Metreleptin

Metreleptin, sold under the brand name Myalept among others, is a synthetic analog of the hormone leptin used to treat various forms of dyslipidemia. It has been approved in Japan for metabolic disorders including lipodystrophy and in the United States as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy.[4]

Metreleptin
Clinical data
Trade namesMyalept, Myalepta
Other namesN-Methionylleptin; r-metHuLeptin, Mettreleptin (genetical recombination) (JAN JP)
AHFS/Drugs.comMonograph
License data
Routes of
administration		Subcutaneous injection
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC714H1167N19O221S6
Molar mass13746.46 g·mol−1

The most common side effects include hypoglycaemia (low blood glucose) and weight loss.[3]

Medical uses

In the European Union, metreleptin is indicated in addition to diet to treat lipodystrophy, where people have a loss of fatty tissue under the skin and a build-up of fat elsewhere in the body such as in the liver and muscles. It is used in adults and children above the age of two years with generalised lipodystrophy (Berardinelli-Seip syndrome and Lawrence syndrome); and in adults and children above the age of twelve years with partial lipodystrophy (including Barraquer-Simons syndrome), when standard treatments have failed.[3]

In the United States, it is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in people with congenital or acquired generalized lipodystrophy.[2]

Research

Metreleptin is currently being investigated for the treatment of diabetes and/or hypertriglyceridemia, in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities.[5] The FDA approved Metreleptin injection for treating complications of leptin deficiency in February 2014.

In a three-year study of metreleptin in patients with lipodystrophy organized by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, metreleptin treatment was associated with a significant decrease in blood glucose (A1c decreased from 9.4% at baseline to 7.0% at study end) and triglyceride concentration (from 500 mg/dl at baseline to 200 mg/dl at study end).[6] Metreleptin is effective in most patients with generalized lipodystrophy where circulating leptin levels are extremely low. Analogous to insulin replacement for patients with type 1 Diabetes, metreleptin restores the function of a deficient hormone. However, in patients with partial lipodystrophy where there is only a relative leptin deficiency, the response to metreleptin is not universal.[7] This may or may not be due to anti-leptin antibodies.

NHS England will commission metreleptin treatment for patients (all ages) with congenital leptin deficiency from April 1, 2019.[8]

Metreleptin is currently researched for its potential benefit in the treatment of anorexia nervosa.[9] It is hypothesized that the gradual loss of body fat mass, and more specifically the ensuing low leptin levels, escalate the preexisting drive for thinness into an obsessive-compulsive-like and addictive-like state. It was shown that short-term metreleptin treatment of patients with anorexia nervosa had rapid on-set of beneficial cognitive, emotional, and behavioral effects.[10] Among other things, depression, drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased rapidly. Whether metreleptin (or another leptin analogue) is a suitable treatment for anorexia nervosa remains to be seen. Potential side effects are weight loss and the development of anti-metreleptin antibodies.

In a clinical study, metreleptin treatment improved non-alcoholic steatohepatitis (fatty liver disease) both in patients with partial lipodystrophy and in those with relative leptin deficiency. Both steatosis and hepatic injury scores decreased.[11] Metreleptin reduces body weight in overweight people with low leptin levels.[12]

Although it is not very effective as a weight loss drug, leptin levels are lowered in people who have lost weight and it is hypothesized that supplemental leptin could help them with weight loss maintenance. However, there is currently no regulatory pathway for drug approval for this indication.[13]

References
  1. "Myalepta 3 mg powder for solution for injection - Summary of Product Characteristics (SmPC)". Electronic Medicines Compendium (EMC). Retrieved 6 October 2020.
  2. "Myalept- metreleptin injection, powder, lyophilized, for solution". DailyMed. U.S. National Library of Medicine. 26 May 2020. Retrieved 6 October 2020.
  3. "Myalepta EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 6 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. Chou K, Perry CM (June 2013). "Metreleptin: first global approval". Drugs. 73 (9): 989–997. doi:10.1007/s40265-013-0074-7. PMID 23740412. S2CID 7740045.
  5. "Amylin Seeks FDA Approval for Metreleptin". diabetesincontrol.com. 11 April 2012.
  6. "Amylin to Present Data Showing Investigational Metreleptin Treatment Led to Long-Term Improvements in Diabetes and Lipid Control in Patients with Lipodystrophy". Press Release. Amylin Pharmaceuticals. 2011-04-15. Retrieved 2011-10-27.
  7. Meral R, Malandrino N, Walter M, Neidert AH, Muniyappa R, Oral EA, Brown RJ (March 2022). "Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients With Partial Lipodystrophy". The Journal of Clinical Endocrinology and Metabolism. 107 (4): e1739–e1751. doi:10.1210/clinem/dgab760. PMC 8947785. PMID 34677608.
  8. "NHS England » Metreleptin for congenital leptin deficiency (all ages)". www.england.nhs.uk. Retrieved 2019-01-18.
  9. Hebebrand J, Hildebrandt T, Schlögl H, Seitz J, Denecke S, Vieira D, et al. (October 2022). "The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: Implications for anorexia nervosa". Neuroscience and Biobehavioral Reviews. 141: 104807. doi:10.1016/j.neubiorev.2022.104807. PMID 35931221. S2CID 251259742.
  10. Milos G, Antel J, Kaufmann LK, Barth N, Koller A, Tan S, et al. (August 2020). "Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects". Translational Psychiatry. 10 (1): 303. doi:10.1038/s41398-020-00977-1. PMC 7453199. PMID 32855384.
  11. Akinci B, Subauste A, Ajluni N, Esfandiari NH, Meral R, Neidert AH, et al. (July 2021). "Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings". Med. 2 (7): 814–835. doi:10.1016/j.medj.2021.04.001. PMC 8920072. PMID 35291351.
  12. Depaoli A, Long A, Fine GM, Stewart M, O'Rahilly ST (1 July 2018). "Efficacy of Metreleptin for Weight Loss in Overweight and Obese Adults with Low Leptin Levels". Diabetes. 67 (Supplement_1). doi:10.2337/db18-296-LB. S2CID 90583209.
  13. Christoffersen BØ, Sanchez-Delgado G, John LM, Ryan DH, Raun K, Ravussin E (April 2022). "Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss". Obesity. 30 (4): 841–857. doi:10.1002/oby.23374. PMC 9310705. PMID 35333444.
  • "Metreleptin". Drug Information Portal. U.S. National Library of Medicine.
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