Setmelanotide Phase 2 Treatment Trial in Participants With Rare Genetic Disorders of Obesity

Study Overview
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Brief Summary
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The purpose of the study was to determine the effect of setmelanotide (RM-493) on weight, hunger assessments, and other factors in participants with rare genetic disorders of obesity.

Official Title
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Setmelanotide (RM-493) Phase 2 Treatment Trial in Patients With Rare Genetic Disorders of Obesity

Conditions
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Genetic Obesity, Obesity, Obesity Due to Melanocortin 4 Receptor Deficiency

Intervention / Treatment
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* Drug: Setmelanotide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with the following genotypes and/or clinical assessment: POMC/PCSK1/LEPR heterozygous - not currently enrolling new participants POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or homozygous deficiency obesity POMC/PCSK1/LEPR composite heterozygous (two or more mutations in two or more genes) deficiency obesity SMS SH2B1 deficiency obesity Chromosomal rearrangement of the 16p11.2 locus causing obesity Carboxypeptidase E (CPE) compound heterozygous or homozygous deficiency obesity Leptin deficiency obesity with loss of response to metreleptin SRC1 deficiency obesity MC4R deficiency obesity Age 6 years and above Obese, defined as Body Mass Index (BMI) ≥ 30 kilogram per meter square (kg/m^2) for participants ≥16 years of age or BMI≥ 95th percentile for age and gender for participants 6 up to 16 years of age. Participant and/or parent or guardian is able 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 childbearing potential must be confirmed non-pregnant, and agree to use contraception as outlined in the protocol. 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. Key Exclusion Criteria: Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents that has resulted in > 2% weight loss. Use of any medication that is approved to treat obesity within three months of first dose of study drug (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion). Gastric bypass surgery within the previous six months or any prior gastric bypass surgery resulting in >10% weight loss durably maintained Diagnosis of schizophrenia, bipolar disorder, personality disorder, major depressive disorder, or other psychiatric disorder(s) Suicidal ideation, attempt or behavior Clinically significant pulmonary, cardiac, or oncologic disease hemoglobin A1c (HbA1c) > 9.0% at Screening History of significant liver disease Glomerular filtration rate (GFR) < 30 milliliter/minute (mL/min) at Screening. History or close family history of melanoma or participant history of oculocutaneous albinism Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing. Participants previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide. Inability to comply with QD injection regimen. Females who are breastfeeding or nursing. Other protocol defined Inclusion/Exclusion criteria may apply.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 16p11.2 Cohort<br>Participants with chromosomal rearrangement of the p11.2 region of chromosome 16 (16p11.2) locus causing obesity received setmelanotide once daily (QD) via subcutaneous (SC) injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: AS Cohort<br>Participants with Alström syndrome (AS) received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: BBS Cohort<br>Participants with Bardet-Biedl syndrome (BBS) received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: MC4R Cohort<br>Participants with melanocortin-4 receptor (MC4R) deficiency obesity received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: POMC/PCSK1/LEPR Heterozygous Cohort<br>Participants with pro-opiomelanocortin (POMC)/proprotein convertase subtilisin/kexin type 1 (PCSK1)/leptin receptor (LEPR) heterozygous mutations received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: POMC/PCSK1/LEPR Composite Heterozygous Cohort<br>Participants with POMC/PCSK1/LEPR composite heterozygous mutations received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: POMC/PCSK1/LEPR Compound Heterozygous Cohort<br>Participants with POMC/PCSK1/LEPR compound heterozygous mutations received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: SH2B1 Cohort<br>Participants with steroid receptor coactivator (SRC) homology 2B adapter protein 1 (SH2B1) haploinsufficiency received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: SMS Cohort<br>Participants with Smith-Magenis Syndrome (SMS) received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|
| Experimental: SRC1 Cohort<br>Participants with steroid receptor coactivator 1 (SRC1) mutations received setmelanotide QD via SC injection for 16 weeks. All participants initiated treatment with setmelanotide (starting dose being age dependent) and the dose was escalated up to a maximum dose of 3.0 mg QD. Participants either continued setmelanotide treatment by enrolling in an extension study (RM-493-022; NCT03651765) immediately following the last dose in this study or if the extension study was not open at the current clinic site, participants continued treatment in the current study for up to 1 year, resulting in treatment duration of up to 16 months. | Drug: Setmelanotide<br>* RM-493 QD SC injection<br>* Other names: RM-493;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With ≥ 5% Reduction in Body Weight From Baseline After 3 Months of Setmelanotide Treatment |  | Baseline to Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An AE (also referred to as an adverse experience) could be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. TEAEs were defined as AEs reported after dosing on Day 1. | From first dose up to Month 16 | 
| Change From Baseline in Body Weight After 3 Months of Setmelanotide Treatment |  | Baseline, Month 3 | 
| Percent Change From Baseline in Body Weight After 3 Months of Setmelanotide Treatment |  | Baseline, Month 3 | 
| Change From Baseline in Daily Hunger Questionnaire Scores After 3 Months of Setmelanotide Treatment in Participants Aged ≥ 12 Years | The mean change in daily hunger questionnaire scores for participants ≥ 12 years of age with obesity in treatment with setmelanotide was evaluated. On the Daily Hunger Questionnaire, each of the 3 items (average hunger in the last 24 hours, most/worst hunger in the last 24 hours, and morning hunger) was assessed daily and scored separately using a numeric rating score for each from 0 to 10, with 0 = not hungry at all and 10 = hungriest possible. | Baseline, Month 3 | 
| Change From Baseline in Daily Hunger Questionnaire Scores After 3 Months of Setmelanotide Treatment in Participants Aged < 12 Years | The mean change in daily hunger questionnaire scores for participants < 12 years of age with obesity in treatment with setmelanotide was evaluated. Hunger was assessed daily using a Daily Hunger Questionnaire with a pictorial (smiley face) version of the Likert rating scale with scores ranged from 0 to 4, with 0 = not hungry at all and 4 = hungriest possible. | Baseline, Month 3 | 
| Number of Participants With Shifts From Baseline in Global Hunger Questionnaire Scores After 3 Months of Setmelanotide Treatment in Participants Aged ≥ 12 Years | For participants ≥ 12 years of age, the following question was asked using the Global Hunger Questionnaire: Overall, how would you rate the hunger you experience now? Possible responses were: No hunger; Mild hunger; Moderate hunger; Severe hunger; and Not answered. | Baseline, Month 3 | 
| Number of Participants With Shifts From Baseline in Global Hunger Questionnaire Scores After 3 Months of Setmelanotide Treatment in Participants Aged < 12 Years | For participants < 12 years of age, the following question was asked to parents or caregivers of participants using the Global Hunger Questionnaire: How hungry is your child acting now? Possible responses were: Not hungry at all; A little hungry; Moderately hungry; Extremely hungry; and Not answered. | Baseline, Month 3 | 
| Percent Change From Baseline in Waist Circumference After 3 Months of Setmelanotide Treatment | Waist circumference (cm) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. All measurements were single measures. Waist circumference was measured when participants were in fasting condition and at approximately the same time at each visit. | Baseline, Month 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pro-opiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, Smith-Magenis Syndrome, MC4R deficiency obesity, SRC1 deficiency obesity, SH2B1 deficiency obesity