Setmelanotide

Last updated

Setmelanotide
Setmelanotide.svg
Clinical data
Trade names Imcivree
Other namesRM-493; BIM-22493; IRC-022493; N2-Acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide
License data
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Identifiers
  • (4R,7S,10S,13R,16S,19R,22R)-22-[[(2S)-2-Acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C49H68N18O9S2
Molar mass 1117.32 g·mol−1
3D model (JSmol)
  • C[C@@H]1C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)C)C(=O)N)Cc2c[nH]c3c2cccc3)CCCN=C(N)N)Cc4ccccc4)Cc5cnc[nH]5
  • InChI=1S/C49H68N18O9S2/c1-26-41(70)63-37(20-30-22-55-25-59-30)46(75)64-35(18-28-10-4-3-5-11-28)44(73)62-34(15-9-17-57-49(53)54)43(72)65-36(19-29-21-58-32-13-7-6-12-31(29)32)45(74)66-38(40(50)69)23-77-78-24-39(47(76)60-26)67-42(71)33(61-27(2)68)14-8-16-56-48(51)52/h3-7,10-13,21-22,25-26,33-39,58H,8-9,14-20,23-24H2,1-2H3,(H2,50,69)(H,55,59)(H,60,76)(H,61,68)(H,62,73)(H,63,70)(H,64,75)(H,65,72)(H,66,74)(H,67,71)(H4,51,52,56)(H4,53,54,57)/t26-,33+,34+,35-,36+,37+,38+,39+/m1/s1
  • Key:HDHDTKMUACZDAA-PHNIDTBTSA-N

Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation. [3] [4] [5]

Contents

The most common side effects include injection site reactions, skin hyperpigmentation (skin patches that are darker than surrounding skin), headache and gastrointestinal side effects (such as nausea, diarrhea, and abdominal pain), among others. [4] Spontaneous penile erections in males and adverse sexual reactions in females have occurred with treatment. [4] Depression and suicidal ideation have also occurred with setmelanotide. [4]

Setmelanotide was approved for medical use in the United States in November 2020, [6] [7] and in the European Union in July 2021. [5] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. [8] [7]

Medical uses

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. [3] [4] [5] Setmelanotide is the first FDA-approved treatment for these genetic conditions. [4]

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. [4]

Pharmacology

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. [9] In addition to reducing appetite, setmelanotide increases resting energy expenditure in both obese animals and humans. [10] 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. [11]

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). [12] (19.6-fold selectivity for MC4 over MC3, the second target of highest activity.)

History

Setmelanotide was invented at Ipsen. [13] It was initially known as BIM-22493 and then as RM-493 and IRC-022493.

It was evaluated in two one-year clinical studies. [4] 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. [4] Most participants had lost more than 10% of their initial body weight after a year of treatment. [4] Some participants also reported feeling less hungry. [4]

The U.S. Food and Drug Administration (FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review. [4] The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc. [4] [6]

Society and culture

Economics

In 2021, the cost was $330 for 1 mg. [14]

Setmelanotide was approved for medical use in the United States in November 2020. [6] [7]

Setmelanotide was approved for medical use in the European Union in July 2021. [5] [15]

Research

Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC4 receptor; [16] [11] the structure of the bound complex has recently been determined. [17] 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. [16] 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. [18] As of December 2014, the drug is in phase II clinical trials for obesity and PWS. [16] [19] [20] [ needs update ] So far, preliminary data has shown no benefit of Setmelanotide in Prader-Willi syndrome. [21]

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. [14]

Related Research Articles

<span class="mw-page-title-main">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

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The melanocyte-stimulating hormones, known collectively as MSH, also known as melanotropins or intermedins, are a family of peptide hormones and neuropeptides consisting of α-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating hormone (β-MSH), and γ-melanocyte-stimulating hormone (γ-MSH) that are produced by cells in the pars intermedia of the anterior lobe of the pituitary gland.

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<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors. The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in chordates. Melanocortins were originally named so because their earliest known function was in melanogenesis. It is now known that the melanocortin system regulates diverse functions throughout the body, including inflammatory response, fibrosis, melanogenesis, steroidogenesis, energy homeostasis, sexual function, and exocrine gland function.

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<span class="mw-page-title-main">Melanocortin 4 receptor</span> Mammalian protein found in Homo sapiens

Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the MC4R gene. It encodes the MC4R protein, a G protein-coupled receptor (GPCR) that binds α-melanocyte stimulating hormone (α-MSH). In mouse models, MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.

<span class="mw-page-title-main">Central melanocortin system</span> System involved in the regulation of weight and peripheral tissue such as hair and skin

The central melanocortin system is defined anatomically as a collection of central nervous system circuits which include:

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An orexigenic, or appetite stimulant, is a drug, hormone, or compound that increases appetite and may induce hyperphagia. This can be a medication or a naturally occurring neuropeptide hormone, such as ghrelin, orexin or neuropeptide Y, which increases hunger and therefore enhances food consumption. Usually appetite enhancement is considered an undesirable side effect of certain drugs as it leads to unwanted weight gain, but sometimes it can be beneficial and a drug may be prescribed solely for this purpose, especially when the patient is suffering from severe appetite loss or muscle wasting due to cystic fibrosis, anorexia, old age, cancer or AIDS. There are several widely used drugs which can cause a boost in appetite, including tricyclic antidepressants (TCAs), tetracyclic antidepressants, natural or synthetic cannabinoids, first-generation antihistamines, most antipsychotics and many steroid hormones. In the United States, no hormone or drug has currently been approved by the FDA specifically as an orexigenic, with the exception of Dronabinol, which received approval for HIV/AIDS-induced anorexia only.

α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone and neuropeptide of the melanocortin family, with a tridecapeptide structure and the amino acid sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. It is the most important of the melanocyte-stimulating hormones (MSHs) (also known as melanotropins) in stimulating melanogenesis, a process that in mammals (including humans) is responsible for pigmentation primarily of the hair and skin. It also plays a role in feeding behavior, energy homeostasis, sexual activity, and protection against ischemia and reperfusion injury.

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Louis Anthony Tartaglia is an American biochemist, pharmaceutical scientist, and entrepreneur. As a scientist, he is known for first identifying and cloning the leptin receptor in 1995, a discovery that prompted immediate coverage in US national media given its expected clinical significance. He is also known for studying signaling mechanisms from the tumor necrosis factor (TNF) receptors, and for publishing studies in the fields of obesity and diabetes which are often discussed in subject reviews. After moving from academia to industry in 1990, for over a decade he accompanied the growth of Millennium Pharmaceuticals, reaching top positions within the company. From executive roles he has occupied in venture capital firms, and as a member of several advisory boards, Tartaglia has helped start a number of therapeutics oriented companies that have found their way into the market, among them Agios, Editas, Rhythm, and Zafgen.

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Hypothalamic obesity is a rare condition that can be congenital or acquired. Congenital causes include Prader-Willi syndrome and mutations of LEP, LEPR, POMC, MC4R, and CART. It can also result from injuries to the hypothalamus either from trauma, therapeutic radiation, brain surgery, and especially craniopharyngioma and its treatments. Possible treatments include bariatric surgery and melanocortin 4 receptor agonists such as setmelanotide.

References

  1. ↑ "Summary Basis of Decision for Imcivree". Health Canada. 7 July 2023. Retrieved 4 October 2023.
  2. ↑ "Details for: Imcivree". Health Canada. 12 July 2023. Retrieved 4 October 2023.
  3. 1 2 3 "Imcivree- setmelanotide solution". DailyMed. Retrieved 25 December 2020.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "FDA approves first treatment for weight management for people with certain rare genetic conditions". U.S. Food and Drug Administration (FDA) (Press release). 27 November 2020. Retrieved 27 November 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. 1 2 3 4 5 "Imcivree EPAR". European Medicines Agency (EMA). 19 May 2021. Retrieved 22 July 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 3 "Drug Approval Package: Imcivree". U.S. Food and Drug Administration (FDA). 23 December 2020. Retrieved 18 January 2021.
  7. 1 2 3 "FDA approves first treatment for weight management". U.S. Food and Drug Administration (FDA). 30 September 2021. Retrieved 12 February 2022.
  8. ↑ "New Drug Therapy Approvals 2020". U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January 2021.
  9. ↑ Kim GW, Lin JE, Blomain ES, Waldman SA (January 2014). "Antiobesity pharmacotherapy: new drugs and emerging targets". Clinical Pharmacology and Therapeutics. 95 (1): 53–66. doi:10.1038/clpt.2013.204. PMC   4054704 . PMID   24105257.
  10. ↑ Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, et al. (April 2015). "RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals". The Journal of Clinical Endocrinology and Metabolism. 100 (4): 1639–45. doi:10.1210/jc.2014-4024. PMC   4399297 . PMID   25675384.
  11. 1 2 Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, et al. (February 2013). "Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques". Diabetes. 62 (2): 490–497. doi:10.2337/db12-0598. PMC   3554387 . PMID   23048186.
  12. ↑ Muniyappa R, Chen K, Brychta R, Abel B, Mullins K, Staker P, et al. (June 2014). "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" (PDF). Endocrine Reviews. Rhythm Pharmaceuticals. 35 (3). Archived from the original (PDF) on 22 May 2015. Retrieved 21 May 2015.
  13. ↑ US Patent US 8,039,435 B2, "Melanocortin Receptor Ligands", 18 October 2011, Inventors: Zheng Xin Dong, Jacques-Pierre Moreau
  14. 1 2 Ryan DH (September 2021). "Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?". Journal of Obesity & Metabolic Syndrome. 30 (3): 196–208. doi:10.7570/jomes21033. PMC   8526285 . PMID   34518444.
  15. ↑ "Imcivree Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  16. 1 2 3 Lee EC, Carpino PA (2015). "Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014)". Pharmaceutical Patent Analyst. 4 (2): 95–107. doi:10.4155/ppa.15.1. PMID   25853469.
  17. ↑ Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, et al. (May 2021). "Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling". Science. 372 (6544): 808–814. Bibcode:2021Sci...372..808I. doi:10.1126/science.abf7958. PMID   33858992. S2CID   233260097.
  18. ↑ "Obesity and Diabetes Caused by Genetic Deficiencies in the MC4 Pathway". Rhythm Pharmaceuticals. Archived from the original on 14 June 2015. Retrieved 21 May 2015.
  19. ↑ Jackson VM, Price DA, Carpino PA (August 2014). "Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies". Expert Opinion on Investigational Drugs. 23 (8): 1055–1066. doi:10.1517/13543784.2014.918952. PMID   25000213. S2CID   23198484.
  20. ↑ "RM-493: A First-in-Class, Phase 2-Ready MC4 Agonist: A New Drug Class for the Treatment of Obesity and Diabetes". Rhythm Pharmaceuticals. Archived from the original on 14 June 2015. Retrieved 21 May 2015.
  21. ↑ Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, et al. (March 2019). "A multidisciplinary approach to the clinical management of Prader-Willi syndrome". Molecular Genetics & Genomic Medicine. 7 (3): e514. doi:10.1002/mgg3.514. PMC   6418440 . PMID   30697974.
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