Explore a selection of our essential drug information below, or:
Identification
- Summary
Setmelanotide is a drug indicated to treat obesity caused by genetic POMC, PCSK1, or LEPR deficiencies or Bardet-Biedl syndrome.
- Brand Names
- Imcivree
- Generic Name
- Setmelanotide
- DrugBank Accession Number
- DB11700
- Background
Setmelanotide is the first available treatment for patients with pro-opiomelanocortin, proprotein subilisin/kexin type 1, or leptin deficiencies.6 It is an agonist of the melanocortin 4 receptor.1 Earlier attempts at agonizing MC4R (such as LY2112688) lead to successful weight loss, but also an increase in blood pressure and heart rate.1 Other earlier treatments for these patients included gastric bypass surgery.1 Patients taking setmelanotide experienced an average weight loss of 0.6 kg/week.1
Imcivree was granted EMA orphan designation on November 19, 2018 7 and FDA approval on November 25, 2020.5 On May 4, 2023, it was approved by Health Canada.11
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Setmelanotide (DB11700)
- Weight
- Average: 1117.32
Monoisotopic: 1116.48580819 - Chemical Formula
- C49H68N18O9S2
- Synonyms
- Setmelanotida
- Setmelanotide
- Setmélanotide
- Setmelanotidum
- External IDs
- BIM-22493
- RM 493
- RM-493
Pharmacology
- Indication
Setmelanotide is indicated for chronic weight management in patients 6 years and older with obesity due to pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor (LEPR) deficiency as determined by an approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance.9,10,11 These conditions affect the MC4R signalling pathway.2
Setmelanotide is also indicated for chronic weight management in patients 6 years and older with obesity due to Bardet-Biedl syndrome.9,10,11
The drug is not reported to be effective in patients with POMC, PCSK1, or LEPR variants classified as benign or likely benign, as well as other types of obesity not listed above.11
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Leptin receptor deficiency obesity •••••••••••• •••••••• Management of Leptin receptor deficiency obesity •••••••••••• ••••••••••• •••••• ••••••••• Management of Obesity •••••••••••• ••••••••••• •••••• ••••••••• Management of Pcsk1 deficiency obesity •••••••••••• ••••••••••• •••••• ••••••••• Management of Pro-opiomelanocortin (pomc) deficiency obesity •••••••••••• ••••••••••• •••••• ••••••••• - Associated Therapies
- Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Setmelanotide agonizes MC4R, downstream of multiple potential genetic deficiencies, to induce a feeling of satiety for chronic weight management.8 It has a moderate duration of action as it is given daily.8 Patients should be counselled regarding the risk of disturbances in sexual arousal, depression and suicidal ideation, and darkening of skin pigmentation.8 Exercise caution in neonates and low birth weight infants, as they may experience serious adverse effects due to benzyl alcohol.8
- Mechanism of action
Grehlin and other hunger signals from the gastrointestinal tract stimulate orexigenic neurons, stimulating the release of agouti-related protein.3 Agouti-related protein inhibits melanocortin 4 receptor (MC4R) activation until satiety signals such as insulin or leptin stimulate anorexigenic neurons.3 Insulin and leptin stimulate production of the POMC-derived melanocortin peptide α-melanocyte simulating hormone, which is a ligand of MC4R.3,1
Orexigenic and anorexigenic neurons contain prohormone convertase 1/3 (PC1/3), which is encoded by the gene proprotein subtilisin/kexin type 1.4 PC1/3 preforms activation cleavage of a number of peptide hormone precursors, including α-melanocyte simulating hormone.4
Setmelanotide is a pro-opiomelanocortin derived peptide that is an agonist of MC4R.1 It is an approximately 20-fold more potent agonist of MC4R than endogenous α-melanocyte stimulating hormone, with an EC50 of 0.27 nM.3,1 By directly agonizing MC4R, upstream genetic deficiencies in the MC4R signalling pathway cannot inhibit satiety, food intake is decreased, and weight loss is achieved.1,3,4
MC4R is a 332 amino acid G-protein coupled receptor (G-PCR).3 Although the lack of cardiovascular adverse effects with setmelanotide treatment are not well understood, it is believed that earlier MC4R antagonists activated multiple G-protein signalling pathways.1 Earlier drugs that targeted G-PCRs either bound with high affinity to the highly conserved orthosteric binding site, or with high specificity to less conserved allosteric sites.3 Setmelanotide is an atypical bitopic ligand that interacts with both the orthosteric and putative allosteric binding site, allowing for both high affinity and specificity.3
Target Actions Organism AMelanocortin receptor 4 agonistHumans - Absorption
Setmelanotide has a Tmax of 8 hours.8
- Volume of distribution
The apparent volume of distribution of setmelanotide is 48.7 L.8
- Protein binding
Setmelanotide is 79.1% protein bound.8
- Metabolism
Setmelanotide is expected to be metabolized to small peptides and amino acids.8
- Route of elimination
A 3mg subcutaneous dose of setmelanotide is 39% eliminated in the urine as the unchanged parent compound.8
- Half-life
The elimination had life of setmelanotide is approximately 11 hours.8
- Clearance
A 3mg subcutaneous dose of setmelanotide has an estimated clearance of 4.86 L/h.8
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Data regarding overdoses of setmelanotide are not readily available.8 In the event of an overdose, patients should be treated with symptomatic and supportive care.8
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Setmelanotide acetate 224I1W20I7 1504602-49-6 PILXXDANZBQUJH-PUHLIQIQSA-N - International/Other Brands
- Imcivree
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Imcivree Solution 10 mg/1mL Subcutaneous Rhythm Pharmaceuticals Netherlands B.V. 2020-12-14 Not applicable US 
Imcivree Injection, solution 10 mg/ml Subcutaneous Rhythm Pharmaceuticals Netherlands B.V. 2021-10-07 Not applicable EU 
Imcivree Injection, solution 10 mg/ml Subcutaneous Rhythm Pharmaceuticals Netherlands B.V. 2023-02-08 Not applicable EU Imcivree Solution 10 mg / mL Subcutaneous Rhythm Pharmaceuticals Netherlands B.V. 2023-07-12 Not applicable Canada 
Categories
- ATC Codes
- A08AA12 — Setmelanotide
- Drug Categories
- Alimentary Tract and Metabolism
- Amino Acids, Peptides, and Proteins
- Anti-Obesity Agents
- Antiobesity Preparations, Excl. Diet Products
- Centrally Acting Antiobesity Products
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Hypothalamic Hormones
- Melanocortin 4 Receptor Agonist
- Melanocortin 4 Receptor Agonists
- Melanocortins
- Melanocyte-Stimulating Hormones
- Nerve Tissue Proteins
- Neuropeptides
- Peptide Hormones
- Peptides
- Pituitary Hormones
- Pituitary Hormones, Anterior
- Pro-Opiomelanocortin
- Protein Precursors
- Proteins
- Receptor, Melanocortin, Type 4, agonists
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Oligopeptides
- Alternative Parents
- Cyclic peptides / N-acyl-alpha amino acids and derivatives / Macrolactams / Alpha amino acid amides / 3-alkylindoles / Substituted pyrroles / Benzene and substituted derivatives / N-acyl amines / Acetamides / Heteroaromatic compounds show 12 more
- Substituents
- 3-alkylindole / Acetamide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-oligopeptide / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Carbonyl group show 30 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans
- Mouse
Chemical Identifiers
- UNII
- N7T15V1FUY
- CAS number
- 920014-72-8
- InChI Key
- HDHDTKMUACZDAA-PHNIDTBTSA-N
- InChI
- 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
- IUPAC Name
- (4R,7S,10S,13R,16S,19R,22R)-13-benzyl-22-[(2S)-5-[(diaminomethylidene)amino]-2-acetamidopentanamido]-10-{3-[(diaminomethylidene)amino]propyl}-16-[(1H-imidazol-5-yl)methyl]-7-[(1H-indol-3-yl)methyl]-19-methyl-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexaazacyclotricosane-4-carboxamide
- SMILES
- [H]N([H])C(=O)[C@@H]1CSSC[C@H](N([H])C(=O)[C@H](CCCN=C(N([H])[H])N([H])[H])N([H])C(C)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC2=CN=CN2[H])C(=O)N[C@H](CC2=CC=CC=C2)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC2=CN([H])C3=CC=CC=C23)C(=O)N1
References
- General References
- Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R, Le Beyec J, Pepin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clement K, Farooqi IS, Van der Ploeg LHT: Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017 Oct;6(10):1321-1329. doi: 10.1016/j.molmet.2017.06.015. Epub 2017 Jul 8. [Article]
- Clement K, Biebermann H, Farooqi IS, Van der Ploeg L, Wolters B, Poitou C, Puder L, Fiedorek F, Gottesdiener K, Kleinau G, Heyder N, Scheerer P, Blume-Peytavi U, Jahnke I, Sharma S, Mokrosinski J, Wiegand S, Muller A, Weiss K, Mai K, Spranger J, Gruters A, Blankenstein O, Krude H, Kuhnen P: MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018 May;24(5):551-555. doi: 10.1038/s41591-018-0015-9. Epub 2018 May 7. [Article]
- Falls BA, Zhang Y: Insights into the Allosteric Mechanism of Setmelanotide (RM-493) as a Potent and First-in-Class Melanocortin-4 Receptor (MC4R) Agonist To Treat Rare Genetic Disorders of Obesity through an in Silico Approach. ACS Chem Neurosci. 2019 Mar 20;10(3):1055-1065. doi: 10.1021/acschemneuro.8b00346. Epub 2018 Aug 13. [Article]
- Ramos-Molina B, Martin MG, Lindberg I: PCSK1 Variants and Human Obesity. Prog Mol Biol Transl Sci. 2016;140:47-74. doi: 10.1016/bs.pmbts.2015.12.001. Epub 2016 Jan 29. [Article]
- FDA: Approval Letter for Imcivree (Setmelanotide) [Link]
- FDA Press Announcements: FDA approves first treatment for weight management for people with certain rare genetic conditions [Link]
- EMA Public Summary of Opinion on Orphan Designation: Setmelanotide [Link]
- FDA Approved Drug Products: Imcivree (Setmelanotide) Subcutaneous Injection [Link]
- FDA Approved Drug Products: IMCIVREE (setmelanotide) injection, for subcutaneous use (June 2022) [Link]
- EMA Summary of Product Characteristics: Imcivree (setmelanotide) solution for injection [Link]
- Health Canada Approved Drug Products: IMCIVREE (setmelanotide) Subcutaneous Injection [Link]
- External Links
- Human Metabolome Database
- HMDB0304856
- PubChem Compound
- 11993702
- PubChem Substance
- 347828065
- ChemSpider
- 10166169
- 2469247
- ChEMBL
- CHEMBL3301624
- Wikipedia
- Setmelanotide
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Approved for Marketing Not Available Laurence-Moon-Bardet-Biedl syndrome / Obesity 1 somestatus stop reason just information to hide 4 Completed Treatment Healthy Volunteers (HV) 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Laurence-Moon-Bardet-Biedl syndrome / Leptin Receptor Deficiency Obesity / Pro-opiomelanocortin (POMC) Deficiency Obesity / Proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency obesity 1 somestatus stop reason just information to hide 3 Completed Treatment Alström Syndrome (AS) / Laurence-Moon-Bardet-Biedl syndrome 1 somestatus stop reason just information to hide 3 Completed Treatment Laurence-Moon-Bardet-Biedl syndrome / POMC Deficiency 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Subcutaneous 10 MG/ML Solution Subcutaneous 10 mg/1mL Solution Subcutaneous 10 mg / mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9458195 No 2016-10-04 2027-10-13 US US8039435 No 2011-10-18 2027-10-13 US US11129869 No 2021-09-28 2034-07-04 US
Properties
- State
- Liquid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0286 mg/mL ALOGPS logP -0.22 ALOGPS logP -5.3 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 11.48 Chemaxon pKa (Strongest Basic) 11 Chemaxon Physiological Charge 2 Chemaxon Hydrogen Acceptor Count 16 Chemaxon Hydrogen Donor Count 15 Chemaxon Polar Surface Area 449.16 Å2 Chemaxon Rotatable Bond Count 18 Chemaxon Refractivity 290.87 m3·mol-1 Chemaxon Polarizability 113.93 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 306.6116 predictedDeepCCS 1.0 (2019) [M+H]+ 308.2648 predictedDeepCCS 1.0 (2019) [M+Na]+ 314.42163 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP)
- Specific Function
- melanocortin receptor activity
- Gene Name
- MC4R
- Uniprot ID
- P32245
- Uniprot Name
- Melanocortin receptor 4
- Molecular Weight
- 36942.325 Da
References
- Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R, Le Beyec J, Pepin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clement K, Farooqi IS, Van der Ploeg LHT: Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017 Oct;6(10):1321-1329. doi: 10.1016/j.molmet.2017.06.015. Epub 2017 Jul 8. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA: Approval Letter for Imcivree (Setmelanotide) [Link]
- FDA Press Announcements: FDA approves first treatment for weight management for people with certain rare genetic conditions [Link]
Drug created at October 20, 2016 20:40 / Updated at October 13, 2024 04:03