DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway

A 2-Stage (Open-Label Followed by Randomized Double-Blind, Placebo-Controlled Stage), Phase 2 Trial of Setmelanotide in Patients With Specific Gene Variants in the Melanocortin-4 Receptor Pathway

The purpose of this study was to evaluate the safety and efficacy of once daily subcutaneous (SC) administration of setmelanotide in participants with obesity and specific gene variants in the MC4R pathway.

Study Overview

• Status: Completed
• Conditions: Genetic Obesity
• Intervention / Treatment: Drug: Placebo; Drug: Setmelanotide

• Study Type: Interventional
• Enrollment (Actual): 164
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2E1
      • University of Alberta
• Germany
  • Berlin, Germany
    • Charite - Universitatsmedizin Berlin
  • Leipzig, Germany, 04103
    • Universitaetsklinikum Leipzig
  • Ulm, Germany, 89075
    • Universitaetsklinikum Ulm
• Greece
  • Patras, Greece
    • University of Patras School of Medicine
• Israel
  • Ramat Gan, Israel, 5265602
    • Chaim Sheba MC, Safra Children's Hospital
• Netherlands
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus Medisch Centrum
• Spain
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Nino Jesus
  • Madrid, Spain, 28040
    • Hospital Fundacion Jimenez Diaz
  • Valencia, Spain, 46014
    • Hospital General de Valencia
• United Kingdom
  • Bristol, United Kingdom
    • Bristol Royal Hospital for Children
  • Cambridge, United Kingdom
    • University of Cambridge
  • London, United Kingdom, NW1 2PG
    • London Medical - The London Diabetes Centre
  • London, United Kingdom, WC1E 6JF
    • University College London Hospitals NHS Foundation Trust
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • HonorHealth Bariatric Center
  • Georgia
    • Suwanee, Georgia, United States, 30071
      • InQuest Medical Reseacrh
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • UMass Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan
    • Dearborn, Michigan, United States, 48126
      • Metro Detroit Endocrinology Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Madison, Mississippi, United States, 39110
      • Mississippi Center for Advanced Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10029
      • Mount Sinai
    • Staten Island, New York, United States, 10308
      • Ten's Medical Center - Pediatric Endocrinology Clinic
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • University of North Carolina
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Clinic
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech
    • Dallas, Texas, United States, 75231
      • Endocrine Associates of Dallas and Plano
    • El Paso, Texas, United States, 79907
      • Hector Granados PA
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Houston, Texas, United States, 77065
      • Accurate Clinical Research
    • McAllen, Texas, United States, 78503
      • Rio Grande Valley Endocrine Center
    • San Antonio, Texas, United States, 78229
      • Clinical Trials of Texas
    • The Woodlands, Texas, United States, 77382
      • Javara Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Participants must have had a pre-identified genetic variant in an established MC4R pathway gene that contributes to obesity
• Age 6 to 65 years, inclusive
• Obesity, defined as Body Mass Index (BMI) ≥40 kilograms per square meter (kg/m^2) for participants ≥18 years of age or BMI ≥97th percentile for age and gender for participants 6 to <18 years of age
• Study participant and/or parent or guardian were able to understand all study procedures and provide consent/assent
• Use of highly effective contraception
• Symptoms or behaviors of hyperphagia

Key Exclusion Criteria:

• Participants with the following genetic variants: biallelic Bardet-Biedl Syndrome (BBS); biallelic Alström Syndrome 1 (ALMS1); homozygous, heterozygous, or compound heterozygous variants in MC4R, Pro-opiomelanocortin (POMC), Proprotein convertase subtilisin/kexin type 1 (PCSK1), Leptin receptor (LEPR), nuclear receptor coactivator 1 (NCOA1; steroid receptor coactivator-1 [SRC1]) or SRC homology 2 B adapter protein 1 (SH2B1) genes as well as 16p11.2 chromosomal deletions that included the SH2B1 gene
• Recent intensive diet and/or exercise regimen with or without the use of weight loss agents including herbal medications that had resulted in weight loss >2% within previous 3 months
• Bariatric surgery within the previous 6 months
• Documented diagnosis of current unstable major psychiatric disorder or a documented worsening of psychiatric condition that required changes in treatment within 2 years
• Any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) or Patient Health Questionnaire 9 (PHQ 9) score of ≥15 during Screening, any suicide attempt in participant's lifetime years, or any suicidal behavior in the last month.
• Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study
• Has significant features of (or meets the diagnostic criteria for) a genetic syndrome that is associated with obesity
• Glycated hemoglobin (HbA1C) >10.0% at Screening
• History of significant liver disease
• Glomerular filtration rate (GFR) <30 milliliter per 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
• Significant hypersensitivity to any excipient in the study drug
• Females who were breastfeeding or nursing

Other protocol defined Inclusion/Exclusion criteria applied.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stage 1: Setmelanotide (Open-Label); Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 milligrams (mg) once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants <12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.	Drug: Setmelanotide; SC injection
Experimental: Stage 2: Setmelanotide (Double-Blind); Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of setmelanotide 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).	Drug: Setmelanotide; SC injection
Placebo Comparator: Stage 2: Placebo (Double-Blind); Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of matching placebo 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).	Drug: Placebo; SC injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1	BMI was calculated using participant's weight and height assessments, using the following formula: BMI = Kilogram (kg)/ square meter (m^2). A significant clinically meaningful response was defined as achieving a ≥5% reduction in BMI from Baseline. Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.	Baseline to Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype	BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2. Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.	Baseline, Week 16
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype	BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2 Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.	Baseline, Week 16
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype	BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2 Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.	Baseline, Week 16
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype	BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2 Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.	Baseline, Week 16
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype	Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.	Baseline, Week 16
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype	Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.	Baseline, Week 16
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype	BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2. The BMI Z-score indicated the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of a reference population (i.e., healthy, age and sex-matched individuals). A decrease of BMI Z-score indicates a reduction in BMI from Baseline whereas an increase of BMI-Z score indicates an increase in BMI from Baseline. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.	Baseline, Week 16
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype	Daily Hunger Questionnaire for participants ≥12 years of age is self-administered questionnaire and comprises three items. For the assessment of this endpoint, maximal hunger was corresponding to the following question: In the last 24 hours, how hungry did you feel when you were the most hungry? The response was scored separately and averaged on weekly basis. Participants rated their hunger on an 11-point numeric rating scale ranging from 0 to 10 (0 = not hungry at all, and 10 = hungriest possible). Weekly average at Week 16 was defined as average of the available score values within 7 days in Week 16. Baseline was defined as the average of the available score values within 7 days before or on the stage 1 open-label treatment. Results are reported by overall participant results and by specific gene cohort.	Baseline, Week 16
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype	Daily Hunger Questionnaire for participants ≥12 years of age is self-administered questionnaire and comprises three items. For the assessment of this endpoint, maximal hunger was corresponding to the following question: In the last 24 hours, how hungry did you feel when you were the most hungry? The response was scored separately and averaged on weekly basis. Participants rated their hunger on an 11-point numeric rating scale ranging from 0 to 10 (0 = not hungry at all, and 10 = hungriest possible). Weekly average at Week 16 was defined as average of the available score values within 7 days in Week 16. Baseline was defined as the average of the available score values within 7 days before or on the stage 1 open-label treatment. Results are reported by overall participant results and by specific gene cohort.	Baseline, Week 16

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Cuda S, Censani M. Progress in pediatric obesity: new and advanced therapies. Curr Opin Pediatr. 2022 Aug 1;34(4):407-413. doi: 10.1097/MOP.0000000000001150. Epub 2022 Jul 5.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Actual): August 4, 2023
• Study Completion (Actual): September 30, 2024

Study Registration Dates

• First Submitted: June 28, 2021
• First Submitted That Met QC Criteria: July 14, 2021
• First Posted (Actual): July 15, 2021

Study Record Updates

• Last Update Posted (Actual): July 2, 2025
• Last Update Submitted That Met QC Criteria: July 1, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Leptin; Genetic Obesity; Melanocortin-4 Receptor
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity
• Other Study ID Numbers: RM-493-034

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
• product manufactured in and exported from the U.S.: Yes