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  • Writer's pictureDr Edin Hamzić & Dženita Omerkić Dautovic, MSc

💊 🧬 Genetic Obesity and Imcivree (Setmelanotide)

Updated: Feb 13

  • This post aims to explain the link between the genetic mutations in the PCSK1, LEPR, and POMC genes that are linked to a type of monogenic obesity the obesity drug Imcivree (Setmelanotide)

💊 What Is Imcivree (Setmelanotide)?

  • Imcivree (active substance is setmelanotide) [citation] is a drug specifically developed for patients with specific genetic defects (genetic obesity) that impact the functioning of the MC4R pathway.

  • Imcivree is the first-ever FDA-approved, EMA-approved, and Medicines and Healthcare Products Regulatory Agency (MHRA)- authorized therapy for patients with rare genetic diseases of obesity.

  • The MC4R pathway is a hypothalamic pathway that regulates appetite, satiety, energy expenditure, and body weight.

  • Setmelanotide, an MC4R agonist (or simply said replacement), is indicated to treat obesity caused by genetic mutations in the POMC, PCSK1, and LEPR genes, as well as in the case of Bardet-Biedl syndrome [citation].

  • Setmelanotide can potentially treat variable genetic disorders that disrupt the melanocortin-4 (MC4R) pathway like above mentioned Bardet-Biedl syndrome.

💊 How Does Setmelanotide Work?

  • Setmelanotide is a melanocortin agonist. It basically serves as a replacement for alpha-melanocyte-stimulating hormone (α-MSH). It is an eight-amino acid cyclic peptide analog of the endogenous MC4 receptor ligand alpha-melanocyte stimulating hormone (α-MSH).

  • In patients with obesity as a result of POMC, PCSK1, and LEPR deficiency associated with insufficient activation of the MC4 receptor, setmelanotide re-establishes MC4 receptor pathway activity, thus reducing hunger and promoting weight loss via lower caloric intake and increased energy expenditure [citation].

📏 What Is Imcivree Used For?

  • As mentioned above, setmelanotide is used to treat caused by genetic POMC, PCSK1, or LEPR deficiencies [citation].

  • Additionally, it is being tested and is in phase 3 of trial design for other rare genetic disorders associated with obesity, including:

🦺 When Was Imcivree FDA Approved?

  • The drug received its FDA approval in the USA on 27 November 2020 [citation] for chronic weight management in patients six years and older with obesity caused by POMC, PCSK1, and LEPR deficiency [citation].

  • Imcivree® (setmelanotide) will be available in Germany starting June 2022 [citation].

💊 Is Imcivree an Orphan Drug?

  • The European Medicines Agency granted it PRIority MEdicines (PRIME) orphan designation on November 19, 2018, for the treatment of obesity and hunger control associated with deficiency disorders of the MC4 receptor pathway [citation].

🏭 Who Makes Imcivree? Who Manufactures Imcivree?

  • Setmelanotide is a melanocortin-4 (MC4) receptor agonist developed by Rhythm Pharmaceuticals (Rhythm), founded in 2008 [citation].

  • Rhythm Pharmaceutical biotechnology company is focused on the commercial production of drugs to treat rare diseases related to obesity. Their headquarters are located in Boston, Massachusetts, USA.

  • Long ago, in March 2010, Rhythm obtained an exclusive worldwide license from Ipsen for research, development, and commercialization of the latter's melanocortin and ghrelin programs targeting obesity, metabolic and gastrointestinal disorders, including setmelanotide [citation].

💉How Do You Get Imcivree? How Is Imcivree Administered?

  • For patients 12 years old and older adults: The recommended starting dose of setmelanotide is 2 mg once daily for two weeks. After that, the daily dose is changed according to how the patient's body tolerates this medicine.

  • In pediatric patients between 6 and <12 years, the recommended starting dose of setmelanotide is 1 mg once daily for two weeks. If the starting dose is not tolerated, 0,5 mg is prescribed as the daily dose. If the 0.5 mg once daily dose is tolerated and additional weight loss is desired, the dose should be titrated to 1 mg once daily [citation].

💵 How Much Does Imcivree Cost?

  • The price of Imcivree is about 330$ per mg [citation]. Therefore, a maximum dose of 3 mg/day costs approximately $360,000 annually.

  • However, considering the average dose in clinical trials was closer to 2 mg daily, the cost is approximately $240,000 [citation].

🧬 Does One Have to Do a Genetic Test to Use Imcivree?

  • Imcivree is prescribed after proven mutations and confirmation of POMC, LEPR, and PCSK1 gene deficiency. Testing is carried out with approved testing for detecting mutations that are interpreted as pathogenic, likely pathogenic, or of uncertain significance [citation].

🧬 What Genetic Tests Are Approved for Imcivree Drug to Be Used?

  • Genetic testing for POMC, PCSK1, and LEPR variants involves whole exome sequencing.

  • Detected variants must show changes considered pathogenic, likely pathogenic, or uncertain.

  • An FDA-approved (POMC/PCSK1/LEPR CDx Panel) test was developed under post-marketing commitment to confirm POMC, PCSK1, and LEPR variants.

  • Genetic tests demonstrate bi-allelic homozygous or compound heterozygous variants in POMC, PCSK1, or LEPR genes.


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