Setmelanotide

Identification

Summary

Setmelanotide is setmelanotide is indicated to treat obesity caused by genetic POMC, PCSK1, or LEPR deficiencies.

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 19 November 20187 and FDA approval on 25 November 2020.5

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
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 deficiency, proprotein subtilisin/kexin type 1 deficiency, or leptin receptor deficiency.6 These conditions affect the MC4R signalling pathway.2

Pharmacology
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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
AMelanocortin receptor 4
agonist
Humans
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
Adverseeffects
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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

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International/Other Brands
Imcivree
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ImcivreeSolution10 mg/1mLSubcutaneousRhythm Pharmaceuticals, Inc2020-12-14Not applicableUS flag
ImcivreeInjection, solution10 mg/mlSubcutaneousRhythm Pharmaceuticals Limited2021-10-07Not applicableEU flag

Categories

Drug Categories
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
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Substituents
3-alkylindole / Acetamide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-oligopeptide / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Carbonyl group
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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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. FDA: Approval Letter for Imcivree (Setmelanotide) [Link]
  6. FDA Press Announcements: FDA approves first treatment for weight management for people with certain rare genetic conditions [Link]
  7. EMA Public Summary of Opinion on Orphan Designation: Setmelanotide [Link]
  8. FDA Approved Drug Products: Imcivree (Setmelanotide) Subcutaneous Injection [Link]
PubChem Compound
11993702
PubChem Substance
347828065
ChemSpider
10166169
RxNav
2469247
ChEMBL
CHEMBL3301624
Wikipedia
Setmelanotide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentHealthy Subjects (HS)1
3CompletedTreatmentAlström Syndrome (AS) / Laurence-Moon-Bardet-Biedl syndrome1
3CompletedTreatmentLeptin Receptor Deficiency Obesity1
3Not Yet RecruitingTreatmentLaurence-Moon-Bardet-Biedl syndrome / LEPR Deficiency Obesity / PCSK1 Deficiency Obesity / POMC Deficiency Obesity1
2CompletedTreatmentBMI >27 kg/m21
2CompletedTreatmentPrader-Willi Syndrome1
2Not Yet RecruitingTreatmentPatients With Specific Gene Defects in the Melanocortin-4 Receptor Pathway1
2RecruitingTreatmentHypothalamic Obesity1
2Unknown StatusTreatmentHomozygous or Compound Heterozygous POMC, LEPR or PCSK1 Gene Mutation1
2, 3Active Not RecruitingTreatmentLeptin Receptor Deficiency Obesity / Obesity Due to Melanocortin 4 Receptor Deficiency (Disorder) / Pro-opiomelanocortin (POMC) Deficiency Obesity (Heterozygous or Epigenetic) / Smith-Magenis Syndrome (SMS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous10 mg/ml
SolutionSubcutaneous10 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9458195No2016-10-042027-10-13US flag
US8039435No2011-10-182027-10-13US flag

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0286 mg/mLALOGPS
logP-0.22ALOGPS
logP-5.3ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)11.48ChemAxon
pKa (Strongest Basic)11ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count16ChemAxon
Hydrogen Donor Count15ChemAxon
Polar Surface Area449.16 Å2ChemAxon
Rotatable Bond Count18ChemAxon
Refractivity290.87 m3·mol-1ChemAxon
Polarizability113.93 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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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
  1. 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]
  2. FDA: Approval Letter for Imcivree (Setmelanotide) [Link]
  3. FDA Press Announcements: FDA approves first treatment for weight management for people with certain rare genetic conditions [Link]

Drug created on October 20, 2016 20:40 / Updated on February 21, 2021 18:53