Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity
Condition: Leptin Receptor Deficiency Obesity
MeSH terms: Obesity; Obesity, Morbid
Intervention: Setmelanotide; Placebo
Intervention description: Once daily subcutaneous injection; Once daily subcutaneous 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: LEPR deficiency obesity; setmelanotide; RM-493; Leptin receptor; Obesity; Melanocortin 4 receptor

Summary:

      To demonstrate statistically significant and clinically meaningful effects of setmelanotide
      on percent body weight change in participants with LEPR deficiency obesity due to rare
      bi-allelic 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 the LEPR gene, with the loss-of-function (LOF) variant for
             each allele conferring a severe obesity phenotype.

          2. Age 6 years and above. 6+: Germany, Netherlands, UK. 12+: France

          3. If adult age ≥18 years, obesity with body mass index (BMI) ≥ 30 kilograms per meters
             squared (kg/m^2); if child or adolescent (< 18 years of age), obesity with weight >
             97th 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 is 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) post-menopausal for at least 12 months (and confirmed with a screening
             FSH level in the post-menopausal lab range), or failure to have progressed to Tanner
             Stage V and/or 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.

          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, severe stable restrictive or obstructive lung disease arising because of
             extreme obesity, evidence of significant heart failure (New York Heart Association
             [NYHA] Class 3 or greater), or oncologic disease, if these were severe enough to
             interfere with the study and/or would confound the results.

          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).

          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 milliliter/minute (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. Volunteer 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.

         15. Participants who have been placed in an institution through an official or court
             order, as well as those who are dependent on the sponsor, Investigator or study site.