Identification

Name
Metreleptin
Accession Number
DB09046
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Hormones
Description

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.

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 / UNII-TL60C27RLH
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MyaleptInjection, powder, lyophilized, for solution11.3 mg/2.2mLSubcutaneousAegerion Pharmaceuticals2015-03-05Not applicableUs
MyaleptInjection, powder, lyophilized, for solution11.3 mg/2.2mLSubcutaneousAmylin Pharmaceuticals, Llc.2014-05-222018-03-31Us
MyaleptInjection, powder, lyophilized, for solution11.3 mg/2.2mLSubcutaneousCatalent Pharma Solution, LLC2015-03-052018-03-23Us
Categories
UNII
TL60C27RLH
CAS number
186018-45-1

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.

Associated Conditions
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
Human
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.

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Metreleptin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Metreleptin.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Metreleptin.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Metreleptin.
5-androstenedioneThe metabolism of 5-androstenedione can be increased when combined with Metreleptin.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be increased when combined with Metreleptin.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin 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.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Metreleptin.
Food Interactions
Not Available

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. [PubMed:25156686]
  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. [PubMed:25267014]
  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. [PubMed:25279500]
  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. [PubMed:25465598]
  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. [PubMed:25249580]
External Links
UniProt
P41159
KEGG Drug
D05014
PubChem Substance
347910398
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
1CompletedDiagnosticEnergy Deficiency Due to Short-term Fasting1
1TerminatedTreatmentDiabetes, Diabetes Mellitus Type 11
1, 2CompletedTreatmentBMI >27 kg/m21
1, 2Unknown StatusTreatmentFasting1
2Active Not RecruitingTreatmentLipodystrophy, Familial Partial1
2Active Not RecruitingTreatmentLipodystrophy, Familial Partial / NAFLD / Nonalcoholic Steatohepatitis1
2CompletedTreatmentBMI >27 kg/m2 / BMI >30 kg/m22
2CompletedTreatmentBMI >30 kg/m22
2CompletedTreatmentFatty Liver Disease, Nonalcoholic1
2CompletedTreatmentFatty Liver Disease, Nonalcoholic / Lipodystrophies / Nonalcoholic Steatohepatitis1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Lipodystrophies1
2CompletedTreatmentLipodystrophies1
2CompletedTreatmentSyndromes1
2RecruitingTreatmentInsulin Resistance1
2RecruitingTreatmentLipodystrophies1
2TerminatedTreatmentBMI >30 kg/m21
2Unknown StatusTreatmentAmenorrhea1
2Unknown StatusTreatmentBMI >30 kg/m2 / Diabetes Mellitus (DM) / Metabolic Syndromes2
2Unknown StatusTreatmentHAART-induced Lipodystrophy and Metabolic Syndrome1
2, 3CompletedTreatmentHypoleptinemia / Insulin Resistance / Lipodystrophy, Congenital Generalized / Partial Lipodystrophy1
3Enrolling by InvitationTreatmentDiabetes Mellitus (DM) / Hyperlipidemias / Lipodystrophies2
Not AvailableActive Not RecruitingTreatmentBMI >30 kg/m2 / Obese experiencing rapid weight loss1
Not AvailableCompletedTreatmentHIV Lipodystrophy1
Not AvailableCompletedTreatmentLipodystrophies1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionSubcutaneous11.3 mg/2.2mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US20070099836No2006-11-292026-11-29Us
US8318666No2012-11-272031-05-09Us
US20130190225No2012-11-052032-11-05Us
US8470772No2013-06-252029-02-27Us

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
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. [PubMed:25249580]

Drug created on April 29, 2015 14:39 / Updated on November 02, 2018 06:57