Inclusion Criteria:

•  Patients must have a pre-identified:
  • Heterozygous genetic variant in the POMC gene or PCSK1 gene;
  • Heterozygous genetic variant in the LEPR gene;
  • Homozygous, heterozygous, or compound heterozygous variant in the SRC1;
  • Homozygous, heterozygous, or compound heterozygous variant in SH2B1 gene, or chromosomal 16p11.2 deletion encompassing the SH2B1 gene;
  • Heterozygous N221D variant in the PCSK1 gene; OR
  • Be an N221D variant of the PCSK1 gene If a patient has composite heterozygous variants eligible for the study she/he will be accounted for the higher category based on ACMG classification;
    • Example: If a patient is a composite heterozygous for POMC pathogenic variant, and LEPR VOUS, the patient will be categorized as POMC pathogenic.
  • If the 2 variants have the same ACMG classification, adjudication will be assigned to the less prevalent gene sub-study;
    • Example:
      • If a patient is a composite heterozygous for LEPR VOUS and SRC1 VOUS, the patient will be categorized as SRC1(sub-study 35c);
      • If a patient is a composite heterozygous for SH2B1 VOUS and SRC1 VOUS, the patient will be assigned to SRC1 (sub-study 35c).
  • If the investigator has genetics results on a patient who may be eligible for the study, but the genetics have not yet been categorized by a CLIA/CAP/ISO15189 certified laboratory, then Rhythm may provide testing and/or categorization through a third-party laboratory.
• Between 6 and 65 years of age at the time of provision of informed consent/assent.
• Obesity, defined as BMI ≥ 30 kg/m^2 for patients ≥ 18 years of age or BMI ≥ 95th percentile for age and gender for patients 6 up to 17 years of age, based on the United States (US) Centers for Disease Control and Prevention criteria.
• Patient and/or parent or guardian is able to communicate well with the Investigator, understand and comply with the requirements of the study (including once daily [QD] injection regimen and all other study procedures), and is able to understand and sign the written informed consent/assent. Patients who are unable to comply with all study procedures due to cognitive limitations or any other reason should not be enrolled into the study.
• Patient and/or parent or guardian reports that patient experienced childhood obesity, defined as the patient and/or parent or guardian reporting that the patient was significantly overweight during childhood.
• For women of child-bearing potential (WOCBP), agrees to use a highly effective form of contraception throughout the study and for 30 days following the study:
  •  Highly effective forms of contraception include:
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal);
    • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
    • Intrauterine device (IUD);
    • Sexual abstinence only if it is the preferred and usual lifestyle of the patient.
• Reported history of lifestyle intervention of diet and exercise.
• Reported history of hyperphagia.

Exclusion Criteria:

• Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents including herbal medications that has resulted in > 2% weight loss.
• Use of any medication that is approved to treat obesity within 3 months of first dose of study drug (e.g., orlistat, phentermine-topiramate, naltrexone-bupropion) if >2% weight loss in the last 3 months.
• History of Bariatric surgery with evidence of weight loss of > 2% in the last 3 months.
• Documented diagnosis of any psychiatric disorder(s) that the Investigator believes will interfere significantly with study compliance.
• Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS) during Screening, any suicide attempt in the past 5 years, or any suicidal behavior in the last month.
• Current, clinically significant pulmonary, cardiac or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with Rhythm to determine eligibility.
• HbA1C > 10% at Screening.
• History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
• Glomerular filtration rate (GFR) < 30 mL/min at Screening.
• History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
• Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by the Investigator during Screening. Any concerning lesions identified during Screening will be biopsied and results known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient may need to be excluded from the study.
• Patient is, in the opinion of the Study Investigator, not suitable to participate in the study.
• Participation in any clinical study with an investigational drug/device within 3 months or 5 half-lives, whichever is longer, prior to the first day of dosing.
• Previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
• Significant hypersensitivity to any excipient in the study drug.
• If female, pregnant or breastfeeding.