MC4R Agonist Setmelanotide: A New Weight Loss Therapy

We have discussed a lot of weight loss drugs based on GLP-1 receptor agonists, and setmelanotide, a new weight loss therapy based on the melanocortin receptor (MC4R) , is approved for the treatment of inherited obesity caused by genetic defects, which is a new breakthrough in the treatment of obesity.

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Know Setmelanotide

It is a novel treatment for a rare genetic form of obesity. Setmelanotide is a potent selective MC4R agonist that plays a crucial role in regulating energy balance, appetite and weight. Setmelanotide’s brand name is Imcivree.

POMC(opioid-promoting melanocortin) deficiency; PCSK1(proprotein subtilysin /Kexin type 1) deficiency; LEPR(leptin receptor) deficiency, three rare inherited genetic defects or mutations that can lead to bulimia, which can lead to severe childhood obesity, which can lead to a variety of endocrine disorders, including adrenocorticotropin deficiency, hypothyroidism, hypogonadism, hypopigmentation, and hypoglycemia.

The melanocortin pathway is involved in many key physiological functions of the human body, including feeding behavior, energy balance, sexual function and behavior, cardiovascular function, kidney function, and immune response.

Setmelanotide acts on the MC4R pathway, reversing bulimia and helping patients lose weight faster by promoting satiety to reduce food intake while increasing resting metabolism to increase energy expenditure.

FDA approved Setmelanotide in 2020, and EU approved it in 2021 for the treatment of obesity caused by POMC, PCSK1,LEPR deficiency, and expanded approval to include Bardet-Biedel syndrome (BBS) in 2022.

Setmelanotide targets specific receptors in the brain that regulate appetite and weight, giving new hope to these obese patients by addressing the underlying biological factors that contribute to obesity. It is the first drug of its kind and a new breakthrough in the treatment of obesity.

Setmelanotide weight loss trails

In Setmelanotide’s Phase 3 clinical trial, participants in POMC, PCSK1,LEPR deficiency patients 6 years of age and older were treated for 12 weeks with a weight loss of more than 5kg to enter a subsequent 8-week placebo-controlled trial followed by a 32-week continuation of treatment. After 1 year of treatment, 80% of patients in the POMC/PSCK1 group lost more than 10% of their body weight, with an average weight loss of 25.6%. Forty-five percent of patients in the LEPR group lost more than 10 percent of their body weight, including some who lost 20 percent or more.

In the trial of patients with BBS, after 1 year of treatment, patients lost an average of 16.3% of their body weight.

Setmelanotide demonstrated its efficacy and safety in patients with POMC, PCSK1,LEPR and BBS.

Setmelanotide may also be beneficial for individuals with more common forms of obesity. Clinical trials have shown encouraging results, with significant weight loss among participants and improvements in related health measures such as blood pressure and cholesterol levels.

In addition, setmelanotide’s mechanism of action sets it apart from other weight loss drugs on the market. By specifically targeting pathways that regulate appetite and weight, it offers a unique approach to tackling obesity that could complement existing strategies or provide an alternative for those who have not found other interventions to be successful.

Setmelanotide weight loss dosage

Setmelanotide has a half-life of about 11 hours, so the frequency of use is once a day.

In the Setmelanotide weight loss trial, the starting dose is 1mg per day for 2 weeks, and if the initial dose is well tolerate, the dose could be increase to 2mg per day. In children, if side effects occur, need to reduce the dose to 0.5mg per day. If the dose of 2mg per day is well tolerate, we can increase the dose to 3mg per day.

For POMC, PCSK1,LEPR patients, if Setmelanotide treatment after 3-4 months, the weight loss is not 5% of the original body weight, indicating that the drug may not be effective for you, you can consider stopping the drug.

For people with BBS, if there is no weight loss after 1 year of treatment with Setmelanotide, it is unlikely that the drug will work for you and you can stop using it.

Setmelanotide side effects

The most common side effect of Setmelanotide is hypersensitivity at the injection site, which can cause blistering, burns, hives, inflammation, infection, itching, bumps, and skin discoloration. Setmelanotide also has side effects, including skin pigmentation, sexual dysfunction, depression, and suicidal ideation

Skin pigmentation occurs because melanocortin receptors are express on melanocytes, and activation of this receptor leads to the accumulation of melanin, which increases skin pigmentation, independent of UV light. Skin pigmentation is reversible when stop using it.

Both male and female patients treated with setmelanotide have experienced sexual dysfunction, including spontaneous penile erection in men and adverse sexual reactions in women. This is because the excitement of MC4R regulates the brain’s sexual processing, which increases libido and sexual imagery.

Conclusion

Setmelanotide represents a significant advance in the treatment of inherited obesity disorders, providing targeted therapies for individuals with specific genetic mutations that affect the MC4R pathway. Its efficacy in promoting significant weight loss and improving metabolic health makes it a valuable option for patients whose traditional weight loss methods have had little success. While potential side effects and the need for genetic testing pose some challenges, the overall benefits of setmelanotide offer a promising prospect for treating rare inherited obesity. As research continues, setmelanotide’s applications may expand, offering hope to more patients struggling with obesity.