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

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

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Genetic Obesity; Obesity Due to Melanocortin 4 Receptor Deficiency
• Intervention / Treatment: Drug: Setmelanotide

• Study Type: Interventional
• Enrollment (Actual): 213
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Edmonton, Canada, T6G 2E1
    • University of Alberta
• France
  • Paris, France, 75013
    • Hôpital de la Pitié-Salpêtrière
  • Paris, France, 75012
    • Hopital Trousseau - Nutrition et Gastroentérologie
  • Saint-Denis, France, 97405
    • Service de pédiatrie CHU de la Réunion - Hôpital Félix Guyon
• Germany
  • Berlin, Germany, 13354
    • Charite Berlin
  • Leipzig, Germany, 04103
    • University of Leipzig
  • Ulm, Germany, 89075
    • University of Ulm
• Greece
  • Patras
    • Río, Patras, Greece, 26504
      • University General Hospital of Patras
• Israel
  • Ramat Gan, Israel, 52621
    • Edmond and Lily Safra Children's Hospital
• Netherlands
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus MC
• Spain
  • Madrid, Spain, 65 28009
    • Hospital Infantil Universitario Nino Jesus
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • University Hospitals Birmingham NHS Foundation Trust
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • London, United Kingdom, W12 0NN
    • Hammersmith Hospital
  • London, United Kingdom
    • Hammersmith Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
      • Synexus Clinical Research US, Inc. - Simon Williamson Clinic, PC
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Synexus Clinical Research US, Inc. - Phoenix Southeast
    • Mesa, Arizona, United States, 85206
      • Synexus Clinical Research US, Inc. - Central Arizona Medical Associates, PC
    • Scottsdale, Arizona, United States, 85258
      • Honor Health Research Institute
  • California
    • Los Angeles, California, United States, 90017
      • Axis Clinical Trials-Downtown
    • Los Angeles, California, United States, 90036
      • Axis Clinical Trials Headquarters
    • San Diego, California, United States, 92108
      • San Diego Wake Research
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Anschutz Health and Wellness Center University of Colorado Anschutz Medical Campus
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Division of Endocrinology and Diabetes Children's National Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
    • Hialeah, Florida, United States, 33016
      • AXIS South Florida Clinical Trials
    • Orlando, Florida, United States, 32804
      • Florida Hospital
    • Pinellas Park, Florida, United States, 33781
      • Synexus Clinical Research US, Inc. - St. Petersburg
  • Illinois
    • Chicago, Illinois, United States, 60602
      • Synexus Clinical Research US, Inc. - Chicago
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Partners
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • NIH Hatfield Clinical Research Center
  • Massachusetts
    • Springfield, Massachusetts, United States, 01107
      • Baystate Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan Medicine
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Precision Medicine for Obesity Research: Gastroenterology & Hepatology Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University St. Louis
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Impact Clinical Trials
  • New York
    • Brooklyn, New York, United States, 11201
      • AXIS New York Clinical Trials
    • Buffalo, New York, United States, 14203
      • University at Buffalo
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10022
      • Axis Clinical Trials
    • New York, New York, United States, 10025
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
    • Raleigh, North Carolina, United States, 27612
      • Wake Research Inc.
  • Ohio
    • Akron, Ohio, United States, 44311
      • Synexus Clinical Research US, Inc. - Akron
    • Cincinnati, Ohio, United States, 45236
      • Synexus Clinical Research US, Inc. - Cincinnati
    • Columbus, Ohio, United States, 43016
      • Synexus Clinical Research US, Inc. - Columbus
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Obesity Institute, Geisinger Clinic
    • Philadelphia, Pennsylvania, United States, 19104
      • Childrens Hospital Of Philadelphia
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • Synexus Clinical Research US, Inc. - Primary Care Associates, PC
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • Wake Research TN
    • Memphis, Tennessee, United States, 38103
      • Le Bonheur Children's Hospital
    • Nashville, Tennessee, United States, 37212-3157
      • Vanderbilt University School of Medicine
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Plano, Texas, United States, 75093
      • Synexus Clinical Research US, Inc. - Plano
    • San Antonio, Texas, United States, 78229
      • Synexus Clinical Research US, Inc. - San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98101
      • Seattle Children's Research Institute
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 16p11.2 Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: AS Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: BBS Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: MC4R Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: POMC/PCSK1/LEPR Heterozygous Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: POMC/PCSK1/LEPR Composite Heterozygous Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: POMC/PCSK1/LEPR Compound Heterozygous Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: SH2B1 Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: SMS Cohort; 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; RM-493 QD SC injection; Other Names: RM-493
Experimental: SRC1 Cohort; 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; RM-493 QD SC injection; Other Names: RM-493

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Rhythm Pharmaceuticals, Inc.
• Investigators: Study Chair: David Meeker, MD, Rhythm Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Meyer JR, Krentz AD, Berg RL, Richardson JG, Pomeroy J, Hebbring SJ, Haws RM. Kidney failure in Bardet-Biedl syndrome. Clin Genet. 2022 Apr;101(4):429-441. doi: 10.1111/cge.14119.

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2017
• Primary Completion (Actual): March 1, 2022
• Study Completion (Actual): March 1, 2022

Study Registration Dates

• First Submitted: January 3, 2017
• First Submitted That Met QC Criteria: January 4, 2017
• First Posted (Estimated): January 6, 2017

Study Record Updates

• Last Update Posted (Actual): August 18, 2023
• Last Update Submitted That Met QC Criteria: July 25, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Smith-Magenis Syndrome; SH2B1 deficiency obesity; LepR deficiency obesity; MC4R deficiency obesity; SRC1 deficiency obesity; Pro-opiomelanocortin (POMC) deficiency obesity
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Genetic Diseases, Inborn
• Other Study ID Numbers: RM-493-014; 2017-000387-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No