, Volume 73, Issue 9, pp 989–997

Metreleptin: First Global Approval

R&D Insight Report


Metreleptin is an analogue of the human hormone leptin being developed by Amylin Pharmaceuticals (a subsidiary of Bristol-Myers Squibb) for the subcutaneous treatment of metabolic disorders including lipodystrophy. The compound is expected to improve insulin sensitivity, hypertriglyceridaemia and hyperglycaemia in patients with lipodystrophy who are unresponsive to conventional treatment. Metreleptin has been approved in Japan as a leptin therapy for the treatment of lipodystrophy. Amylin has also completed a submission for regulatory approval to the US FDA for metreleptin in the treatment of diabetes mellitus and/or hypertriglyceridaemia in patients with rare forms of lipodystrophy. Clinical development of the drug is also underway in the USA for the treatment of type 1 diabetes. Amgen was previously assessing the use of metreleptin as a treatment for amenorrhoea; however, it appears that development in this indication has been discontinued. This article summarizes the milestones in the development of metreleptin leading to this first approval for lipodystrophy.


  1. 1.
    Oral EA, Chan JL. Rationale for leptin-replacement therapy for severe lipodystrophy. Endocr Pract. 2010;16(2):324–33.PubMedCrossRefGoogle Scholar
  2. 2.
    Chan JL, Lutz K, Cochran E, et al. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract. 2011;17(6):922–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Chan JL, Oral EA. Clinical classification and treatment of congenital and acquired lipodystrophy. Endocr Pract. 2010;16(2):310–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol. 2011;7(3):137–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Garg A. Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96(11):3313–25.PubMedCrossRefGoogle Scholar
  6. 6.
    Cottrell EC, Mercer JG. Leptin receptors. In: Joost HG, editor. Appetite Control. New York: Springer; 2012. p. 3–21.CrossRefGoogle Scholar
  7. 7.
    Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Shionogi Co Ltd. Shionogi Filed a New Drug Application for Recombinant Human Leptin for Lipodystrophy [media release]. 01 Aug 2012. http://www.shionogi.co.jp/ir_en/news/detail/e_120801.pdf. Accessed 22 May 2013.
  9. 9.
    Shionogi Co Ltd. Shionogi Receives Marketing and Manufacturing Approval of a Drug for Lipodystrophy, “METRELEPTIN for Subcutaneous Injection 11.25 mg SHIONOGI” [media release]. 25 Mar 2013. http://www.shionogi.co.jp/ir_en/news/detail/e_130325.pdf. Accessed 22 May 2013.
  10. 10.
    Simha V, Subramanyam L, Szczepaniak L, et al. Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab. 2012;97(3):785–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Javor ED, Cochran EK, Musso C, et al. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes. 2005;54(Suppl. 1):12.Google Scholar
  12. 12.
    Ebihara K, Kusakabe T, Hirata M, et al. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab. 2007;92:532–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Beltrand J, Beregszaszi M, Chevenne D, et al. Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy. Pediatrics. 2007;120:e291–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Amylin Pharmaceuticals Inc. Amylin completes biologics license application for metreleptin to treat diabetes and/or hypertriglyceridemia in patients with rare forms of lipodystrophy [media release]. 03 Apr 2012. http://www.amylin.com. Accessed 22 May 2013.
  15. 15.
    Amylin Pharmaceuticals Inc. amylin outlines corporate strategy to maximize global value of diabetes franchise and advance key pipeline candidates [media release]. 09 Jun 2012. http://www.amylin.com. Accessed 22 May 2013.
  16. 16.
    Amylin Pharmaceuticals Inc. Amylin submits clinical and nonclinical sections of rolling biologics license application for metreleptin to treat rare forms of lipodystrophy [media release]. 20 Dec 2010. http://www.amylin.com. Accessed 22 May 2013.
  17. 17.
    European Medicines Agency. Public summary of opinion on orphan designation. Metreleptin for the treatment of Lawrence syndrome. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2012/08/WC500131631.pdf. Accessed 2013.
  18. 18.
    Bristol-Myers Squibb C. Bristol-Myers Squibb Completes Acquisition of Amylin Pharmaceuticals, Inc [media release]. 09 Aug 2012. http://www.bms.com. Accessed 22 May 2013.
  19. 19.
    Mantzoros CS. W(h)ither metreleptin for lipodystrophy and the metabolic syndrome? Endocr Pract. 2010;16(2):162–6.PubMedCrossRefGoogle Scholar
  20. 20.
    McDuffie J, Riggs P, Calis K, et al. Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. J Clin Endocrin Metab. 2004;89(9):4258–63.CrossRefGoogle Scholar
  21. 21.
    Vatier C, Fetita S, Boudou P, et al. Metreleptin therapy in leptin-deficient patients with lipodystrophic syndromes: effects on insulin secretion. Diabetologia. 2012;55:S79–80.Google Scholar
  22. 22.
    Brinkoetter M, Magkos F, Vamvini M, et al. Leptin treatment reduces body fat but does not affect lean body mass or the myostatin-follistatin-activin axis in lean hypoleptinemic women. Am J Physiol Endocrinol Metab. 2011;301(1):E99–104.PubMedCrossRefGoogle Scholar
  23. 23.
    Sienkiewicz E, Magkos F, Aronis KN, et al. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism. 2011;60(9):1211–21.PubMedCrossRefGoogle Scholar
  24. 24.
    Matarese G, La Rocca C, Moon H-S, et al. Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia. Proc Natl Acad Sci USA. 2013;110(9):E818–27.PubMedCrossRefGoogle Scholar
  25. 25.
    Sekhar RV, Jahoor F, Iyer D, et al. Leptin replacement therapy does not improve the abnormal lipid kinetics of hypoleptinemic patients with HIV-associated lipodystrophy syndrome. Metabolism. 2012;61(10):1395–403.PubMedCrossRefGoogle Scholar
  26. 26.
    Chan JL, Wong SL, Mantzoros CS. Pharmacokinetics of subcutaneous recombinant methionyl human leptin administration in healthy subjects in the fed and fasting states: regulation by gender and adiposity. Clin Pharmacokinet. 2008;47:753–64.PubMedCrossRefGoogle Scholar
  27. 27.
    Chan JL, Wong SL, Orlova C. Pharmacokinetics of recombinant methionyl human leptin after subcutaneous administration: variation of concentration-dependent parameters according to assay. J Clin Endocrinol Metab. 2007;92:2307–11.PubMedCrossRefGoogle Scholar
  28. 28.
    Fujioka K, Patane J, Lubina J. CSF leptin levels after exogenous administration of recombinant methionyl human leptin. JAMA. 1999;282:1517–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Ahren B, Baldwin RM, Havel PJ. Pharmacokinetics of human leptin in mice and rhesus monkeys. Int J Obes Relat Metab Disord. 2000;24(12):1579–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Mallard SP, Selby LL, Khoo HM. Pharmacokinetics of recombinant methionyl human leptin in male CD-1 mice. Pharm Res. 1997;14(Suppl.):78–9.Google Scholar
  31. 31.
    Wong SL, Bunkin DA, Young J. Placental transfer of r-metHuLEPTIN following subcutaneous injection (abstract no. PII-37). Clin Pharmacol Ther. 2000;67:124.Google Scholar
  32. 32.
    Oral EA, Neidert A, Hakim B, et al. Metabolic effects of metreleptin treatment in familial partial lipodystrophy (FPL). Endocrine Reviews Conference: 94th Annual Meeting and Expo of the Endocrine Society, ENDO. 2012;33(3):MON-246.Google Scholar
  33. 33.
    Chong AY, Lupsa BC, Cochran EK, et al. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010;53:27–35.PubMedCrossRefGoogle Scholar
  34. 34.
    Jazet I, Jonker J, Wijngaarden M, et al. Therapy resistant diabetes mellitus and lipodystrophy: leptin therapy leads to improvement. Ned Tijdschr Geneeskd. 2013;154(4):A5482.Google Scholar
  35. 35.
    Park JY, Javor ED, Cochran EK. Long-term efficacy of leptin replacement in patients with Dunnigan-type familial partial lipodystrophy. Metabolism. 2007;56:508–16.PubMedCrossRefGoogle Scholar
  36. 36.
    Lee JH, Chan JL, Sourlas E. Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. J Clin Endocrinol Metab. 2006;91:2605–11.PubMedCrossRefGoogle Scholar
  37. 37.
    Magkos F, Brennan A, Sweeney L, et al. Leptin replacement improves postprandial glycemia and insulin sensitivity in human immunodeficiency virus-infected lipoatrophic men treated with pioglitazone: a pilot study. Metabolism. 2011;60(7):1045–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Brown R, Cochran EK, Miller S, et al. Clinical effects of metreleptin treatment in pediatric patients with lipodystrophy [abstract no. 3490.3]. Pediatric Endocrine Society (PES) Annual Meeting; May 4–7; 2013; Washington, DC.Google Scholar
  39. 39.
    O’Neil PM, Rogers RL, Malcolm R et al. Assessment of behavioral and mood changes among obese persons receiving exogenous leptin. Obesity Res (Journal of Obesity). 1999;7 Suppl. 1:92.Google Scholar
  40. 40.
    Greenberg AS, Fulioka K, Heymsfield S, et al. Clinical effects of leptin in obesity. Abstract no. S54-3 81st Annual Meeting Endocrine Society Jun 12 1999.Google Scholar
  41. 41.
    Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282(16):1568–75.PubMedCrossRefGoogle Scholar
  42. 42.
    Shetty GK, Matarese G, Magkos F, et al. Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet. Eur J Endocrinol. 2011;165(2):249–54.PubMedCrossRefGoogle Scholar
  43. 43.
    Ravussin E, Smith SR, Mitchell JA, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity. 2009;17(9):1736–43.PubMedCrossRefGoogle Scholar
  44. 44.
    Smith SR, Blundell J, Ravussin E, et al. Enhanced weight loss following pramlintide/metreleptin combination treatment in overweight and obese subjects is accompanied by improved control of eating [abstract 64-OR]. Obesity. 2008;16(Suppl. 1):64–5.Google Scholar
  45. 45.
    Weyer C, Koda J, Smith S, et al. Enhanced weight loss following pramlintide/metreleptin combination treatment in obese subjects: clinical evidence for restoration of leptin responsiveness by amylin agonism. Diabetes. 2008;57(Suppl. 1):482 ((plus poster) abstr. 1738-P).Google Scholar
  46. 46.
    Hollander P, Lewis GF, Schwartz S. A randomized, double-blinded, placebo-controlled study to determine the effects of subcutaneous (SC) recombinant methionyl human leptin (A-100) on glycemic control in obese subjects with diet-treated type 2 diabetes mellitus (DM). Diabetes. 2000;49(Suppl. 1):359.Google Scholar
  47. 47.
    Moon H-S, Matarese G, Brennan AM, et al. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes. 2011;60(6):1647–56.PubMedCrossRefGoogle Scholar
  48. 48.
    Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci USA. 2011;108(16):6585–90.PubMedCrossRefGoogle Scholar
  49. 49.
  50. 50.
    Brown RJ, Lutz K, Cochran E, et al. Metreleptin treatment for metabolic abnormalities associated with lipodystrophy: achieving A1C and triglyceride targets [abstract OR17-1]. ENDO; 2013 Jun 15–18, San Francisco.Google Scholar
  51. 51.
    US National Institutes of Health. Effects of metreleptin in type I diabetes mellitus. 2013. http://clinicaltrials.gov/show/NCT01268644. Accessed 22 May 2013.

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Adis R & D InsightAucklandNew Zealand
  2. 2.AdisAucklandNew Zealand

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