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Also: RM-493 · BIM-22493 · MC4R agonist
Four separate measurements, never averaged. Independent evidence counts only studies with no sponsor attached. Methodology version v2.0-2026-10 · how we grade evidence
Marketed to reduce body weight or BMI and to control hyperphagia in people whose obesity is caused by specific defects in, or injury to, the hypothalamic melanocortin pathway: biallelic POMC or PCSK1 or LEPR deficiency, genetically confirmed Bardet-Biedl syndrome, and acquired hypothalamic obesity. The claim is explicitly mechanism-targeted and genotype- or lesion-restricted.
Every indication is an ultra-rare genetic or acquired hypothalamic obesity syndrome. This is not an approved general obesity drug in any jurisdiction and must not be presented as one.
The evidence sits in an unusual shape. The mechanism is unusually well confirmed in humans, while the trials the original approvals rest on are uncontrolled single-arm studies in 10 and 11 patients, with their P values computed against historical data rather than a concurrent control group. A properly randomised placebo-controlled trial, TRANSCEND, arrived only in 2026 and is also manufacturer-run. A well-confirmed mechanism does not compensate for an uncontrolled trial design.
There is no independent evidence base for this drug at all: no investigator-initiated trial, no non-manufacturer meta-analysis, and no independent efficacy or safety synthesis in any indication. Given the rarity of the indications that is understandable, but it is stated here rather than smoothed over.
At a glance
An MC4R agonist. In the hypothalamic leptin–melanocortin pathway, POMC-derived α-MSH normally activates MC4R to suppress food intake; loss-of-function upstream at POMC, PCSK1 or LEPR, or structural hypothalamic damage, breaks that signal and produces severe hyperphagia and early-onset obesity. Setmelanotide is intended to restore signalling downstream of the defect by agonising MC4R directly. The human genetic evidence is unusually strong for a mechanism claim: the drug works in patients with defects upstream of the receptor and the response tracks with genotype, which is close to a biological proof of the pathway. Skin hyperpigmentation, near-universal in the POMC cohort, is an expected on-target melanocortin effect.
Dated determinations, each flagged for whether it is final and whether it covers safety only. A safety review is not an efficacy finding, and most reporting in this category conflates the two.
Granted 19 March 2026; a separate source reported the approval announcement on 20 March 2026. This is the one indication supported by a randomised placebo-controlled trial (TRANSCEND), which is also manufacturer-run.
Granted 16 June 2022 on a 38-patient trial in which the randomised placebo-controlled period lasted 14 weeks and the primary endpoint was read at 52 weeks on open-label treatment. The same trial showed no significant weight effect in Alström syndrome.
CHMP opinion 20 May 2021, authorised 16 July 2021. The indications now cover acquired hypothalamic obesity from hypothalamic injury or impairment (adults and children aged 4 and over); genetically confirmed Bardet-Biedl syndrome (adults and children aged 2 and over); and genetically confirmed biallelic loss-of-function POMC, including PCSK1, or LEPR deficiency (adults and children aged 2 and over). Post-authorisation variations received CHMP positive opinions in July 2022, June 2024 and March 2026. Marketing authorisation holder Rhythm Pharmaceuticals Netherlands B.V.
Approved 27 November 2020; a product page header elsewhere lists 25 November 2020 and the discrepancy is unresolved in the source. Extended down to patients as young as 2 years on 20 December 2024. The approval rests on two uncontrolled single-arm trials in 10 and 11 patients whose significance tests were computed against historical data. This is a genotype-restricted orphan indication, not a general obesity approval.
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