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

Phase 2

Completed

• Conditions: Genetic Obesity; Obesity; Obesity Due to Melanocortin 4 Receptor Deficiency
• Interventions: Drug: Setmelanotide

• Registration Number: NCT03013543
• Lead Sponsor: Rhythm Pharmaceuticals, Inc.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-01-03
• Study First Submitted QC: 2017-01-04
• Study First Posted: 2017-01-06
• Study Start: 2017-02-10
• Primary Completion: 2022-03-01
• Study Completion: 2022-03-01
• Status Verified: 2023-07
• Results First Submitted: 2023-07-25
• Results First Submitted QC: 2023-07-25
• Last Update Submitted: 2023-07-25
• Results First Posted: 2023-08-18
• Last Update Posted: 2023-08-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 213

Inclusion Criteria

1. Participants with the following genotypes and/or clinical assessment:

   1. POMC/PCSK1/LEPR heterozygous - not currently enrolling new participants
   2. POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or homozygous deficiency obesity
   3. POMC/PCSK1/LEPR composite heterozygous (two or more mutations in two or more genes) deficiency obesity
   4. SMS
   5. SH2B1 deficiency obesity
   6. Chromosomal rearrangement of the 16p11.2 locus causing obesity
   7. Carboxypeptidase E (CPE) compound heterozygous or homozygous deficiency obesity
   8. Leptin deficiency obesity with loss of response to metreleptin
   9. SRC1 deficiency obesity
   10. MC4R deficiency obesity

2. Age 6 years and above

3. 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.

4. 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

5. Female participants of childbearing potential must be confirmed non-pregnant, and agree to use contraception as outlined in the protocol.

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.

Key

Exclusion Criteria

1. 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.
2. 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).
3. Gastric bypass surgery within the previous six months or any prior gastric bypass surgery resulting in >10% weight loss durably maintained
4. Diagnosis of schizophrenia, bipolar disorder, personality disorder, major depressive disorder, or other psychiatric disorder(s)
5. Suicidal ideation, attempt or behavior
6. Clinically significant pulmonary, cardiac, or oncologic disease
7. hemoglobin A1c (HbA1c) > 9.0% at Screening
8. History of significant liver disease
9. Glomerular filtration rate (GFR) < 30 milliliter/minute (mL/min) at Screening.
10. History or close family history of melanoma or participant history of oculocutaneous albinism
11. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions.
12. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
13. Participants previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
14. Inability to comply with QD injection regimen.
15. Females who are breastfeeding or nursing.

Other protocol defined Inclusion/Exclusion criteria may apply.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
16p11.2 Cohort	Setmelanotide	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.
MC4R Cohort	Setmelanotide	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.
POMC/PCSK1/LEPR Composite Heterozygous Cohort	Setmelanotide	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.
POMC/PCSK1/LEPR Heterozygous Cohort	Setmelanotide	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.
POMC/PCSK1/LEPR Compound Heterozygous Cohort	Setmelanotide	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.
SH2B1 Cohort	Setmelanotide	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.
SRC1 Cohort	Setmelanotide	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.
SMS Cohort	Setmelanotide	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.
AS Cohort	Setmelanotide	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.
BBS Cohort	Setmelanotide	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With ≥ 5% Reduction in Body Weight From Baseline After 3 Months of Setmelanotide Treatment	Baseline to Month 3

Secondary Outcome Measures

Name	Time	Method
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	Baseline, Month 3	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.
Change From Baseline in Daily Hunger Questionnaire Scores After 3 Months of Setmelanotide Treatment in Participants Aged < 12 Years	Baseline, Month 3	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.
Number of Participants With Shifts From Baseline in Global Hunger Questionnaire Scores After 3 Months of Setmelanotide Treatment in Participants Aged ≥ 12 Years	Baseline, Month 3	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.
Percent Change From Baseline in Waist Circumference After 3 Months of Setmelanotide Treatment	Baseline, Month 3	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.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	From first dose up to Month 16	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.
Change From Baseline in Body Weight After 3 Months of Setmelanotide Treatment	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	Baseline, Month 3	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.

Trial Locations

Locations (57)

Synexus Clinical Research US, Inc. - Simon Williamson Clinic, PC; 🇺🇸 Birmingham, Alabama, United States

Synexus Clinical Research US, Inc. - Phoenix Southeast; 🇺🇸 Chandler, Arizona, United States

Synexus Clinical Research US, Inc. - Central Arizona Medical Associates, PC; 🇺🇸 Mesa, Arizona, United States

Honor Health Research Institute; 🇺🇸 Scottsdale, Arizona, United States

Axis Clinical Trials-Downtown; 🇺🇸 Los Angeles, California, United States

Axis Clinical Trials Headquarters; 🇺🇸 Los Angeles, California, United States

San Diego Wake Research; 🇺🇸 San Diego, California, United States

Anschutz Health and Wellness Center University of Colorado Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States

Division of Endocrinology and Diabetes Children's National Hospital; 🇺🇸 Washington, District of Columbia, United States

University of Florida College of Medicine; 🇺🇸 Gainesville, Florida, United States

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