setmelanotide

Setmelanotide is indicated for chronic weight management (weight loss and weight maintenance for at least one year) in people six years and older with obesity due to three rare genetic conditions: pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic (causing disease), likely pathogenic, or of uncertain significance.{{cite press release | title=FDA approves first treatment for weight management for people with certain rare genetic conditions | website=U.S. Food and Drug Administration (FDA) | date=27 November 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-first-treatment-weight-management-people-certain-rare-genetic-conditions | access-date=27 November 2020}} {{PD-notice}} Setmelanotide is the first FDA-approved treatment for these genetic conditions.

Setmelanotide is not approved for obesity due to suspected POMC, PCSK1, or LEPR deficiency with variants classified as benign (not causing disease) or likely benign or other types of obesity, including obesity associated with other genetic syndromes and general (polygenic) obesity.

Setmelanotide binds to and activates MC₄ receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects.{{cite journal | vauthors = Kim GW, Lin JE, Blomain ES, Waldman SA | title = Antiobesity pharmacotherapy: new drugs and emerging targets | journal = Clinical Pharmacology and Therapeutics | volume = 95 | issue = 1 | pages = 53–66 | date = January 2014 | pmid = 24105257 | pmc = 4054704 | doi = 10.1038/clpt.2013.204 }} In addition to reducing appetite, setmelanotide increases resting energy expenditure in both obese animals and humans.{{cite journal | vauthors = Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, Zhao X, Ring M, Psota TL, Cone RD, Panaro BL, Gottesdiener KM, Van der Ploeg LH, Reitman ML, Skarulis MC | display-authors = 6 | title = RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 4 | pages = 1639–45 | date = April 2015 | pmid = 25675384 | pmc = 4399297 | doi = 10.1210/jc.2014-4024 }} Importantly, unlike certain other MC₄ receptor agonists, such as LY-2112688, setmelanotide has not been found to produce increases in heart rate or blood pressure.

Setmelanotide has been reported to possess the following activity profile (cAMP, EC₅₀): MC₄ (0.27 nM) > MC₃ (5.3 nM) ≈ MC₁ (5.8 nM) > MC₅ (1600 nM) ≟ MC₂ (>1000 nM).{{cite journal | vauthors = Muniyappa R, Chen K, Brychta R, Abel B, Mullins K, Staker P, Van der Ploeg L, Connors H, Gottesdiener K, Reitman ML, Skarulis MC | display-authors = 6 | journal = Endocrine Reviews | date = June 2014 | volume = 35 | issue = 3 | title = A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Effect of a Melanocortin Receptor 4 (MC4R) Agonist, RM-493, on Resting Energy Expenditure (REE) in Obese Subjects | publisher = Rhythm Pharmaceuticals | url = http://www.rhythmtx.com/pdfs/ICE-ENDO%202014%20Rhythm%20RM-493%20REE.pdf | access-date = 21 May 2015 | archive-date = 22 May 2015 | archive-url = https://web.archive.org/web/20150522112137/http://www.rhythmtx.com/pdfs/ICE-ENDO%202014%20Rhythm%20RM-493%20REE.pdf | url-status = dead }} (19.6-fold selectivity for MC₄ over MC₃, the second target of highest activity.)

Setmelanotide was invented at Ipsen.US Patent US 8,039,435 B2, "Melanocortin Receptor Ligands", 18 October 2011, Inventors: Zheng Xin Dong, Jacques-Pierre Moreau It was initially known as BIM-22493 and then as RM-493 and IRC-022493.

It was evaluated in two one-year clinical studies. The first study enrolled 10 participants with obesity and confirmed or suspected POMC or PCSK1 deficiency while the second study enrolled 11 participants with obesity and confirmed or suspected LEPR deficiency; all participants were six years or older. Most participants had lost more than 10% of their initial body weight after a year of treatment. Some participants also reported feeling less hungry.

The U.S. Food and Drug Administration (FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review. The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc.

In 2021, the cost was $330 for 1 mg.{{cite journal | vauthors = Ryan DH |title=Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice? |journal=Journal of Obesity & Metabolic Syndrome |date=September 2021 |volume=30 |issue=3 |pages=196–208 |doi=10.7570/jomes21033 | pmid = 34518444 | pmc = 8526285 }}

Setmelanotide was approved for medical use in the United States in November 2020.{{cite web | title=FDA approves first treatment for weight management | website=U.S. Food and Drug Administration (FDA) | date=30 September 2021 | url=https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-weight-management-people-certain-rare-genetic-conditions | access-date=12 February 2022}}

Setmelanotide was approved for medical use in the European Union in July 2021.{{cite web | title=Imcivree Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1564.htm | access-date=3 March 2023}}

Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC₄ receptor;{{cite journal | vauthors = Lee EC, Carpino PA | title = Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014) | journal = Pharmaceutical Patent Analyst | volume = 4 | issue = 2 | pages = 95–107 | year = 2015 | pmid = 25853469 | doi = 10.4155/ppa.15.1 }}{{cite journal | vauthors = Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, Pranger L, Cowley MA, Grove KL, Culler MD | display-authors = 6 | title = Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques | journal = Diabetes | volume = 62 | issue = 2 | pages = 490–497 | date = February 2013 | pmid = 23048186 | pmc = 3554387 | doi = 10.2337/db12-0598 }} the structure of the bound complex has recently been determined.{{cite journal | vauthors = Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M | display-authors = 6 | title = Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling | journal = Science | volume = 372 | issue = 6544 | pages = 808–814 | date = May 2021 | pmid = 33858992 | doi = 10.1126/science.abf7958 | s2cid = 233260097 | bibcode = 2021Sci...372..808I | url = https://qmro.qmul.ac.uk/xmlui/handle/123456789/71518 }} Its peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It was first discovered at Ipsen and is being developed by Rhythm Pharmaceuticals for the treatment of obesity and diabetes. In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC₄ receptor deficiency and associated symptoms such as excessive appetite and obesity.{{cite web | title = Obesity and Diabetes Caused by Genetic Deficiencies in the MC4 Pathway | publisher = Rhythm Pharmaceuticals | url = http://www.rhythmtx.com/PROGRAMS/obesitydiabetes.html | access-date = 21 May 2015 | archive-date = 14 June 2015 | archive-url = https://web.archive.org/web/20150614103824/http://www.rhythmtx.com/PROGRAMS/obesitydiabetes.html | url-status = dead }} As of December 2014, the drug is in phase II clinical trials for obesity and PWS.{{cite journal | vauthors = Jackson VM, Price DA, Carpino PA | title = Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies | journal = Expert Opinion on Investigational Drugs | volume = 23 | issue = 8 | pages = 1055–1066 | date = August 2014 | pmid = 25000213 | doi = 10.1517/13543784.2014.918952 | s2cid = 23198484 }}{{cite web | title = RM-493: A First-in-Class, Phase 2-Ready MC4 Agonist: A New Drug Class for the Treatment of Obesity and Diabetes | publisher = Rhythm Pharmaceuticals | url = http://www.rhythmtx.com/PROGRAMS/RM493.html | access-date = 21 May 2015 | url-status = dead | archive-url = https://web.archive.org/web/20150614100443/http://www.rhythmtx.com/PROGRAMS/RM493.html | archive-date = 14 June 2015 }}{{update inline|date=November 2017}} So far, preliminary data has shown no benefit of Setmelanotide in Prader-Willi syndrome.{{cite journal | vauthors = Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, Childers A, Shelton AR, Bingham NC, Shoemaker AH, Miller JL | display-authors = 6 | title = A multidisciplinary approach to the clinical management of Prader-Willi syndrome | journal = Molecular Genetics & Genomic Medicine | volume = 7 | issue = 3 | pages = e514 | date = March 2019 | pmid = 30697974 | pmc = 6418440 | doi = 10.1002/mgg3.514 }}

The drug has some efficacy in obese people who lack the genetic variants that the drug is approved for, but its safety and efficacy in this wider population is not well understood.

{{Reflist}}

• {{ClinicalTrialsGov|NCT02896192|Setmelanotide for the Treatment of Early-Onset POMC Deficiency Obesity}}
• {{ClinicalTrialsGov|NCT03287960|Setmelanotide for the Treatment of LEPR Deficiency Obesity}}

{{Anorectics}}

{{Melanocortin receptor modulators}}

{{Portal bar | Medicine}}

Category:Anorectics

Category:Anti-obesity drugs

Category:Melanocortin receptor agonists

Category:Orphan drugs

Category:Peptides