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Identifying patients with obesity due to POMC, PCSK1, or LEPR deficiency

POMC, PCSK1, and LEPR deficiencies are all rare autosomal recessive disorders that lead to hyperphagia and early-onset, severe obesity1

POMC deficiency

Proopiomelanocortin deficiency

PCSK1 deficiency

Proprotein convertase subtilisin/kexin type 1 deficiency

LEPR deficiency

Leptin receptor deficiency

POMC, PCSK1, and LEPR deficiencies impact various systems throughout the body

POMC deficiency1-5

Brain
  • Hyperphagia and consequent obesity
Endocrine
  • Adrenal insufficiency

Additional clinical features may include:

  • Endocrine: Hypothyroidism, hypoglycemia
  • Reproductive: Hypogonadotropic hypogonadism
  • Physical: Red hair and light skin pigmentation
  • Hepatic: Liver failure

PCSK1 deficiency1-4,6-8

Brain
  • Hyperphagia and consequent obesity
Digestive
  • GI symptoms, including postnatal diarrhea within the first weeks of life
  • Failure to thrive in infancy
Kidneys
  • Metabolic acidosis
  • Polydipsia/polyuria
Endocrine
  • Abnormal glucose homeostasis
  • Hypothyroidism
  • Hypocortisolism

LEPR deficiency1,2,9,10

Brain
  • Hyperphagia and consequent obesity
Endocrine
  • Hyperinsulinemia
Reproductive
  • Hypogonadotropic hypogonadism
  • Delayed puberty

Additional clinical features may include:

  • Endocrine: Diabetes
  • Frequent infections

Not all obesity is the same

MC4R pathway-driven obesity in POMC, PCSK1, or LEPR deficiency is different from general obesity.

Identifying the type of obesity your patient has can:

  • Help you determine the optimal management of their specific disease1,11
  • Reduce the cumulative impact of their obesity, especially if diagnosed early12,13

General Obesity2,14

Occurrence: Can occur at any age, including later in life

Cause: Interaction of multiple factors, including:

  • Age/race/gender
  • Concurrent illnesses
  • Common genetic variants
  • Concomitant medications
  • Environmental factors
  • Nutrition and physical activity

MC4R pathway-driven obesity in POMC, PCSK1, or LEPR deficiency1,2,12

Occurrence: MC4R pathway impairment is present at birth, leading to hyperphagia (insatiable hunger) and early-onset obesity

  • May develop as early as a few months old; often appears in early childhood and continues into adolescence and adulthood

Cause: Rare genetic variants/impairment of gene expression or function that can impair the MC4R pathway

Not all hunger is the same

Identifying the type of hunger your patient has can:

  • Lead to optimal management of their increased hunger and impaired satiety1
  • Contribute to a diagnosis of the underlying disease pathology
  • Reduce the progression of obesity and its cumulative impact on overall health, especially if diagnosed early12,13

Episodic/Periodic

Occasional overeating15

Eating beyond a feeling of satiety at a special occasion or celebratory meal (e.g., Thanksgiving).

Hedonic overeating15,16

Eating beyond satiety and metabolic needs. Influenced by appetite and cravings.

Cause: The pleasure centers in the brain, often driven by emotion or environmental circumstances

Binge eating15-17

Episodic consumption of large amounts of food beyond hunger and in the presence of satiety within a short period with a loss of control. If recurring, defined as Binge Eating Disorder.

Behaviors:

  • Rapid eating
  • Eating in isolation
  • Distress due to eating behavior

Cause: Psychological factors, family history, dieting, gender

Persistent

Hyperphagia caused by MC4R pathway impairment12,18

Hyperphagia is a chronic pathological condition characterized by insatiable hunger and impaired satiety, often accompanied by a persistent preoccupation with food and abnormal food-seeking behaviors. Differentiated from other types of overeating by its severity and persistence. For some patients, symptoms and behaviors may range in severity.

Characteristics12:

  • Persistent preoccupation with food
  • Prolonged time to satiation and shortened duration of satiety
  • Prolonged feeling of hunger
  • Specific abnormal behaviors

Behaviors15,19-22:

  • Distress if food is unavailable
    • Children: may exhibit as tantrums or persistent negotiation/demand for food
    • Adults: may manifest as emotional effects including sadness, frustration, irritability, anxiety, and/or guilt
  • Abnormal food-seeking behaviors such as night eating or hiding food (children may also steal/sneak food)
  • Eating excessively—not to be confused with binge eating

Cause1: Rare genetic variants in the melanocortin-4 receptor (MC4R) pathway, a signaling pathway in the hypothalamus

According to 2023 American Academy of Pediatrics (AAP) and Obesity Medicine Association (OMA) guidelines, managing hyperphagia can be challenging and may require the use of pharmacotherapy.12,14

These conditions can be difficult to diagnose based solely on clinical manifestations, but genetic testing may be able to help. For more information about genetic testing for POMC, PCSK1, and LEPR deficiencies, please visit UncoveringRareObesity.com.23

A Rhythm representative can share resources and information about diagnosing obesity due to POMC, PCSK1, or LEPR deficiency.

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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 pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

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:

  • Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign
  • Other types of obesity not related to POMC, PCSK1, or LEPR deficiency, 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 and increased frequency of penile erections in males 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 and suicidal ideation 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 occurred in the majority of IMCIVREE-treated patients. IMCIVREE may also cause development of new melanocytic nevi or darkening of pre-existing nevi. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmented lesions.

Adverse Reactions

  • Most common adverse reactions (incidence ≥20%) included injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, 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.

Please see full Prescribing Information for additional Important Safety Information.

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 Jun 5;12:87-93. doi:10.2147/TACG.S199092 2. 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 3. Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity–assessment, treatment, and prevention: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(3):709-757. doi:10.1210/jc.2016-2573 4. Courbage S, Poitou C, Le Beyec-Le Bihan J, et al. Implication of heterozygous variants in genes of the leptin-melanocortin pathway in severe obesity. J Clin Endocrinol Metab. 2021;106(10):2991-3006. doi:10.1210/clinem/dgab404 5. National Organization for Rare Disorders. POMC deficiency. NORD. Updated March 6, 2023. Accessed April 1, 2025. https://rarediseases.org/rare-diseases/pomc-deficiency 6. Stijnen P, Ramos-Molina B, O’Rahilly S, Creemers JW. PCSK1 mutations and human endocrinopathies: from obesity to gastrointestinal disorders. Endocr Rev. 2016;37(4):347-371. doi:10.1210/er.2015-1117 7. Martín MG, Lindberg I, Solorzano-Vargas RS, et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology. 2013;145(1):138-148. doi:10.1053/j.gastro.2013.03.048 8. National Organization for Rare Disorders. PCSK1 deficiency. NORD. Updated February 22, 2023. Accessed April 1, 2025. https://rarediseases.org/rare-diseases/pcsk1-deficiency 9. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356(3):237-247. doi:10.1056/NEJMoa063988 10. National Organization for Rare Disorders. LEPR deficiency. NORD. Updated February 21, 2023. Accessed April 1, 2025. https://rarediseases.org/rare-diseases/lepr-deficiency 11. IMCIVREE [prescribing information]. Boston, MA. Rhythm Pharmaceuticals, Inc., 2026. 12. Hampl SE, Hassink SG, Skinner AC, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. 2023;151(2):e2022060640. doi:10.1542/peds.2022-060640 13. Manara E, Paolacci S, D’Esposito F, et al. Mutation profile of BBS genes in patients with Bardet-Biedl syndrome: an Italian study. Ital J Pediatr. 2019;45(1):72. Published 2019 Jun 13. doi:10.1186/s13052-019-0659-1 14. Tondt J, Freshwater M, Afreen S, et al. Obesity Algorithm 2023. Obesity Medicine Association; 2023. Accessed January 7, 2025. https://obesitymedicine.org/obesity-algorithm 15. Haqq AM, Kebbe M, Tan Q, Manco M, Salas XR. Complexity and stigma of pediatric obesity. Child Obes. 2021 May 20;17(4):229-240. doi:10.1089/chi.2021.0003 16. Espel-Huynh HM, Muratore AF, Lowe MR. A narrative review of the construct of hedonic hunger and its measurement by the Power of Food Scale. Obes Sci Pract. 2018 Feb 28;4(3):238-249. doi:10.1002/osp4.161 17. NIH Symptoms and Causes of Binge Eating Disorder–NIDDK https://www.niddk.nih.gov/health-information/weight-management/binge-eating-disorder/symptoms-causes 18. Heymsfield SB, Clément K, Dubern B, et al. Defining hyperphagia for improved diagnosis and management of MC4R pathway-associated disease: a roundtable summary. Curr Obes Rep. 2025;14(1):13. Published 2025 Jan 25. doi:10.1007/s13679-024-00601-z 19. Heymsfield SB, Avena NM, Baier L, et al. Hyperphagia: current concepts and future directions proceedings of the 2nd International Conference on Hyperphagia. Obesity (Silver Spring). 2014 Feb;22(0 1):S1-S17. doi:10.1002/oby.20646 20. Forsythe E, Mallya UG, Yang M, et al. Burden of hyperphagia and obesity in Bardet–Biedl syndrome: a multicountry survey. Orphanet J Rare Dis. 2023 Jan 16;18(1):12. doi:10.1186/s13023-023-02723-4 21. Ervin C, Norcross L, Mallya UG, et al. Interview-based patient- and caregiver-reported experiences of hunger and improved quality of life with setmelanotide treatment in Bardet-Biedl syndrome. Adv Ther. 2023;40(5):2394-2411. doi:10.1007/s12325-023-02443-y 22. Sherafat-Kazemzadeh R, Ivey L, Kahn SR, et al. Hyperphagia among patients with Bardet-Biedl syndrome. Pediatr Obes. 2013 Oct;8(5):e64-7. doi:10.1111/j.2047-6310.2013.00182 23. Malhotra S, Sivasubramanian R, Srivastava G. Evaluation and management of early onset genetic obesity in childhood. J Pediatr Genet. 2021;10(3):194-204. doi:10.1055/s-0041-1731035

Indication and 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 pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

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:

  • Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign
  • Other types of obesity not related to POMC, PCSK1, or LEPR deficiency, 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 and increased frequency of penile erections in males 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 and suicidal ideation 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 occurred in the majority of IMCIVREE-treated patients. IMCIVREE may also cause development of new melanocytic nevi or darkening of pre-existing nevi. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmented lesions.

Adverse Reactions

  • Most common adverse reactions (incidence ≥20%) included injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, 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.

Please see full Prescribing Information for additional Important Safety Information.

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 Jun 5;12:87-93. doi:10.2147/TACG.S1990922. 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:10.1159/0004450613. Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity–assessment, treatment, and prevention: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(3):709-757. doi:10.1210/jc.2016-25734. Courbage S, Poitou C, Le Beyec-Le Bihan J, et al. Implication of heterozygous variants in genes of the leptin-melanocortin pathway in severe obesity. J Clin Endocrinol Metab. 2021;106(10):2991-3006. doi:10.1210/clinem/dgab4045. National Organization for Rare Disorders. POMC deficiency. NORD. Updated March 6, 2023. Accessed April 1, 2025. https://rarediseases.org/rare-diseases/pomc-deficiency6. Stijnen P, Ramos-Molina B, O’Rahilly S, Creemers JW. PCSK1 mutations and human endocrinopathies: from obesity to gastrointestinal disorders. Endocr Rev. 2016;37(4):347-371. doi:10.1210/er.2015-11177. Martín MG, Lindberg I, Solorzano-Vargas RS, et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology. 2013;145(1):138-148. doi:10.1053/j.gastro.2013.03.0488. National Organization for Rare Disorders. PCSK1 deficiency. NORD. Updated February 22, 2023. Accessed April 1, 2025. https://rarediseases.org/rare-diseases/pcsk1-deficiency9. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356(3):237-247. doi:10.1056/NEJMoa06398810. National Organization for Rare Disorders. LEPR deficiency. NORD. Updated February 21, 2023. Accessed April 1, 2025. https://rarediseases.org/rare-diseases/lepr-deficiency11. IMCIVREE [prescribing information]. Boston, MA. Rhythm Pharmaceuticals, Inc., 2026.12. Hampl SE, Hassink SG, Skinner AC, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. 2023;151(2):e2022060640. doi:10.1542/peds.2022-06064013. Manara E, Paolacci S, D’Esposito F, et al. Mutation profile of BBS genes in patients with Bardet-Biedl syndrome: an Italian study. Ital J Pediatr. 2019;45(1):72. Published 2019 Jun 13. doi:10.1186/s13052-019-0659-114. Tondt J, Freshwater M, Afreen S, et al. Obesity Algorithm 2023. Obesity Medicine Association; 2023. Accessed January 7, 2025. https://obesitymedicine.org/obesity-algorithm15. Haqq AM, Kebbe M, Tan Q, Manco M, Salas XR. Complexity and stigma of pediatric obesity. Child Obes. 2021 May 20;17(4):229-240. doi:10.1089/chi.2021.000316. Espel-Huynh HM, Muratore AF, Lowe MR. A narrative review of the construct of hedonic hunger and its measurement by the Power of Food Scale. Obes Sci Pract. 2018 Feb 28;4(3):238-249. doi:10.1002/osp4.16117. NIH Symptoms and Causes of Binge Eating Disorder–NIDDK https://www.niddk.nih.gov/health-information/weight-management/binge-eating-disorder/symptoms-causes18. Heymsfield SB, Clément K, Dubern B, et al. Defining hyperphagia for improved diagnosis and management of MC4R pathway-associated disease: a roundtable summary. Curr Obes Rep. 2025;14(1):13. Published 2025 Jan 25. doi:10.1007/s13679-024-00601-z19. Heymsfield SB, Avena NM, Baier L, et al. Hyperphagia: current concepts and future directions proceedings of the 2nd International Conference on Hyperphagia. Obesity (Silver Spring). 2014 Feb;22(0 1):S1-S17. doi:10.1002/oby.2064620. Forsythe E, Mallya UG, Yang M, et al. Burden of hyperphagia and obesity in Bardet–Biedl syndrome: a multicountry survey. Orphanet J Rare Dis. 2023 Jan 16;18(1):12. doi:10.1186/s13023-023-02723-421. Ervin C, Norcross L, Mallya UG, et al. Interview-based patient- and caregiver-reported experiences of hunger and improved quality of life with setmelanotide treatment in Bardet-Biedl syndrome. Adv Ther. 2023;40(5):2394-2411. doi:10.1007/s12325-023-02443-y22. Sherafat-Kazemzadeh R, Ivey L, Kahn SR, et al. Hyperphagia among patients with Bardet-Biedl syndrome. Pediatr Obes. 2013 Oct;8(5):e64-7. doi:10.1111/j.2047-6310.2013.0018223. Malhotra S, Sivasubramanian R, Srivastava G. Evaluation and management of early onset genetic obesity in childhood. J Pediatr Genet. 2021;10(3):194-204. doi:10.1055/s-0041-1731035
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