Metreleptin

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Metreleptin
Clinical data
Trade names Myalept, Myalepta
Other namesN-Methionylleptin; r-metHuLeptin, Mettreleptin (genetical recombination) (JAN JP)
AHFS/Drugs.com Monograph
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
Formula C714H1167N19O221S6
Molar mass 13746.46 g·mol−1

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. [9]

Contents

The most common side effects include hypoglycaemia (low blood glucose) and weight loss. [8]

It was approved for medical use in Canada in January 2024. [1]

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. [8]

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. [7]

Research

Metreleptin is 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. [10] The FDA approved Metreleptin injection for treating complications of leptin deficiency in February 2014.[ medical citation needed ]

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). [11] 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. [12] 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 1 April 2019. [13]

Metreleptin is undergoing research for its potential benefit in the treatment of anorexia nervosa. [14] 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. [15] 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. [16] Metreleptin reduces body weight in overweight people with low leptin levels. [17]

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 no regulatory pathway for drug approval for this indication. [18]

Related Research Articles

<span class="mw-page-title-main">Anorexia (symptom)</span> Medical symptom

Anorexia is a medical term for a loss of appetite. While the term outside of the scientific literature is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others indicate a serious clinical condition or pose a significant risk.

An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's physical or mental health. Types of eating disorders include binge eating disorder, where the patient eats a large amount in a short period of time; anorexia nervosa, where the person has an intense fear of gaining weight and restricts food or overexercises to manage this fear; bulimia nervosa, where individuals eat a large quantity (binging) then try to rid themselves of the food (purging); pica, where the patient eats non-food items; rumination syndrome, where the patient regurgitates undigested or minimally digested food; avoidant/restrictive food intake disorder (ARFID), where people have a reduced or selective food intake due to some psychological reasons; and a group of other specified feeding or eating disorders. Anxiety disorders, depression and substance abuse are common among people with eating disorders. These disorders do not include obesity. People often experience comorbidity between an eating disorder and OCD. It is estimated 20–60% of patients with an ED have a history of OCD.

<span class="mw-page-title-main">Leptin</span> Hormone that inhibits hunger

Leptin is a protein hormone predominantly made by adipocytes. Its primary role is likely to regulate long-term energy balance.

Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Appetite has a relationship with every individual's behavior. Appetitive behaviour also known as approach behaviour, and consummatory behaviour, are the only processes that involve energy intake, whereas all other behaviours affect the release of energy. When stressed, appetite levels may increase and result in an increase of food intake. Decreased desire to eat is termed anorexia, while polyphagia is increased eating. Dysregulation of appetite contributes to anorexia nervosa, bulimia nervosa, cachexia, overeating, and binge eating disorder.

Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy, is used when describing the loss of fat from one area. This condition is also characterized by a lack of circulating leptin which may lead to osteosclerosis. The absence of fat tissue is associated with insulin resistance, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome.

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<span class="mw-page-title-main">Donepezil</span> Medication used for dementia

Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to change the progression of the disease. Treatment should be stopped if no benefit is seen. It is taken by mouth or via a transdermal patch.

Polyphagia or hyperphagia is an abnormally strong, incessant sensation of hunger or desire to eat often leading to overeating. In contrast to an increase in appetite following exercise, polyphagia does not subside after eating and often leads to rapid intake of excessive quantities of food. Polyphagia is not a disorder by itself; rather, it is a symptom indicating an underlying medical condition. It is frequently a result of abnormal blood glucose levels, and, along with polydipsia and polyuria, it is one of the "3 Ps" commonly associated with uncontrolled diabetes mellitus.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

<span class="mw-page-title-main">Pramlintide</span> Diabetes medication

Pramlintide is an injectable amylin analogue drug for diabetes, developed by Amylin Pharmaceuticals. Pramlintide is sold as an acetate salt.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin.

<span class="mw-page-title-main">Amylin Pharmaceuticals</span> Biopharmaceutical company

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Barraquer–Simons syndrome is a rare form of lipodystrophy, which usually first affects the head, and then spreads to the thorax. It is named for Luis Barraquer Roviralta (1855–1928), a Spanish physician, and Arthur Simons (1879–1942), a German physician. Some evidence links it to LMNB2.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

Congenital generalized lipodystrophy is an extremely rare autosomal recessive condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of lipodystrophy disorder where the magnitude of fat loss determines the severity of metabolic complications. Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide.

Acquired generalized lipodystrophy (AGL), also known as Lawrence syndrome and Lawrence–Seip syndrome, is a rare skin condition that appears during childhood or adolescence, characterized by fat loss affecting large areas of the body, particularly the face, arms, and legs. There are four types of lipodystrophy based on its onset and areas affected: acquired or inherited, and generalized or partial. Both acquired or inherited lipodystrophy present as loss of adipose tissues, in the absence of nutritional deprivation. The near-total loss of subcutaneous adipose tissue is termed generalized lipodystrophy while the selective loss of adipose tissues is denoted as partial lipodystrophy. Thus, as the name suggests, AGL is a near-total deficiency of adipose tissues in the body that is developed later in life. It is an extremely rare disease with only about 100 cases reported worldwide. There are three main etiologies of AGL suspected: autoimmune, panniculitis-associated, or idiopathic. After its onset, the disease progresses over a few days, weeks, months, or even in years. Clinical presentations of AGL are similar to other lipodystrophies, including metabolic complications and hypoleptinemia. Treatments are also similar and mainly supportive for symptomatic alleviation. Although HIV- or drug-induced lipodystrophy are types of acquired lipodystrophy, their origins are very specific and distinct and hence are usually not discussed with AGL.

<span class="mw-page-title-main">Anorexia nervosa</span> Type of eating disorder

Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin.

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<span class="mw-page-title-main">Marfanoid–progeroid–lipodystrophy syndrome</span> Medical condition

Marfanoid–progeroid–lipodystrophy syndrome (MPL), also known as Marfan lipodystrophy syndrome (MFLS) or progeroid fibrillinopathy, is an extremely rare medical condition which manifests as a variety of symptoms including those usually associated with Marfan syndrome, an appearance resembling that seen in neonatal progeroid syndrome, and severe partial lipodystrophy. It is a genetic condition that is caused by mutations in the FBN1 gene, which encodes profibrillin, and affects the cleavage products of profibrillin, fibrillin-1, a fibrous structural protein, and asprosin, a glucogenic protein hormone. As of 2016, fewer than 10 cases of the condition have been reported. Lizzie Velásquez and Abby Solomon have become known publicly through the media for having the condition.

References

  1. 1 2 "Myalepta Product information". Health Canada . 22 October 2009. Retrieved 3 March 2024.
  2. ↑ "Notice: Multiple additions to the Prescription Drug List (PDL) [2024-02-28]". Health Canada . 28 February 2024. Retrieved 2 March 2024.
  3. ↑ "Details for: Myalepta". Health Canada . 17 January 2024. Retrieved 3 March 2024.
  4. ↑ "Regulatory Decision Summary for Myalepta". Drug and Health Products Portal. 17 January 2024. Retrieved 2 April 2024.
  5. ↑ "Myalepta 3 mg powder for solution for injection - Summary of Product Characteristics (SmPC)". Electronic Medicines Compendium (EMC). Retrieved 6 October 2020.
  6. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  7. 1 2 "Myalept- metreleptin injection, powder, lyophilized, for solution". DailyMed. U.S. National Library of Medicine. 26 May 2020. Retrieved 6 October 2020.
  8. 1 2 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.
  9. ↑ 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.
  10. ↑ "Amylin Seeks FDA Approval for Metreleptin". diabetesincontrol.com. 11 April 2012. Archived from the original on 8 April 2014. Retrieved 26 February 2014.
  11. ↑ "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. 15 April 2011. Retrieved 27 October 2011.[ permanent dead link ]
  12. ↑ Meral R, Malandrino N, Walter M, Neidert AH, Muniyappa R, Oral EA, et al. (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.
  13. ↑ "NHS England » Metreleptin for congenital leptin deficiency (all ages)". www.england.nhs.uk. Retrieved 18 January 2019.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
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