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Identifying patients with obesity due to BBS

BBS is a rare autosomal recessive ciliopathy that is clinically and genetically diverse1

Almost all major body systems contain primary cilia, which are vital to several biological processes.2,3

Ciliary dysfunction impairs various systems through the body:

Brain1

  • Hyperphagia*
  • Obesity (any age) 72–92% or overweight (<2 years old) 55%
  • Cognitive and neurodevelopmental manifestations 67–72%

Kidneys1

  • CAKUT 26–81% or CKD 31–39%

Reproductive1

  • Hypogonadism 34–47%
  • Genital anomalies 20–70%

Eyes1

  • Retinal dystrophy 87–97%

Skeletal1

  • Postaxial polydactyly 75%

Additional clinical features of BBS may include1:

  • Brain: speech delay, developmental delay, ataxia/poor coordination, anosmia/hyposmia
  • Skeletal: dental anomalies, brachydactyly, syndactyly, craniofacial dysmorphisms
  • Body organs: laterality defects
  • Hearing: conductive or sensorineural hearing loss

Heart defects may be observed.4

Primary cilia dysfunction within each organ system contributes to the highly variable phenotype.1

*Hyperphagia is a common manifestation of BBS resulting from impairment of the MC4R pathway. Although hyperphagia is not used as a diagnostic criterion for BBS, it may be an early indicator and can substantially affect patient health and quality of life.

CAKUT: congenital anomalies of the kidney and urinary tract | CKD: chronic kidney disease

Ciliary dysfunction in the hypothalamus causes impairment of the MC4R pathway, which plays a fundamental role in regulating energy intake and expenditure.2,5

MC4R pathway impairment can lead to:

Early-onset obesity

Hyperphagia

Not all obesity is the same

MC4R pathway-driven obesity in BBS is different from general obesity.

Identifying the type of obesity your patient has can:

  • Help you determine the optimal management of their specific disease6,7
  • Reduce the cumulative impact of their obesity, especially if diagnosed early8,9

General Obesity10,11

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 BBS7,8,10

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 in the BBS genes 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 satiety7
  • Contribute to a diagnosis of the underlying disease pathology
  • Reduce the progression of obesity and its cumulative impact on overall health, especially if diagnosed early8

Episodic/Periodic

Occasional overeating12

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

Hedonic overeating12,13

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 eating12-14

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 impairment8,15

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.

Characteristics8:

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

Behaviors12,16-19:

  • 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

Cause: Rare genetic variants in the melanocortin-4 receptor (MC4R) pathway, a signaling pathway in the hypothalamus7

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.8,11

Knowing a root cause of your patient’s hunger and early-onset obesity can be an important first step in making an accurate diagnosis, which can lead to optimal management of their disease.7-9

A Rhythm representative can share resources and information about diagnosing obesity due to BBS.

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Learn more about patient resources for treatment initiation.

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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 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 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 skin hyperpigmentation, injection site reactions, nausea, 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. Pomeroy JJ, Richards J, Sweeney BR, et al. Streamlining diagnosis of Bardet-Biedl syndrome: new diagnostic algorithm with updated criteria. Am J Med Genet A. doi:10.1002/ajmg.a.70199 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. Pala R, Alomari N, Nauli SM. Primary cilium-dependent signaling mechanisms. Int J Mol Sci. 2017;18(11):2272. doi:10.3390/ijms18112272 4. Forsythe E, Kenny J, Bacchelli C, Beales PL. Managing Bardet-Biedl syndrome-now and in the future. Front Pediatr. 2018;6:23. doi:10.3389/fped.2018.00023 5. Beales PL, Cetiner M, Haqq AM, et al. Hyperphagia in Bardet-Biedl syndrome: pathophysiology, burden, and management. Obes Rev. 2025;26(7):e13915. doi:10.1111/obr.13915 6. IMCIVREE [prescribing information]. Boston, MA: Rhythm Pharmaceuticals, Inc; 2026. 7. 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 8. 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 9. 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. doi:10.1186/s13052-019-0659-1 10. 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 11. Tondt J, et al. Obesity Algorithm® 2023. Obesity Medicine Association; 2023. Accessed August 11, 2023. https://obesitymedicine.org/obesity-algorithm 12. Haqq AM, Kebbe M, Tan Q, Manco M, Salas XR. Complexity and stigma of pediatric obesity. Child Obes. 2021;17(4):229-240. doi:10.1089/chi.2021.0003 13. 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;4(3):238-249. doi:10.1002/osp4.161 14. Symptoms & Causes of Binge Eating Disorder. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). https://www.niddk.nih.gov/health-information/weight-management/binge-eating-disorder/symptoms-causes 15. 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. doi:10.1007/s13679-024-00601-z 16. 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;22(suppl 1[0 1]):S1-S17. doi:10.1002/oby.20646 17. Forsythe E, Haws RM, Argente J, et al. Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results. Orphanet J Rare Dis. 2023;18(1):12. doi:10.1186/s13023-022-02602-4 18. 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 19. Sherafat-Kazemzadeh R, Ivey L, Kahn SR, et al. Hyperphagia among patients with Bardet-Biedl syndrome. Pediatr Obes. 2013;8(5):e64-e67. doi:10.1111/j.2047-6310.2013.00182.x

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 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 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 skin hyperpigmentation, injection site reactions, nausea, 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. Pomeroy JJ, Richards J, Sweeney BR, et al. Streamlining diagnosis of Bardet-Biedl syndrome: new diagnostic algorithm with updated criteria. Am J Med Genet A. doi:10.1002/ajmg.a.701992. Blaess S, Wachten D. The BBSome: a nexus controlling energy metabolism in the brain. J Clin Invest. 2021;131(8):e148903. doi:10.1172/JCI1489033. Pala R, Alomari N, Nauli SM. Primary cilium-dependent signaling mechanisms. Int J Mol Sci. 2017;18(11):2272. doi:10.3390/ijms181122724. Forsythe E, Kenny J, Bacchelli C, Beales PL. Managing Bardet-Biedl syndrome-now and in the future. Front Pediatr. 2018;6:23. doi:10.3389/fped.2018.000235. Beales PL, Cetiner M, Haqq AM, et al. Hyperphagia in Bardet-Biedl syndrome: pathophysiology, burden, and management. Obes Rev. 2025;26(7):e13915. doi:10.1111/obr.139156. IMCIVREE [prescribing information]. Boston, MA: Rhythm Pharmaceuticals, Inc; 2026.7. 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.S1990928. 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.2022-0606409. 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. doi:10.1186/s13052-019-0659-110. 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:10.1159/00044506111. Tondt J, et al. Obesity Algorithm® 2023. Obesity Medicine Association; 2023. Accessed August 11, 2023. https://obesitymedicine.org/obesity-algorithm12. Haqq AM, Kebbe M, Tan Q, Manco M, Salas XR. Complexity and stigma of pediatric obesity. Child Obes. 2021;17(4):229-240. doi:10.1089/chi.2021.000313. 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;4(3):238-249. doi:10.1002/osp4.16114. Symptoms & Causes of Binge Eating Disorder. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). https://www.niddk.nih.gov/health-information/weight-management/binge-eating-disorder/symptoms-causes15. 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. doi:10.1007/s13679-024-00601-z16. 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;22(suppl 1[0 1]):S1-S17. doi:10.1002/oby.2064617. Forsythe E, Haws RM, Argente J, et al. Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results. Orphanet J Rare Dis. 2023;18(1):12. doi:10.1186/s13023-022-02602-418. 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-y19. Sherafat-Kazemzadeh R, Ivey L, Kahn SR, et al. Hyperphagia among patients with Bardet-Biedl syndrome. Pediatr Obes. 2013;8(5):e64-e67. doi:10.1111/j.2047-6310.2013.00182.x
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