Indications for Imcivree (setmelanotide)

Imcivree (setmelanotide) injection for subcutaneous (SC or SQ) use is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to:

1. Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS)
2. Bardet-Biedl syndrome (BBS)

Imcivree (setmelanotide) is NOT indicated for the treatment of patients with the following conditions as Imcivree (setmelanotide) 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 BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity

Mechanism of Action

Melanocortin 4 (MC4) receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. POMC, PCSK1, and LEPR deficiencies, though extremely rare, are associated with insufficient activation of the MC4 receptors. Imcivree (setmelanotide) addresses the underlying cause of obesity in these rare instances, when gene variation is interpreted as pathogenic, likely pathogenic, or of uncertain significance, by restoring MC4 receptor activity resulting in reduced hunger and enhanced weight loss through decreased caloric intake and increased energy expenditure.

Information on an FDA- approved test for the detection of variants in the POMC, PCSK1, or LEPR is available at http://www.fda.gov/CompanionDiagnostics.

Definitions

• Bardet-Biedl syndrome (BBS) is a rare disorder caused by genetic changes in many genes that affects many parts of the body. Signs and symptoms for this condition vary depending on the person, but it may cause problems such as loss of vision, obesity, extra fingers or toes (polydactyly), abnormalities of the genitalia, kidney abnormalities, and learning difficulties.
• Body Mass Index (BMI) is a value that is calculated based on an individual's weight and height and helps determine whether a person is underweight, overweight, or normal weight.
• Deficiency is the state of lacking a required amount of something or possessing defective versions which results in decreased function.
• Genetic variation is a permanent alteration in the sequence, number, structure, or function of the unit of inheritance, also known as a gene.
• Heterozygous describes a genetic disorder inherited from one parent.
• Homozygous describes a rare genetic disorder inherited from both parents.
• Monogenic means involving or controlled by a single gene.
• Obesity is a condition diagnosed when a person has a body mass index (BMI) of 30 kg/m2 or higher.
• Pathogenic describes a condition that causes or is capable of causing disease or dysfunction.
• Syndromic means occurring or associated with a syndrome, such as Alström syndrome, Bardet-Biedl syndrome, or Prader-Willi syndrome.

Medical Necessity Criteria for Initial Authorization

The Plan considers Imcivree (setmelanotide) medically necessary when ALL of the following criteria are met:

1. The member is 6 years of age or older; AND
2. The member requires treatment for monogenic or syndromic obesity due to ONE of the following:

• a. Bardet-Biedl syndrome (BBS) meeting BOTH of the following:
  1. At least ONE of the following diagnostic requirements for BBS (see Table 1):
     • 4 primary features; or
     • 3 primary and 2 secondary features; and
  2. Meets ONE of the following:
     • Is 16 years of age or older and has a BMI greater than or equal to (≥) 30 kg/m2; or
     • Is between 6 to 15 years of age and weight is greater than (>) 97th percentile for age and sex on growth chart assessment;

• pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency AND BOTH of the following:
1. Has been confirmed by genetic testing (by an FDA-approved/cleared test) demonstrating variants in POMC, PCSK1, or LEPR genes that are BOTH:
   1. homozygous or compound heterozygous (a different gene mutation on each allele); and
   2. interpreted as pathogenic, likely pathogenic, or of uncertain significance; and
2. Meets ONE of the following:
   1. Is 18 years of age or older and has a BMI greater than or equal to (≥) 30 kg/m2; or
   2. Is between 6 to 17 years of age with weight greater than or equal to (≥) 95th percentile for age and sex on growth chart assessment;
• The member does NOT have ANY of the following:
  1. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain; or
  2. Severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2) AND is 6 to less than 12 years of age; or
  3. end stage renal disease (eGFR less than 15 mL/min/1.73 m2);
• Clinical chart documentation is provided for review to substantiate the above listed requirements.

If the above prior authorization criteria are met, Imcivree (setmelanotide) will be approved for:

• 12-months for Obesity and a Clinical Diagnosis of BBS; or
• 4-months for Obesity Due to POMC, PCSK1, or LEPR Deficiency

Medical Necessity Criteria for Reauthorization:

Reauthorization for 12 months will be granted if BOTH of the following are met:

1. The member still meets the applicable initial criteria; AND
2. Recent (within the last month) chart documentation shows ONE of the following:
   1. For Obesity and a Clinical Diagnosis of BBS - the member lost at least 5% of baseline body weight or 5% of baseline BMI for patients aged less than 18 years; or
   2. For Obesity Due to POMC, PCSK1, or LEPR Deficiency - the member lost at least 5% of baseline body weight or 5% of baseline BMI for patients with continued growth potential.

Experimental or Investigational / Not Medically Necessary:

Imcivree (setmelanotide) for any other indication is considered not medically necessary by the Plan, as it is deemed to be experimental, investigational, or unproven.

References

1. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999 Jun;36(6):437-46. PMID: 10874630; PMCID: PMC1734378.
2. Beales PL. Lifting the lid on Pandora's box: the Bardet-Biedl syndrome. Curr Opin Genet Dev. 2005 Jun;15(3):315-23. doi: 10.1016/j.gde.2005.04.006. PMID: 15917208.
3. Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020 Dec;8(12):960-970. doi: 10.1016/S2213-8587(20)30364-8
4. Haws RM, Gordon G, Han JC, Yanovski JA, Yuan G, Stewart MW. The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design. Contemp Clin Trials Commun. 2021 May 3;22:100780. doi: 10.1016/j.conctc.2021.100780
5. Imcivree (setmelanotide) [prescribing information]. Boston, MA; Rhythm Pharmaceuticals Inc; November 2023.
6. Mayoclinic.org. Obesity. 2020. Available at: https://www.mayoclinic.org/diseases-conditions/obesity/symptoms-causes/syc-20375742. Accessed 23 Feb 2021.
7. Merriam-Webster.com Dictionary. Merriam-Webster. Available at: https://www.merriam-webster.com/dictionary. Accessed 23 Feb 2021.
8. Greene V, Vicaire S, Megarbane A, Kaplan J, Drouin-Garraud V, Hamdani M, Sigaudy S, Francannet C, Roume J, Bitoun P, Goldenberg A, Philip N, Odent S, Green J, Cossée M, Davis EE, Katsanis N, Bonneau D, Verloes A, Poch O, Mandel JL, Dollfus H. Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease. Hum Genet. 2010 Mar;127(5):583-93. doi: 10.1007/s00439-010-0804-9. Epub 2010 Feb 23. PMID: 20177705; PMCID: PMC3638942.
9. Wabitsch, M., Fehnel, S., Mallya, U. G., Sluga-O’Callaghan, M., Richardson, D., Price, M., & Kühnen, P. (2022). Understanding the Patient Experience of Hunger and Improved Quality of Life with Setmelanotide Treatment in POMC and LEPR Deficiencies. Advances in therapy, 39(4), 1772-1783.

Clinical Guideline Revision / History Information

Original Date: 03/11/2021

Reviewed/Revised: 12/01/2021, 03/17/2022, 12/08/2022, 12/14/2023