OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Setmelanotide – Imcivree®

DRUG CLASS

Weight Loss Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Setmelanotide	920014-72-8	C49-H68-N18-O9-S2

ANNOTATED BIBLIOGRAPHY

References updated: 05 July 2024

Abbreviations: (LEPR), leptin receptor; (PCSK1), proprotein convertase subtilisin/kexin type 1 (PCSK1); POMC, pro-opiomelanocortin; ULN, upper limit of normal range.

• FDA. Integrated Review. 2020. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2020/213793Orig1s000MedR.pdf

  (FDA Integrated review of the data on setmelanotide safety and efficacy submitted in support of the application for its approval as therapy of several rare genetic forms of obesity mentions that “Overall, no trends or clinically meaningful changes were observed in clinical laboratory assessments throughout the studies.”).
• Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, et al.; Setmelanotide POMC and LEPR Phase 3 Trial Investigators. 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. Lancet Diabetes Endocrinol. 2020;8:960-970. [PubMed: 33137293]

  (Among 21 patients with obesity due to POMC deficiency [n=10] or LEPR deficiency [n=11] treated with setmelanotide injections for 12 weeks, followed by an 8 week placebo controlled withdrawal, and then a 32 week open label extension period, most patients lost weight and 80% of POMC vs 45% of LEPR subjects lost more than 10% of body weight, while adverse events included injection site reactions in 100%, hyperpigmentation in 71%, and nausea in 43%, but only one subject discontinued therapy because of an adverse event [eosinophilia], ALT and AST levels tended to improve with the weight loss, and there were no serious hepatic adverse events).
• Haws R, Brady S, Davis E, Fletty K, Yuan G, Gordon G, Stewart M, Yanovski J. Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome. Diabetes Obes Metab. 2020;22:2133-2140. [PMC free article: PMC7689750] [PubMed: 32627316]

  (Among 8 adolescents and adults with obesity due to Bardet-Biedl syndrome treated with setmelanotide, weight loss averaged 9% at 3 months and 16% at 12 months, while side effects included injection site reactions, hyperpigmentation, nausea, and vomiting and there were no discontinuations for adverse events; no mention of ALT or hepatotoxicity).
• Markham A. Setmelanotide: first approval. Drugs. 2021;81:397-403. [PubMed: 33638809]

  (Review of the chemical structure, mechanism of action, history of development, pharmacology, clinical efficacy, and safety of setmelanotide shortly after its approval as therapy of genetic forms of obesity in the US, discusses the frequency of common side effects, but does not mention ALT elevations or hepatotoxicity).
• Setmelanotide (Imcivree) for rare genetic forms of obesity. Med Lett Drugs Ther. 2021;63(1629):e3-e4. [PubMed: 34544109]

  (Concise review of the mechanism of action, clinical efficacy, safety, and costs of setmelanotide shortly after its approval for use in the US, discusses common adverse events; no mention of ALT elevations or hepatotoxicity).
• Haqq AM, Chung WK, Dollfus H, Haws RM, Martos-Moreno GÁ, Poitou C, Yanovski JA, et al. 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. Lancet Diabetes Endocrinol. 2022;10:859-868. [PMC free article: PMC9847480] [PubMed: 36356613]

  (Among 38 patients with obesity due to Bardet-Biedl or Alström syndrome treated with setmelanotide or placebo subcutaneously once daily for 14 weeks, followed by open label drug for 52 weeks, weight loss occurred with therapy but varied by age and diagnosis, while adverse events occurred in 97% and were severe in 5%, but none were liver related; no mention of ALT elevations or hepatotoxicity).
• Roth CL, Scimia C, Shoemaker AH, Gottschalk M, Miller J, Yuan G, Malhotra S, et al. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial. Lancet Diabetes Endocrinol. 2024;12:380-389. [PubMed: 38697184]

  (Among 18 patients with acquired hypothalamic obesity treated with setmelanotide for up to one year, the mean weight loss was 15% and adverse events included nausea in 61%, vomiting 33%, hyperpigmentation 33%, diarrhea 22%, and two subjects discontinued therapy because of elevations in serum aminotransferase levels at 4 weeks [recurring after 6 days on re-exposure] and 12 months, specific values and other details not provided).