Setmelanotide, sold under the brand name Imcivree, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used for the treatment of genetic obesity caused by a rare single-gene mutation. The most common side effects include injection site reactions, skin hyperpigmentation (skin patches that are darker than surrounding skin), headache and gastrointestinal side effects (such as nausea, diarrhea, and abdominal pain), among others. Spontaneous penile erections in males and adverse sexual reactions in females have occurred with treatment. Depression and suicidal ideation have also occurred with setmelanotide. Setmelanotide was approved for medical use in the United States in November 2020, and in the European Union in July 2021. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) considers it to be a

first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...

Medical uses

Setmelanotide is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for chronic weight management (weight loss and weight maintenance for at least one year) in people six years and older with obesity due to three rare genetic conditions:

pro-opiomelanocortin Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is Protein biosynthesis, synthesized in Corticotropic cell, corticotrophs of the anterior pituitary from the 267-amino-acid-long Precursor polypeptide, pol ...

(POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and

leptin receptor Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the ''LEPR'' gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD2 ...

(LEPR) deficiency confirmed by

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic (causing disease), likely pathogenic, or of uncertain significance. Setmelanotide is the first FDA-approved treatment for these genetic conditions. Setmelanotide is not approved for obesity due to suspected POMC, PCSK1, or LEPR deficiency with variants classified as benign (not causing disease) or likely benign or other types of obesity, including obesity associated with other genetic syndromes and general (polygenic) obesity.

Pharmacology

Setmelanotide binds to and activates MC₄ receptors in the

paraventricular nucleus The paraventricular nucleus (PVN) is a nucleus in the hypothalamus, located next to the third ventricle. Many of its neurons project to the posterior pituitary where they secrete oxytocin, and a smaller amount of vasopressin. Other secretions ...

(PVN) of the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

and in the lateral hypothalamic area (LHA), areas involved in the regulation of

appetite 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 reg ...

, and this action is thought to underlie its

appetite suppressant An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...

effects. In addition to reducing appetite, setmelanotide increases resting energy expenditure in both obese animals and humans. Importantly, unlike certain other MC₄ receptor agonists, such as LY-2112688, setmelanotide has not been found to produce increases in

heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

. Setmelanotide has been reported to possess the following activity profile ( cAMP, EC₅₀): MC₄ (0.27 nM) > MC₃ (5.3 nM) ≈ MC₁ (5.8 nM) > MC₅ (1600 nM) ≟ MC₂ (>1000 nM). (19.6-fold selectivity for MC₄ over MC₃, the second target of highest activity.)

History

Setmelanotide was invented at Ipsen. It was initially known as BIM-22493 and then as RM-493 and IRC-022493. It was evaluated in two one-year clinical studies. The first study enrolled 10 participants with obesity and confirmed or suspected POMC or PCSK1 deficiency while the second study enrolled 11 participants with obesity and confirmed or suspected LEPR deficiency; all participants were six years or older. Most participants had lost more than 10% of their initial body weight after a year of treatment. Some participants also reported feeling less hungry. The U.S.

(FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review. The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc.

Society and culture

Economics

In 2021, the cost was $330 for 1 mg.

Legal status

Setmelanotide was approved for medical use in the United States in November 2020. Setmelanotide was approved for medical use in the European Union in July 2021.

Research

Setmelanotide is a peptide

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

and investigational

anti-obesity medication 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 con ...

which acts as a selective

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the MC₄ receptor; the structure of the bound complex has recently been determined. Its peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It was first discovered at Ipsen and is being developed by Rhythm Pharmaceuticals for the treatment of

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

and

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

. In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of

Prader–Willi syndrome Prader–Willi syndrome (PWS) is a rare genetic disorder caused by a loss of function of specific genes on chromosome 15. In newborns, symptoms include hypotonia, weak muscles, poor feeding, and slow development. Beginning in childhood, those ...

(PWS), a

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

which includes MC₄ receptor deficiency and associated symptoms such as excessive appetite and obesity. As of December 2014, the drug is in phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for obesity and PWS. So far, preliminary data has shown no benefit of Setmelanotide in Prader-Willi syndrome. The drug has some efficacy in obese people who lack the genetic variants that the drug is approved for, but its safety and efficacy in this wider population is not well understood.

References

External links

* * {{Portal bar , Medicine Anorectics Anti-obesity drugs Melanocortin receptor agonists Orphan drugs Peptides