A daily MC4R agonist (Imcivree) approved for rare genetic obesity and acquired hypothalamic obesity, not common obesity.
Also called Imcivree, setmelanotide acetate, MC4R agonist
When Setmelanotide's status or evidence changes, it's in the next morning's email.
Setmelanotide is an 8-amino-acid ring-shaped peptide that switches on the melanocortin 4 receptor (MC4R) in the brain. MC4R is part of the leptin-melanocortin pathway, the brain circuit that controls hunger and body weight. When a gene in that pathway is broken, as in POMC, PCSK1 or LEPR deficiency or Bardet-Biedl syndrome, people have extreme hunger from early childhood. Setmelanotide skips the broken step and activates the receptor directly. Rhythm Pharmaceuticals sells it as Imcivree, a once-daily injection.
The results depend on the cause. In POMC deficiency, 8 of 10 trial participants lost at least 10% of their weight in about a year; in LEPR deficiency, 5 of 11 did. In Bardet-Biedl syndrome, BMI fell 7.9% after 52 weeks. The biggest trial, TRANSCEND, tested it in acquired hypothalamic obesity, the weight gain that follows damage to the hypothalamus from a tumor, lesion or injury. BMI fell 16.5% on setmelanotide and rose 3.3% on placebo over 52 weeks, and FDA approved that use on March 19, 2026.
It is not a drug for common obesity, and the label says so. The side effect most people notice is darker skin: setmelanotide also touches MC1R, the receptor that drives melanin, so skin and moles darken, which reverses after stopping. Spontaneous erections, nausea, injection site reactions and depression are labeled risks, and people with hypothalamic damage need monitoring for adrenal crises and sodium swings.
What it binds to, and what happens inside the body after that, step by step.
In the hypothalamus, the POMC protein is processed into alpha-MSH, which activates MC4R and turns hunger down. Leptin and its receptor feed into this pathway. Genetic defects or physical damage upstream of MC4R break that chain. Setmelanotide activates MC4R directly, restoring the fullness signal.
Human results and animal results are kept apart below. A result in rats tells you a mechanism is plausible. It does not tell you what happens in a person.
An approved drug, but the evidence base is small because the conditions are rare. The genetic indications rest on open-label trials of 10 to 44 people, with a placebo-controlled phase only in Bardet-Biedl syndrome. Acquired hypothalamic obesity has a proper phase 3 RCT (TRANSCEND, 120 participants in the NEJM report) with a 52-week placebo arm. There is no evidence for common obesity.
120 people aged 4 to 66 with acquired hypothalamic obesity
BMI changed -16.5% on setmelanotide vs +3.3% on placebo at 52 weeks; serious adverse events were 28% vs 8%. The FDA label, using 142 randomized patients, reports an 18.4% placebo-adjusted BMI reduction.
Read the study10 people with POMC deficiency and 11 with LEPR deficiency, aged 6 and older
8 of 10 (80%) with POMC deficiency and 5 of 11 (45%) with LEPR deficiency lost at least 10% of body weight at about 1 year.
Read the study38 people aged 6 and older with Bardet-Biedl or Alstrom syndrome
32.3% of people 12 and older with Bardet-Biedl syndrome lost at least 10% of their weight after 52 weeks; results in Alstrom syndrome were inconclusive.
Read the study12 children aged 2 to 5 with POMC or LEPR deficiency or Bardet-Biedl syndrome
Mean BMI change was -18% at 52 weeks: -26% in POMC or LEPR deficiency and -10% in Bardet-Biedl syndrome.
Read the study2 patients with POMC deficiency
Hunger fell and the patients lost 51.0 kg over 42 weeks and 20.5 kg over 12 weeks.
Read the studyNo preclinical studies are listed as key studies here. The human data above carries the evidence.
When a new Setmelanotide study in people is published, the daily email covers it.
These are questions the published research has not answered.
Prescription-only, prescribed after genetic testing for the genetic indications. FDA approved Imcivree on November 25, 2020, added Bardet-Biedl syndrome in June 2022, children from age 2 in December 2024, and acquired hypothalamic obesity on March 19, 2026 (Drugs@FDA supplement dates), which Rhythm describes as the first FDA-approved therapy for that condition. The EU authorized Imcivree in July 2021, and EU product information now also lists acquired hypothalamic obesity from age 4. Not named on the WADA Prohibited List and not in WADA's Monitoring Program.
When the FDA or WADA changes Setmelanotide's status, it's in the next morning's email.
How much of Setmelanotide is left after a single dose
Simple first-order model from the published half-life. Real clearance varies with dose, route, kidney and liver function and formulation. This is not a dosing schedule.
This table records the doses that trials and approved labels used, with the source for each row. It is a record of research, not a recommendation, and it is open to free members.
Which symptoms are expected and which mean stop and get help: side effects and red flags.
Tap a claim to see what the studies found.
The label specifically excludes general (polygenic) obesity. Trials enrolled only people with defined genetic defects or hypothalamic damage.
Both act on melanocortin receptors and both darken skin. But setmelanotide was designed to target MC4R, with about 20-fold weaker MC1R activity, and is an approved drug for weight. Using it for a tan has never been studied.
The label says the pigment change reverses after stopping Imcivree.
Since March 2026 it is also approved for acquired hypothalamic obesity in adults and children 4 and older, where TRANSCEND showed a 16.5% BMI drop vs a 3.3% rise on placebo.
These pairings come up often. Almost none have been tested together in a trial, and the evidence note on each says so plainly.
Discussed for hypothalamic or genetic obesity because the two act on different appetite pathways.
EvidenceWe found no published controlled trial of the combination. Both cause nausea and vomiting.
Not applicable: Imcivree is supplied as a ready-to-use solution in multi-dose vials.
Unopened vials: refrigerate at 36 to 46 F (2 to 8 C) until expiration, or keep at 36 to 77 F (2 to 25 C) for up to 30 days. Opened vials: discard after 30 days. Discard if exposed to temperatures above 86 F (30 C). Keep vials in the carton.
One email when a trial reads out, a label changes or the FDA acts on a peptide. Free, every source linked, unsubscribe any time.