Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity

A Phase 3 Multi-Center, 1-Year, Open-Label Study of Setmelanotide in Pediatric Patients Aged 2 to <6 Years of Age With Rare Genetic Causes of Obesity

This is a phase 3 open-label, clinical study to evaluate the efficacy, safety and tolerability of setmelanotide over 1 year of treatment, in pediatric participants aged 2 to <6 years with obesity due to either biallelic variants of the pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) genes or Bardet-Biedl Syndrome (BBS).

Study Overview

• Status: Completed
• Conditions: Bardet-Biedl Syndrome; POMC Deficiency Obesity; PCSK1 Deficiency Obesity; LEPR Deficiency Obesity
• Intervention / Treatment: Drug: Setmelanotide

Detailed Description

Pediatric participants aged 2 to <6 years with obesity due to either biallelic variants of the POMC, PCSK1 or LEPR genes or BBS will be enrolled into this phase 3 open-label clinical trial at one of approximately 8 clinical centers in North America, Europe, or Australia. All participants will be assigned to receive setmelanotide via daily subcutaneous (SC) injection for 1 year.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Randwick, Australia, NSW 2031
    • Sydney Children's Hospital
• Spain
  • Madrid, Spain, 28009
    • Hospital Infantil Niño Jesus
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital, Wellcome Trust-MRC Institute of Metabolic Science
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center, Division of Pediatric Endocrinology, Diabetes and Metabolism
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic Research Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 1 year (Child)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Participants must have obesity due to either:

   1. POMC, PCSK1, or LEPR deficiency, confirmed by genetic testing demonstrating biallelic variants that are interpreted as pathogenic, likely pathogenic, or of undetermined significance (VUS) by the American College of Medical Genetics and Genomics criteria (ACMG), or
   2. BBS confirmed clinical and genetic diagnosis
2. Age between 2 to <6 years at the time of informed consent
3. Obesity, defined as body mass index (BMI) ≥97th percentile for age and gender and body weight of at least 15 kilograms (kg) at the time of enrollment.
4. Symptoms or behaviors of hyperphagia
5. Parent or guardian of study participant is able to understand and comply with the requirements of the study (including QD injection regimen and all other study procedures) and is able to understand and sign the written consent/assent.

Key Exclusion Criteria

1. Glycated hemoglobin (HbA1c) >9.0% at screening
2. History of significant liver disease
3. Glomerular filtration rate (GFR) <60 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2)
4. History or close family history of melanoma, or participant history of oculocutaneous albinism.
5. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion)
6. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
7. Previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
8. Significant hypersensitivity to any excipient in the study drug.
9. Inadequate hepatic function
10. Any other uncontrolled endocrine, metabolic or medical condition(s) known to impact body weight

Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Setmelanotide: PPL Group; Participants with POMC)/PCSK1/LEPR biallelic mutations collectively referred to as PPL received setmelanotide at a dose of 0.5 milligrams (mg) per day (QD) via SC injection for 52 weeks. The dose was escalated by increments of 0.5 mg every 2 weeks, if tolerated, at the dose escalation visits (Weeks 2, 4, and 6) to a maximum dose of 0.5 to 2.0 mg QD with the maximum dose based on body weight. Following the last dose in this study, participants who were considered likely to benefit from continued setmelanotide treatment and who had completed this trial could be eligible to enter an open-label long-term extension (LTE) trial with setmelanotide.	Drug: Setmelanotide; SC injection once daily.; Other Names: IMCIVREE
Experimental: Setmelanotide: BBS Group; Participants with BBS received setmelanotide at a dose of 0.5 mg QD via SC injection for 52 weeks. The dose was escalated by increments of 0.5 mg every 2 weeks, if tolerated, at the dose escalation visits (Weeks 2, 4, and 6) to a maximum dose of 0.5 to 2.0 mg QD with the maximum dose based on body weight. Following the last dose in this study, participants who were considered likely to benefit from continued setmelanotide treatment and who had completed this trial could be eligible to enter an open-label long-term extension (LTE) trial with setmelanotide.	Drug: Setmelanotide; SC injection once daily.; Other Names: IMCIVREE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Greater Than or Equal to (≥) 0.2 Reduction of BMI Z-Score From Baseline to Week 52	A "responder" was defined as a decrease from baseline to 52 weeks in the participant's BMI z-score of ≥0.2. BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2. The BMI Z-scores were based on the World Health Organization's Child Growth Standards 2007 and indicated the number of standard deviations away from the mean. A Z-score of 0 was equal to the mean of a reference population (i.e., healthy, age and sex-matched individuals). A decrease of BMI Z-score (< 0) indicated a reduction in BMI from Baseline whereas an increase of BMI-Z score (> 0) indicated an increase in BMI from Baseline. Baseline was defined as the most recent measurement prior to the first administration of study drug.	Baseline up to Week 52
Mean Percent Change From Baseline in BMI	Mean percent change from baseline to Week 52 in BMI was reported. BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2. Baseline was defined as the most recent measurement prior to the first administration of study drug.	Baseline, Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Absolute Change From Baseline in BMI Z-score	Mean absolute change from baseline to Week 52 in BMI Z-score was reported. BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2. The BMI Z-scores were based on the World Health Organization's Child Growth Standards 2007 and indicated the number of standard deviations away from the mean. A Z-score of 0 was equal to the mean of a reference population (i.e., healthy, age and sex-matched individuals). A decrease of BMI Z-score (< 0) indicated a reduction in BMI from Baseline whereas an increase of BMI-Z score (> 0) indicated an increase in BMI from Baseline. Baseline was defined as the most recent measurement prior to the first administration of study drug.	Baseline, Week 52
Mean Change From Baseline in Percent of the 95th Percentile of BMI	Mean change from baseline to Week 52 in percent of the 95th percentile of BMI was reported. BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2. BMI Percentile-scores are measures of relative weight adjusted for child age and gender. The percent of the BMI 95th percentile score expresses the participant's BMI as a percentage of the Centers for Disease Control (CDC) 95th percentile reference population. Baseline was defined as the most recent measurement prior to the first administration of study drug.	Baseline, Week 52
Mean Change From Baseline in Bone Age	Mean change from baseline to Week 52 in bone age was reported. A standard bone age measurement (of the hand/wrist area) was obtained at the beginning and the end of the trial to monitor for growth related safety concerns. Baseline was defined as the most recent measurement prior to the first administration of study drug.	Baseline, Week 52
Number of Participants With Shift From Baseline in Ages & Stages Questionnaires, Third Edition (ASQ-3)	ASQ-3: developmental screening questionnaire that consists of 5 areas: communication, gross motor, fine motor, problem solving, and personal-social. Each area has 6 questions scored as Yes=10 points, Sometimes=5 points, and Not yet=0 points. A child can score between 0-60 points for each area with total score range: 0 to 300; higher scores are indicative of improvement. Total area score is then compared to age-adjusted standardized score cutoff (determined by developers of tool) which indicate whether child's development appears to be on schedule according to these categories: Below=Total analysis score (TAS) is below cutoff. Further assessment with professional may be needed; Monitor=TAS is close to cutoff. Provide learning activities and monitor; Above= TAS is above cutoff, and child's development appears to be on schedule. Shift from baseline for each developmental area of assessment according to these 3 outcome categories was reported. Total score was not applicable.	From Baseline to Week 52
Change From Baseline in Body Weight	Change from baseline to Week 52 in body weight was reported.	Baseline, Week 52
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A TEAE was defined as any AE that started or worsened in intensity on or after the date of the first administration of study drug.	From first dose of study drug up to Week 56
Number of Participants With TEAEs Graded by Severity	A TEAE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A TEAE was defined as any AE that started or worsened in intensity on or after the date of the first administration of study drug. TEAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) criteria. Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe; Grade 4- Life Threatening; Grade 5- Death related to AE.	From first dose of study drug up to Week 56

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2022
• Primary Completion (Actual): September 18, 2023
• Study Completion (Actual): November 8, 2024

Study Registration Dates

• First Submitted: March 29, 2021
• First Submitted That Met QC Criteria: July 7, 2021
• First Posted (Actual): July 19, 2021

Study Record Updates

• Last Update Posted (Estimated): November 27, 2024
• Last Update Submitted That Met QC Criteria: November 11, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Obesity; Pediatric Obesity; Bardet Biedl Syndrome; POMC Deficiency; PCSK1; LEPR
• Additional Relevant MeSH Terms: Ciliopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Overnutrition; Body Weight; Eye Diseases; Eye Diseases, Hereditary; Congenital Abnormalities; Abnormalities, Multiple; Overweight; Hypothalamic Diseases; Retinitis Pigmentosa; Obesity; Bardet-Biedl Syndrome; Laurence-Moon Syndrome
• Other Study ID Numbers: RM-493-033

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