Metreleptin

Identification

Summary

Metreleptin is a leptin analogue used as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

Brand Names
Myalept
Generic Name
Metreleptin
DrugBank Accession Number
DB09046
Background

Metreleptin, a recombinant analog of the human hormone leptin, is an orphan drug used to treat complications of leptin deficiency in people with congenital or acquired lipodystrophy. Affecting less than 500 people worldwide, lipodystrophy is characterized by a lack of adipose tissue, fat deposition in the muscles and liver, and metabolic complications such as hypertriglyceridemia, insulin resistance, diabetes mellitus, and fatty liver disease. These metabolic abnormalities are often aggravated by excessive food intake, which is further aggravated by leptin deficiency, a protein secreted by adipose tissue. Administration of Metreleptin results in improvement of metabolic symptoms including improvements in insulin resistance, reduced HbA1c and fasting glucose, reduced triglycerides, and reductions in food intake. Metreleptin is produced in E. coli and differs from native human leptin by the addition of a methionine residue at its amino terminus. It is administered as a once daily subcutaneous injection. On Feb. 24, 2014, Metreleptin was approved by the FDA for the treatment of complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. Metreleptin is marketed under the brand Myalept® by Aegerion Pharmaceuticals, Inc.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Hormones
Protein Structure
Db09046
Protein Chemical Formula
C714H1167N191O221S6
Protein Average Weight
16155.4429 Da
Sequences
>Peptide Sequence 
MVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLA
VYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGY
STEVVALSRLQGSLQDMLWQLDLSPGC
Download FASTA Format
Synonyms
  • Metreleptin
  • Metreleptina
  • Métréleptine
  • Metreleptinum
  • N-Methionylleptin
  • r-metHuLeptin
External IDs
  • Leptin A-100
  • Mettreleptin

Pharmacology

Indication

Metreleptin is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

In patients with leptin deficiency, clinical trials demonstrated that exogenous leptin administration results in weight loss, reduction in mean HbA1c and fasting glucose levels, reduced blood insulin, and reduced triglyceride levels leading to improved insulin sensitivity and reductions in food intake.

Mechanism of action

Metreleptin functions by binding to and activating the human leptin receptor (ObR), which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.

TargetActionsOrganism
ALeptin receptor
agonist
Humans
Absorption

Peak serum leptin concentration (Cmax) occurred approximately 4.0 to 4.3 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthy subjects.

Volume of distribution

Following intravenous administration of metreleptin, leptin volume of distribution was approximately 4 to 5 times plasma volume; volumes (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and 3.0 mg/kg/day doses, respectively.

Protein binding

Not Available

Metabolism

No formal metabolism studies have been conducted with metreleptin. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation.

Route of elimination

Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation.

Half-life

3.8 to 4.7 hours

Clearance

The clearance of metreleptin is expected to be delayed in the presence of leptin antibodies.

Adverse Effects
Adverseeffects
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Toxicity

The most common adverse events reported for metreleptin use have been headache, hypoglycemia, weight loss, and abdominal pain. A boxed warning states that anti-metreleptin antibodies, serious infections, and worsening metabolic control have been reported in patients taking the drug, and that some patients with acquired generalized lipodystrophy taking metreleptin have developed T-cell lymphoma. Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with metreleptin which can lead to inhibition of endogenous leptin action and loss of drug efficacy. As part of a Risk Evaluation and Mitigation Strategy (REMS), the FDA has required healthcare providers to be trained in the use of metreleptin before prescribing it and to attest that patients for whom they prescribe metreleptin have a labeled indication for the drug. Metreleptin is classified as category C (no adequate studies in women) for use during pregnancy.

Two-year carcinogenicity studies in rodents have not been conducted with metreleptin. No proliferative or preneoplastic lesions were observed in mice or dogs following treatment up to six months. However, leptin is reported in the literature to promote cell proliferation in vitro and tumor progression in some mouse models of cancer. Metreleptin was not mutagenic in the Ames bacterial mutagenicity assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells and human peripheral blood lymphocytes. Metreleptin was not mutagenic or clastogenic in an in vivo mouse micronucleus assay. In a fertility study in mice, metreleptin had no adverse effects on mating, fertility, or early embryonic development at doses ranging between 7 and 15 times the maximum recommended clinical dose based on body surface area of a 20- and 60-kg patient, respectively.

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.
DrugInteraction
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be increased when combined with Metreleptin.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Metreleptin.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Metreleptin.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Metreleptin.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Metreleptin.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Metreleptin.
AcetohexamideMetreleptin may increase the hypoglycemic activities of Acetohexamide.
AlbendazoleThe metabolism of Albendazole can be increased when combined with Metreleptin.
AlectinibThe metabolism of Alectinib can be increased when combined with Metreleptin.
AlfentanilThe metabolism of Alfentanil can be increased when combined with Metreleptin.
Interactions
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Food Interactions
  • Take with or without food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MyaleptInjection, powder, lyophilized, for solution11.3 mg/2.2mLSubcutaneousAmryt Pharmaceuticals DAC2015-03-05Not applicableUS flag
MyaleptInjection, powder, lyophilized, for solution11.3 mg/2.2mLSubcutaneousAmylin Pharmaceuticals, Llc.2014-05-222018-03-31US flag
MyaleptInjection, powder, lyophilized, for solution11.3 mg/2.2mLSubcutaneousCatalent Pharma Solution, LLC2015-03-052018-03-23US flag
MyaleptaInjection, powder, for solution5.8 mgSubcutaneousAmryt Pharmaceuticals DAC2020-12-15Not applicableEU flag
MyaleptaInjection, powder, for solution3 mgSubcutaneousAmryt Pharmaceuticals DAC2020-12-15Not applicableEU flag
MyaleptaInjection, powder, for solution5.8 mgSubcutaneousAmryt Pharmaceuticals DAC2020-12-15Not applicableEU flag
MyaleptaInjection, powder, for solution11.3 mgSubcutaneousAmryt Pharmaceuticals DAC2020-12-15Not applicableEU flag
MyaleptaInjection, powder, for solution3 mgSubcutaneousAmryt Pharmaceuticals DAC2020-12-15Not applicableEU flag
MyaleptaInjection, powder, for solution11.3 mgSubcutaneousAmryt Pharmaceuticals DAC2020-12-15Not applicableEU flag

Categories

ATC Codes
A16AA07 — Metreleptin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
TL60C27RLH
CAS number
186018-45-1

References

General References
  1. Paz-Filho G, Mastronardi CA, Licinio J: Leptin treatment: facts and expectations. Metabolism. 2015 Jan;64(1):146-56. doi: 10.1016/j.metabol.2014.07.014. Epub 2014 Aug 3. [Article]
  2. Tsoukas MA, Farr OM, Mantzoros CS: Leptin in congenital and HIV-associated lipodystrophy. Metabolism. 2015 Jan;64(1):47-59. doi: 10.1016/j.metabol.2014.07.017. Epub 2014 Aug 12. [Article]
  3. Farr OM, Fiorenza C, Papageorgiou P, Brinkoetter M, Ziemke F, Koo BB, Rojas R, Mantzoros CS: Leptin therapy alters appetite and neural responses to food stimuli in brain areas of leptin-sensitive subjects without altering brain structure. J Clin Endocrinol Metab. 2014 Dec;99(12):E2529-38. doi: 10.1210/jc.2014-2774. [Article]
  4. Rodriguez AJ, Neeman T, Giles AG, Mastronardi CA, Paz Filho G: Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints. Arq Bras Endocrinol Metabol. 2014 Nov;58(8):783-97. Epub 2014 Nov 1. [Article]
  5. Moon HS, Huh JY, Dincer F, Schneider BE, Hasselgren PO, Mantzoros CS: Identification and saturable nature of signaling pathways induced by metreleptin in humans: comparative evaluation of in vivo, ex vivo, and in vitro administration. Diabetes. 2015 Mar;64(3):828-39. doi: 10.2337/db14-0625. Epub 2014 Sep 23. [Article]
UniProt
P41159
KEGG Drug
D05014
PubChem Substance
347910398
RxNav
1491625
ChEMBL
CHEMBL2107857
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Metreleptin
FDA label
Download (1.81 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentGeneralized Lipodystrophy1
3Active Not RecruitingTreatmentDiabetes / Hyperlipidemias / Lipodystrophies1
2Active Not RecruitingTreatmentDiabetes / Hyperlipidemias / Lipodystrophies1
2CompletedTreatment(NAFLD) / Lipodystrophy, Familial Partial / Non Alcoholic Steatohepatitis (NASH)1
2CompletedTreatmentAmenorrhea1
2CompletedTreatmentBMI >27 kg/m2 / Obesity (Disorder)2
2CompletedTreatmentDiabetes / Obesity (Disorder) / Syndrome, Metabolic2
2CompletedTreatmentFatty Liver, Non-alcoholic Fatty Liver Disease, NAFLD1
2CompletedTreatmentFatty Liver, Non-alcoholic Fatty Liver Disease, NAFLD / Lipodystrophies / Non Alcoholic Steatohepatitis (NASH)1
2CompletedTreatmentHAART-induced Lipodystrophy and Metabolic Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionSubcutaneous11.3 mg/2.2mL
Injection, powder, for solutionParenteral; Subcutaneous11.3 MG
Injection, powder, for solutionParenteral; Subcutaneous3 MG
Injection, powder, for solutionParenteral; Subcutaneous5.8 MG
Injection, powder, for solutionSubcutaneous11.3 mg
Injection, powder, for solutionSubcutaneous3 mg
Injection, powder, for solutionSubcutaneous5.8 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US20070099836No2006-11-292026-11-29US flag
US8318666No2012-11-272031-05-09US flag
US20130190225No2012-11-052032-11-05US flag
US8470772No2013-06-252029-02-27US flag

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Transmembrane signaling receptor activity
Specific Function
Receptor for obesity factor (leptin). On ligand binding, mediates signaling through JAK2/STAT3. Involved in the regulation of fat metabolism and, in a hematopoietic pathway, required for normal lym...
Gene Name
LEPR
Uniprot ID
P48357
Uniprot Name
Leptin receptor
Molecular Weight
132492.66 Da
References
  1. Moon HS, Huh JY, Dincer F, Schneider BE, Hasselgren PO, Mantzoros CS: Identification and saturable nature of signaling pathways induced by metreleptin in humans: comparative evaluation of in vivo, ex vivo, and in vitro administration. Diabetes. 2015 Mar;64(3):828-39. doi: 10.2337/db14-0625. Epub 2014 Sep 23. [Article]

Drug created on April 29, 2015 20:39 / Updated on April 30, 2021 13:07