EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R Pathway


About this study

The purpose of this trial is to evaluate the proportion of obese patients who respond to setmelanotide at 52 weeks of treatment. The trial includes multiple independent sub-studies of setmelanotide in patients with obesity and at least one of 6 specific gene defects in the Melanocortin-4 Receptor pathway. 

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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.




Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Andres Acosta, M.D., Ph.D.

Open for enrollment

Contact information:

Megan Schaefer

(507) 266-6004


More information


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