4R carrier arm: weight −3.48 kg (95% CI −4.99 to −1.96), p<0.0001; obese controls: −3.07 kg (95% CI −4.11 to −2.04), p<0.0001; heterozygous MC4R carriers responded; complete LOF MC4R = non-responders · model: human · archive: downloaded (gold OA) ↩

5. doi:10.1016/S2213-8587(24)00273-0 · PMID 39549719 · Argente J, Verge CF, Okorie U, et al. · Lancet Diabetes Endocrinol 2025;13(1):29–37 · n=12 enrolled (7 POMC/LEPR + 5 BBS; 11 completed) · Phase 3 open-label · 10/12 (83%) ≥0.2-point BMI Z-score reduction at 52 wk; mean BMI −18% overall (−26% POMC/LEPR, −10% BBS); no serious AEs · model: human; ages 2–5 years · archive: not yet downloaded; abstract verified via PubMed efetch 2026-05-09 ↩