Setmelanotide

Introduction

Setmelanotide is a drug intended to treat hereditary obesity caused by an uncommon single-gene mutation. It is marketed under the Imcivree brand.

Injection site reactions, skin hyperpigmentation (skin patches, skin darkening), headaches, and gastrointestinal side effects (abdominal pain, nausea, and diarrhea) are among the most frequent adverse effects. Additionally, setmelanotide has been linked to depression and suicidal thoughts.

In November 2020, setmelanotide received approval for medical usage in the US; in July 2021, it received approval in the EU. It is regarded as a first-in-class drug by the U.S. Food and Drug Administration (FDA).

What is setmelanotide?

Setmelanotide is used to help persons 6 years of age and older with specific genetic deficits lose weight and control their hunger.

To ensure that setmelanotide is the best course of action for you, your doctor will conduct testing.

There are additional uses for setmelanotide that are not covered in this pharmaceutical guide.

For patients with deficits in leptin, proprotein subilisin/kexin type 1, or pro-opiomelanocortin, setmelanotide is the first medication that can be used. It is a melanocortin 4 receptor agonist. Previous attempts to agonize MC4R (LY2112688) increased heart rate and blood pressure, as well as successful weight reduction. Gastric bypass surgery was one of the other older treatments for these people. The average weekly weight loss for patients on setmelanotide was 0.6 kg.

Mechanism of action

Agouti-related protein is released when orexigenic neurons are stimulated by grehlin and other hunger signals from the gastrointestinal system. Melanocortin 4 receptor (MC4R) activation is inhibited by agouti-related protein until anorexigenic neurons are stimulated by satiety signals like insulin or leptin. The POMC-derived melanocortin peptide α-melanocyte simulating hormone, a ligand of MC4R, is produced in response to insulin and leptin.

Prohormone convertase 1/3 (PC1/3), encoded by the gene proprotein subtilisin/kexin type 1.4, is found in orexigenic and anorexigenic neurons. PC1/3 performs activation cleavage of several peptide hormone precursors, including the α-melanocyte mimicking hormone.

An agonist of MC4R, setmelanotide, is a peptide produced from pro-opiomelanocortin. With an EC50 of 0.27 nM, it is about 20 times more effective than endogenous α-melanocyte-stimulating hormone as an MC4R agonist. A decrease in food intake and weight loss are the results of directly agonizing MC4R, which prevents upstream genetic defects in the MC4R signaling pathway from inhibiting satiety.

MC4R is a G-protein coupled receptor (G-PCR) with 332 amino acids. It is thought that previous MC4R antagonists triggered various G-protein signaling pathways despite the lack of cardiovascular side effects associated with setmelanotide administration. Previous medications that targeted G-PCRs either bound to less conserved allosteric sites with high selectivity or the highly conserved orthosteric binding site with great affinity. High affinity and specificity are made possible by the unusual bitopic ligand setmelanotide, which interacts with both the orthosteric and putative allosteric binding sites.

Medical applications

People six years of age and older who are obese due to three rare genetic conditions—pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency—can use setmelanotide for chronic weight management (weight loss and weight maintenance for at least a year). These conditions are confirmed by genetic testing that shows variants in the genes for POMC, PCSK1, or LEPR that are either pathogenic (causing disease), likely pathogenic, or of uncertain significance. The first FDA-approved medication for these genetic disorders is setmelanotide.

For obesity resulting from suspected POMC, PCSK1, or LEPR deficiency with variations categorized as benign (not causing disease) or likely benign, as well as other kinds of obesity, such as obesity linked to other genetic disorders and general (polygenic) obesity, setmelanotide is not licensed.

Pharmacology

It is believed that setmelanotide’s appetite suppressant effects are caused by binding to and activating MC4 receptors in the lateral hypothalamic area (LHA) and the paraventricular nucleus (PVN) of the hypothalamus, regions involved in appetite regulation. Setmelanotide decreases hunger and raises resting energy expenditure in obese humans and animals. Importantly, setmelanotide has not been shown to raise blood pressure or heart rate, in contrast to some other MC4 receptor agonists, like LY-2112688.

According to reports, setmelanotide has the following activity profile (cAMP, EC50): MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM) ≈ MC4 (0.27 nM) > MC3 (5.3 nM). [13] (19.6-fold MC4 selectivity over MC3, the second most active target.)

Indication

If an approved test shows variants in the genes for leptin receptor (LEPR), proprotein subtilisin/kexin type 1 (PCSK1), or pro-opiomelanocortin (POMC) that are interpreted as pathogenic, likely pathogenic, or of uncertain significance, then setmelanotide is indicated for chronic weight management in patients aged 6 and older who are obese due to these conditions. The MC4R signaling pathway is impacted by several situations.

For individuals aged 6 and up who suffer from obesity caused by Bardet-Biedl syndrome, setmelanotide is also recommended for long-term weight control.

Patients with benign or probable benign POMC, PCSK1, or LEPR variations, as well as those with additional forms of obesity not previously mentioned, have not been reported to benefit from the medication.

Side effects of setmelanotide

If you have any of the following symptoms of an allergic reaction: hives, trouble breathing, or swelling of your face, lips, tongue, or throat, get emergency medical attention.

Some patients who use setmelanotide experience suicidal thoughts. You need to contact your physician immediately if you experience any sudden changes in behavior or mood or if you have suicidal thoughts.

Serious side effects are possible with setmelanotide. Make an immediate call to your physician if you have:

• A prolonged stimulation lasts longer than four hours.

Setmelanotide side effects can include:

• Bleeding, leaking, redness, warmth, swelling, or bruises where an injection was injected;
• darkening of the skin;
• headache
• male erection in the absence of sexual activity; or
• Stomach pain, diarrhea, vomiting, or nausea.

Warnings

Only use as instructed. If you have any allergies, medical conditions, or other medications, let your doctor know.

Before using this medication,

Inform your doctor know if you have ever had:

• Renal disease;
• Depression, suicidal thoughts or actions, or
• Skin discoloration and darker skin.

Pregnancy-related weight loss may be harmful to the fetus. If you are or intend to become pregnant, let your doctor know.

Avoid breastfeeding.

A component in setmelanotide may result in severe adverse effects or even death in premature or extremely young infants. Give a child setmelanotide only after consulting a doctor.

How does one inject setmelanotide?

Read all drug instructions or instruction sheets, and do as directed on your prescription label. Take the medication as prescribed.

Once a day, at the start of the day, you will receive an injection of setmelanotide beneath your skin.

Setmelanotide can be taken with or without food.

If you have any questions about how to use an injection, ask your doctor or pharmacist.

Don’t prepare an injection until you’re ready to inject it. If the medication is hazy, has changed color, or contains particles, give your pharmacist a call.

Never use a syringe or needle again.

Put them in a “sharps” container that can’t be punctured, and dispose of it according to local or state regulations. Keep dogs and children away from it.

If, after a given period of treatment, you have not dropped a specific quantity of weight, your doctor may advise you to discontinue taking setmelanotide.

A skin examination should be performed both before and during setmelanotide treatment.

Observe all storage guidelines that come with setmelanotide. For more details on how to keep this medication, speak with your pharmacist.

Setmelanotide Dosage

Average Adult Obesity Dosage

First dosage: 2 mg administered once daily for two weeks subcutaneously

If further weight loss is desired and a dose of 2 mg is tolerated, Increase to once daily, 3 mg subcutaneously.
If not accepted: Titrate to 2 mg subcutaneously once daily if more weight reduction is desired after reducing to 1 mg once daily.

Dosage for maintenance: 1–3 mg daily
Dosage maximum: 3 mg daily

Comments:

• Before beginning treatment with this medication, perform a genetic test to confirm POMC, PCSK1, or LEPR deficiency.
• To determine tolerance, monitor for gastrointestinal side effects.
• It is doubtful that the patient would attain and maintain clinically significant weight loss with prolonged treatment if, after 12 to 16 weeks, they have not dropped at least 5% of their starting body weight.
• The FDA has not authorized or certified the available tests for the identification of POMC, PCSK1, or LEPR mutations.

Use: For long-term weight control in adults and children aged 6 and up who are obese due to a deficiency in proopiomelanocortin (POMC), proprotein convertase/subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) as demonstrated by genetic testing showing variations in the genes for POMC, PCSK1, or LEPR that are considered pathogenic, likely pathogenic, or of uncertain significance.

Normal Dosage for Obesity in Children

6 to under 12 years old:

First dosage: 1 mg administered once daily for two weeks subcutaneously

• Reduce to 0.5 mg once daily subcutaneously if not tolerated.
• Titrate to 1 mg subcutaneously once daily if 0.5 mg once daily is tolerated and more weight loss is desired.
• If further weight loss is desired and a dose of 1 mg is tolerated, Increase to once daily, 2 mg subcutaneously.
• Reduce to 1 mg once daily if the 2 mg dose is not tolerated.
• The dosage may be raised to 3 mg once a day if the 2 mg once daily dose is tolerated and more weight loss is required.

Doses for maintenance: 0.5–3 mg daily
Dosage maximum: 3 mg daily

12 years of age or older:

• Initial dosage: twice daily for two weeks, 2 mg subcutaneously
• If further weight loss is desired and tolerated: Increase to once daily, 3 mg subcutaneously.
• If not accepted: Titrate to 2 mg subcutaneously once daily if more weight reduction is desired after reducing to 1 mg once daily.

Dosage for maintenance: 1–3 mg daily
Dosage maximum: 3 mg daily

Comments:

• Before beginning treatment with this medication, perform a genetic test to confirm POMC, PCSK1, or LEPR deficiency.
• To determine tolerance, monitor for gastrointestinal side effects.
• It is unlikely that a patient would achieve and maintain clinically meaningful weight loss with continuous treatment if, after 12 to 16 weeks, they have not dropped at least 5% of their baseline body weight (or 5% of their baseline BMI for patients with maintained growth potential).
• The FDA has not authorized or certified the available tests for the identification of POMC, PCSK1, or LEPR mutations.

Use: For long-term weight control in adults and children aged 6 and up who are obese due to a deficiency in proopiomelanocortin (POMC), proprotein convertase/subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) as demonstrated by genetic testing showing variations in the genes for POMC, PCSK1, or LEPR that are considered pathogenic, likely pathogenic, or of uncertain significance.

What occurs if I don’t take my dose?

Use your subsequent dose at the scheduled time and skip the missing one. Avoid taking two doses at once.

What would happen if I overdosed?

Get help right away or contact the Poison Help Line at 1-800-222-1222.

What should I stay away from when taking setmelanotide?

Any dietary, beverage, or exercise limitations should be followed as directed by your physician.

Which other medications will interact with setmelanotide?

Setmelanotide may interact with other medications, such as vitamins, herbal remedies, and both prescription and over-the-counter medications. Inform your physician of all other medications you use.

FAQs

Reference

• Wikipedia contributors. (2025a, January 4). Setmelanotide. Wikipedia. https://en.wikipedia.org/wiki/Setmelanotide
• Setmelanotide Uses, Side Effects & Warnings. (n.d.). Drugs.com. https://www.drugs.com/mtm/setmelanotide.html
• Systemic mastocytosis and the central role of the KIT D816V mutation. (n.d.). IMCIVREE® (Setmelanotide) Injection. https://www.imcivree.com/hcp/ppl/dosing-administration/