Setmelanotide for the Treatment of Early-Onset Pro-Opiomelanocortin (POMC) Deficiency Obesity

An Open-Label, 1-Year Trial, Including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Early Onset POMC Deficiency Obesity Due to Bi-Allelic Loss-of-Function POMC or PCSK1 Genetic Mutation

To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with pro-opiomelanocortin (POMC) deficiency or proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency obesity due to rare biallelic or loss-of function mutations at the end of 1 year of treatment.

Inclusion Criteria:

1. Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each allele) genetic status for either the POMC or PCSK1 genes, with the loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype.
2. Age 6 years and above.
3. If adult age ≥ 18 years, obesity with body mass index (BMI) ≥ 30 kilograms per square meter (kg/m^2); if child or adolescent, obesity with BMI ≥ 95th percentile for age on growth chart assessment.
4. Study participant and/or parent or guardian is able to communicate well with the investigator, to understand and comply with the requirements of the study, and be able to understand and sign the written informed consent/assent, after being informed about the study.
5. Female participants of child-bearing potential must agree to use contraception as outlined in the protocol. Female participants of non-childbearing potential, defined as surgically sterile (status post-hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months (and confirmed with a screening follicular stimulating hormone [FSH] level in the post-menopausal lab range), or have delayed pubertal development and failure to have achieved menarche, do not require contraception during the study.
6. Male participants with female partners of childbearing potential must agree to a double barrier method if they become sexually active during the study. Male participants must not donate sperm during and for 90 days following their participation in the study.

Exclusion Criteria:

1. 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 weight loss or weight stabilization. Participants may be reconsidered approximately 1 month after cessation of such intensive regimens.
2. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain.
3. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders (DSM-III) disorders that the investigator believes will interfere significantly with study compliance.
4. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
5. Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS). Any lifetime history of a suicide attempt, or any suicidal behavior in the last month.
6. Current, clinically significant pulmonary, cardiac, or oncologic disease.
7. History of significant liver disease or liver injury, or current liver assessment for a cause of abnormal liver tests (as indicated by abnormal liver function tests, alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin [> 2.0 x upper limit of normal (ULN) for any of these tests]) for an etiology other than non-alcoholic fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD, including diagnosed non-alcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic cirrhosis will be exclusionary, but the presence of NAFLD would not be exclusionary.
8. History or presence of impaired renal function as indicated by clinically significant abnormal creatinine, blood urea nitrogen (BUN), or urinary constituents (e.g., albuminuria) or moderate to severe renal dysfunction as defined by the Cockcroft Gault equation < 30 mL/min.
9. History or close family history (parents or siblings) of skin cancer or melanoma, or participant history of ocular-cutaneous albinism.
10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions, determined as part of a screening comprehensive skin evaluation performed by a qualified dermatologist.
11. Participant is, in the opinion of the study investigator, not suitable to participate in the study.
12. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
13. Significant hypersensitivity to study drug.
14. Inability to comply with every day (QD) injection regimen.