The MC4R pathway is a key signaling pathway in the hypothalamus that regulates hunger and energy expenditure1

  • The BBSome
    plays a central role in cilia
    function, including trafficking of the leptin
    receptors (LEPR) to allow leptin activation and satiety signaling1-3
  • Leptin binding to LEPR triggers a signaling cascade, including secretion of alpha-melanocyte-stimulating hormone (α-MSH) from the POMC neuron. α-MSH binds to the MC4 receptor1
  • Activation of the MC4R pathway regulates hunger and satiety, and energy expenditure, so weight and energy remain in balance1
Functional MC4R pathway activity
Functional MC4R pathway activity

Unlike general obesity, a root cause of obesity due to BBS is impairment of the MC4R pathway which can occur due to ciliary dysfunction1

  • In people with BBS, a variant in one or more BBS genes can disrupt the BBSome. This causes ciliary dysfunction and disruption of LEPR signaling2,7
  • Alpha-melanocyte-stimulating hormone (α-MSH) production is impaired or deficient, preventing activation of the MC4 receptor1
  • Impairment of the MC4R pathway leads to decreased satiety signaling, hyperphagia, and reduced energy expenditure. This often leads to early-onset obesity1
Impaired MC4R pathway activity
Impaired MC4R pathway activity

IMCIVREE is the first and only precision medicine to target impairment of the hypothalamic MC4R pathway, a root cause of hyperphagia and obesity due to BBS1,8

  • IMCIVREE, an MC4R agonist, targets a root cause of obesity due to BBS8-10
  • IMCIVREE acts in place of alpha-melanocyte-stimulating hormone (α-MSH) to activate the MC4 receptor and help re-establish MC4R pathway activity8-10
  • Re-established pathway activity helps to bring hunger and satiety signals, and energy expenditure, into balance. This can lead to reduced weight8
Re-establish MC4R pathway activity
Re-establish MC4R pathway activity

IMCIVREE is foundational to the long-term treatment of obesity due to BBS. Continuous treatment with IMCIVREE helps re-establish and maintain MC4R pathway activity8,11

 

MC4R=melanocortin-4 receptor; POMC=proopiomelanocortin.

References: 1. Eneli I, Xu J, Webster M, et al. Tracing the effect of the melanocortin-4 receptor pathway in obesity: study design and methodology of the TEMPO registry. Appl Clin Genet. 2019;12:87-93. doi:10.2147/TACG.S199092. 2. Blaess S, Wachten D. The BBSome: a nexus controlling energy metabolism in the brain. J Clin Invest. 2021;131(8):e148903. doi:10.1172/JCI148903. 3. Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet. 2009;18(7):1323-1331. doi:10.1093/hmg/ddp031. 4. Ciliopathy Alliance. Cilia. 2024. Accessed December 11, 2024. https://ciliopathyalliance.org/cilia. 5. Hsiao YC, Tuz K, Ferland RJ. Trafficking in and to the primary cilium. Cilia. 2012;1(1):4. doi:10.1186/2046-2530-1-4. 6. National Cancer Institute. NCI Dictionary of Cancer Terms. Accessed December 11, 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/. 7. Huvenne H, Dubern B, Clément K, Poitou C. Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016. Obes Facts. 2016;9(3):158-173. doi:10.1159/000445061. 8. IMCIVREE [prescribing information]. Boston, MA. Rhythm Pharmaceuticals, Inc. 9. Trapp CM, Censani M. Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity. Curr Opin Endocrinol Diabetes Obes. 2023;30(2):136-140. doi:10.1097/MED.0000000000000798. 10. Haws R, Brady S, Davis E, et al. Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome. Diabetes Obes Metab. 2020;22(11):2133-2140. doi:10.1111/dom.14133. 11. Haqq AM et al. Lancet Diabetes Endocrinol. 2022;10(12):859-868. doi:10.1016/S2213-8587(22)00277-7.

Indication

IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 2 years and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome (BBS).

Limitations of Use

IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective:

  • Other types of obesity not related to BBS or other FDA-approved indications for IMCIVREE, including obesity associated with other genetic syndromes and general (polygenic) obesity
Important Safety Information

CONTRAINDICATIONS

Prior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported.

WARNINGS AND PRECAUTIONS

Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention.

Depression and Suicidal Ideation: Depression, suicidal ideation, and depressed mood have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur.

Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue IMCIVREE.

Skin Hyperpigmentation, Darkening of Pre-existing Nevi, and Development of New Melanocytic Nevi: Generalized or focal increases in skin pigmentation, darkening of pre-existing nevi, development of new melanocytic nevi and increase in size of existing melanocytic nevi have occurred. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmentary lesions.

Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: IMCIVREE is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs.

ADVERSE REACTIONS

  • Most common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection

USE IN SPECIFIC POPULATIONS

Treatment with IMCIVREE is not recommended when breastfeeding. Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at 833-789-6337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see the full Prescribing Information for additional Important Safety Information.

Important Safety Information

Indication

IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 2 years and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome (BBS).

Limitations of Use

IMCIVREE is not indicated for the treatment of patients with the following conditions as IMCIVREE would not be expected to be effective:

  • Other types of obesity not related to BBS or other FDA-approved indications for IMCIVREE, including obesity associated with other genetic syndromes and general (polygenic) obesity
Important Safety Information

CONTRAINDICATIONS

Prior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported.

WARNINGS AND PRECAUTIONS

Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention.

Depression and Suicidal Ideation: Depression, suicidal ideation, and depressed mood have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur.

Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue IMCIVREE.

Skin Hyperpigmentation, Darkening of Pre-existing Nevi, and Development of New Melanocytic Nevi: Generalized or focal increases in skin pigmentation, darkening of pre-existing nevi, development of new melanocytic nevi and increase in size of existing melanocytic nevi have occurred. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmentary lesions.

Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: IMCIVREE is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs.

ADVERSE REACTIONS

  • Most common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection

USE IN SPECIFIC POPULATIONS

Treatment with IMCIVREE is not recommended when breastfeeding. Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at 833-789-6337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see the full Prescribing Information for additional Important Safety Information.