| Primary information |
|---|
| ThPP ID | Th1208 |
| Therapeutic Peptide/Protein Name | Metreleptin |
| Sequence | MVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPIL view full sequnce in fasta |
| Functional Classification | Ib |
| Molecular Weight | 16155.4429 |
| Chemical Formula | C714H1167N191O221S6 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting Point (℃) | NA |
| Half Life | 3.8 to 4.7 hours |
| 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. |
| Indication/Disease | It 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Clearance | The clearance of metreleptin is expected to be delayed in the presence of leptin antibodies. |
| Categories | |
| Patents Number | US20070099836 |
| Date of Issue | 39050 |
| Date of Expiry | 46355 |
| Drug Interaction | Chlorotrianisene, Chlorpropamide, Cyclosporine, Dienogest, Etonogestrel, Gliclazide, Glimepiride, Glipizide, Glyburide, Insulin Aspart, Insulin Degludec, Insulin Detemir, Insulin Glargine, Insulin Glulisine, Insulin Human, Insulin Lispro, Levonorgestrel, Medroxyprogesterone acetate, Norethisterone, Theophylline, Tolazamide, Tolbutamide, Warfarin |
| Target | Leptin receptor |
| Information of corresponding available drug in the market |
|---|
| Brand Name | Myalept |
| Company | Amylin Pharmaceuticals, LLC |
| Brand Discription | MYALEPT (metreleptin) for injection is a recombinant human leptin analog for injection that binds to and activates the leptin receptor. Metreleptin (recombinant methionyl-human leptin) is produced in E. coli and differs from native human leptin by the addition of a methionine residue at its amino terminus. Metreleptin is a 147-amino acid |
| Prescribed for | MYALEPT (metreleptin) for injection 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. |
| Chemical Name | NA |
| Formulation | NA |
| Physcial Appearnce | Lyophilized powder for solution |
| Route of Administration | subcutaneous |
| Recommended Dosage | The starting daily dose (injection volume) should be 0.06 mg/kg for a baseline weight of less than 40kg. For a weight greater than 40 kg, the starting dose should be 2.5 mg (0.5 mL) for males and 5 mg (1 mL) for females. |
| Contraindication | MYALEPT is contraindicated in patients with general obesity not associated with congenital leptin deficiency. MYALEPT has not been shown to be effective in treating general obesity, and the development of anti-metreleptin antibodies with neutralizing activity has been reported in obese patients treated with MYALEPT; Also, is contraindicated in patients with prior severe hypersensitivity reactions to metreleptin or to any of the product components. Known hypersensitivity reactions have included urticaria and generalized rash. |
| Side Effects | As observed from an open-lable single-arm study the most frequesnt reactions were headache, hypoglycaemia, decreased weight, abdominal pain, athralgia, dizziness, ear infection, fatigue, nausea, ovarian cyst, upper respiratory tract infection, anaemia, diarrhea, back pain, paresthesia, proteinuria, pyrexia. |
| Useful Link | http://www.rxlist.com/myalept-drug/side-effects-interactions.htm |
| PubMed ID | 25270293, 25270293, 20664824, 18985183, 17520107, 15605126, 12616707, 25270293, 25148234 |
| 3-D Structure | Th1208 (View) or (Download) |