Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity

Study Overview
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Brief Summary
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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.

Detailed Description
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Eligible participants will enter a 14-week, randomized, double-blind, placebo-controlled treatment period (Period 1) that will be followed by a 38-week open-label treatment period (Period 2) in which all participants will receive setmelanotide. Following Period 2, participants will continue receiving open-label setmelanotide for 14 weeks (Period 3), after which they could enroll into a separate treatment extension study.

Official Title
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A Phase 3 Trial of Setmelanotide (RM-493), a Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Patients With Moderate to Severe Obesity

Conditions
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Bardet Biedl Syndrome (BBS), Alström Syndrome (AS)

Intervention / Treatment
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* Drug: Setmelanotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BBS clinical diagnosis or AS diagnosis Greater than or equal to (≥) 6 years of age. 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. 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. 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. 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: 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. 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. 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. 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. 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. 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. 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. Moderate to severe renal dysfunction defined as <30 mL/min. 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. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion). Participant 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 prior to the first day of dosing. Significant hypersensitivity to study drug. Inability to comply with once daily (QD) injection regimen.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Setmelanotide (Double-Blind)<br>Participants received once daily SC injection of setmelanotide for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). Participants ≥16 years of age started on setmelanotide 2.0 mg with dose escalation to 3.0 mg. Participants <16 years of age started on setmelanotide 1.0 mg with dose escalation to 3.0 mg. | Drug: Setmelanotide<br>* SC injection of setmelanotide<br>* Other names: RM-493;|
| Placebo Comparator: Placebo (Double-Blind)<br>Participants received once daily SC injection of placebo (matching setmelanotide) for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). | Drug: Placebo<br>* SC injection of placebo<br>|
| Experimental: Setmelanotide (Open-label)<br>After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3). | Drug: Setmelanotide<br>* SC injection of setmelanotide<br>* Other names: RM-493;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants (≥12 Years of Age at Baseline) Who Reached ≥10% Weight Loss Threshold After 1 Year (Period 2): Pivotal Cohort | The percentage of participants (≥12 years of age at baseline) who achieved a ≥10% reduction from baseline in body weight at Period 2 or after 52 weeks of treatment with setmelanotide were analyzed. There was a 14-week placebo-controlled period at the beginning of the trial. After completion of the placebo-controlled period, all participants from the placebo group switched to setmelanotide treatment. The placebo group was integrated into the 52-week analysis so that the participants who received placebo, had 52 weeks of setmelanotide treatment after the first dose of active treatment. Placebo participants were also included in this analysis. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percent Change From Baseline in Body Weight (≥12 Years of Age) at Week 52 (Period 2): Pivotal Cohort | The mean percent change from baseline in body weight at 52 weeks was analyzed. There was a 14-week placebo-controlled period at the beginning of the trial. After completion of the placebo-controlled period, all participants from the placebo group switched to setmelanotide treatment. The placebo group was integrated into the 52-week analysis so that the participants who received placebo, had 52 weeks of setmelanotide treatment after the first dose of active treatment. Placebo participants were also included in this analysis. | Baseline, Week 52 | 
| Mean Percent Change From Baseline in the Weekly Average of the Daily Hunger Score (≥12 Years of Age) at Week 52 (Period 2): Pivotal Cohort | Mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0= not hungry at all to 10= hungriest possible on Likert-type scale. On Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on weekly basis. Weekly average hunger score of daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. There was a 14-week placebo-controlled period at the beginning of the trial. After completion of the placebo-controlled period, all participants from the placebo group switched to setmelanotide treatment. Placebo group was integrated into the 52-week analysis so that participants who received placebo, had 52 weeks of setmelanotide treatment after the first dose of active treatment. Placebo participants were also included in this analysis. | Baseline, Week 52 | 
| Number of Participants (≥12 Years of Age With no Cognitive Impairment) Who Achieved a ≥ 25% Improvement in the Weekly Average of the Daily Hunger Score From Baseline at Week 52 (Period 2): Pivotal Cohort | Number of participants (≥12 years of age with no cognitive impairment) achieving ≥25% improvement from baseline in hunger score at Week 52 was assessed. Hunger score ranged from 0= not hungry at all to 10= hungriest possible on Likert-type scale. On Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on weekly basis. Weekly average hunger score of daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. There was a 14-week placebo-controlled period at the beginning of the trial. After completion of placebo-controlled period, all participants from placebo group switched to setmelanotide treatment. Placebo group was integrated into the 52-week analysis so that participants who received placebo, had 52 weeks of setmelanotide treatment after the first dose of active treatment. Placebo participants were also included in this analysis. | Baseline, Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BBS, MC4R Pathway, Obesity, AS