Setmelanotide for the Treatment of Early-Onset Pro-Opiomelanocortin (POMC) Deficiency Obesity
Condition: Pro-opiomelanocortin (POMC) Deficiency Obesity
MeSH terms: Obesity
Intervention: Setmelanotide; Placebo
Intervention description: Once daily SC injection; Once daily SC injection
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
Masking: None (Open Label)
Masking description: During the 8 week double-blind placebo-controlled withdrawal period, participants received 4 weeks of daily setmelanotide and 4 weeks of daily placebo. Participants, investigators, and sites remained blinded as to when placebo treatment was administered.
Enrollment: 15.0
Sex: All
Minimum age: 6 Years
Healthy volunteers: No
Keywords: POMC deficiency obesity; PCSK1 deficiency obesity; Setmelanotide; RM-493; Obesity; Melanocortin 4 receptor; MC4R pathway

Summary:

      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.
    

Eligibility criteria:

        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.