Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
Condition: Bardet Biedl Syndrome (BBS); Alström Syndrome (AS)
MeSH terms: Bardet-Biedl Syndrome; Laurence-Moon Syndrome; Alstrom Syndrome; Obesity; Obesity, Morbid; Syndrome
Intervention: Setmelanotide; Placebo
Intervention description: SC injection of setmelanotide; SC injection of placebo
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 52.0
Sex: All
Minimum age: 6 Years
Healthy volunteers: No
Keywords: MC4R Pathway; Obesity; BBS; AS

Summary:

      This pivotal, phase 3 study is designed to confirm the efficacy and safety of setmelanotide,
      a potent melanocortin receptor type 4 (MC4R) agonist, for the treatment of obesity and
      hyperphagia in participants with Bardet Biedl syndrome (BBS) or Alström syndrome (AS). The
      study's primary efficacy endpoint is to evaluate the proportion of participants (≥ 12 years
      of age at baseline) who lose ≥ 10% of their baseline body weight following approximately (~)
      52 weeks of treatment with setmelanotide compared to a historical control rate.
    

Eligibility criteria:

        Inclusion Criteria:

          1. BBS clinical diagnosis or AS diagnosis

          2. Greater than or equal to (≥) 6 years of age.

          3. Obese, defined as BMI ≥30 kilograms/meters^2 for participants ≥16 years of age or
             weight >97th percentile for age and sex on growth chart assessment for participants 6
             to 15 years of age.

          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.

          5. Female participants of child-bearing potential must be confirmed non-pregnant and
             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 follicle stimulating hormone (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 use a
             double barrier method contraception if they become sexually active during the study or
             within 90 days following their participation in the study. Male participants must also
             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 >2%
             weight loss. These participants may be reconsidered approximately 1 month after
             cessation of such intensive regimens.

          2. Current or prior (within prior 2 months) use of any medication, including those
             approved to treat obesity, that could impact the efficacy results of this study (e.g.,
             orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide).
             Participants on a stable dose and regimen (for at least 2 months) of medication to
             treat attention deficit hyperactivity disorder (ADHD) may be enrolled in the study as
             long as they agree to remain on the same dose and regimen during the study.

          3. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the
             baseline pre-operative weight with no evidence of weight regain. Specifically,
             participants may be considered if surgery was not successful, resulted in <10% weight
             loss compared to pre-operative baseline weight, or there is clear evidence of weight
             regain after an initial response to bariatric surgery. All participants with a history
             of bariatric surgery must be discussed with, and receive approval from, the Sponsor
             prior to enrollment.

          4. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic
             and Statistical Manual of Mental Disorders fifth edition (DSM-V) disorders that the
             Investigator believes will interfere significantly with study compliance.
             Neurocognitive disorders affecting ability to consent will not be disqualifying as
             long as an appropriate guardian able to give consent has been appointed.

          5. In participants with no significant neurocognitive deficits:

               -  A Patient Health Questionnaire-9 (PHQ-9) score of ≥15 and/or

               -  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 considered
             severe enough to interfere with the study and/or confound the results. Any participant
             with a potentially clinically significant disease should be reviewed with the Sponsor
             to determine eligibility.

          7. History of significant liver disease or liver injury, or a current liver assessment
             due to abnormal liver tests (as indicated by abnormal liver function tests, alanine
             transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum
             bilirubin >1.5x the 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 is exclusionary, but the
             presence of NAFLD is not exclusionary.

          8. Moderate to severe renal dysfunction defined as <30 mL/min.

          9. History or close family history (parents or siblings) of skin cancer or melanoma
             (excluding non-invasive basal or squamous cell lesion), or participant history of
             ocular-cutaneous albinism.

         10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions
             (excluding non-invasive basal or squamous cell lesion).

         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 once daily (QD) injection regimen.