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

NCT04963231 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: RM-493-034
• Study Type: interventional
• Target: 164
• Locations: 8 countries
• Sites: 36

Brief Summary

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.

Conditions

Genetic Obesity

Keywords

Melanocortin-4 Receptor; Genetic Obesity; Leptin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype

  Baseline, Week 16

• Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype

  Baseline, Week 16

• Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype

  Baseline, Week 16

• Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype

  Baseline, Week 16

• Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype

  Baseline, Week 16

Study Arms (3)

Stage 1: Setmelanotide (Open-Label)

EXPERIMENTAL

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

Stage 2: Setmelanotide (Double-Blind)

EXPERIMENTAL

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

Stage 2: Placebo (Double-Blind)

PLACEBO COMPARATOR

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

Interventions

Setmelanotide DRUG

SC injection

Stage 1: Setmelanotide (Open-Label); Stage 2: Setmelanotide (Double-Blind)

Placebo DRUG

SC injection

Stage 2: Placebo (Double-Blind)

Eligibility Criteria

• Age: 6 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Rhythm Pharmaceuticals, Inc.: lead

Study Sites (36)

HonorHealth Bariatric Center

Scottsdale, Arizona, 85258, United States

Location

InQuest Medical Reseacrh

Suwanee, Georgia, 30071, United States

Location

UMass Memorial Medical Center

Worcester, Massachusetts, 01655, United States

Location

University of Michigan

Ann Arbor, Michigan, 48105, United States

Location

Metro Detroit Endocrinology Center

Dearborn, Michigan, 48126, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Mississippi Center for Advanced Medicine

Madison, Mississippi, 39110, United States

Location

Mount Sinai

New York, New York, 10029, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Ten's Medical Center - Pediatric Endocrinology Clinic

Staten Island, New York, 10308, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27517, United States

Location

Geisinger Clinic

Danville, Pennsylvania, 17822, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Texas Tech

Amarillo, Texas, 79106, United States

Location

Endocrine Associates of Dallas and Plano

Dallas, Texas, 75231, United States

Location

Hector Granados PA

El Paso, Texas, 79907, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Accurate Clinical Research

Houston, Texas, 77065, United States

Location

Rio Grande Valley Endocrine Center

McAllen, Texas, 78503, United States

Location

Clinical Trials of Texas

San Antonio, Texas, 78229, United States

Location

Javara Research

The Woodlands, Texas, 77382, United States

Location

University of Alberta

Edmonton, Alberta, T6G 2E1, Canada

Location

Charite - Universitatsmedizin Berlin

Berlin, Germany

Location

Universitaetsklinikum Leipzig

Leipzig, 04103, Germany

Location

Universitaetsklinikum Ulm

Ulm, 89075, Germany

Location

University of Patras School of Medicine

Pátrai, Greece

Location

Chaim Sheba MC, Safra Children's Hospital

Ramat Gan, 5265602, Israel

Location

Erasmus Medisch Centrum

Rotterdam, 3015 GD, Netherlands

Location

Hospital Sant Joan de Deu

Barcelona, 08950, Spain

Location

Hospital Infantil Universitario Nino Jesus

Madrid, 28009, Spain

Location

Hospital Fundación Jimenez Díaz

Madrid, 28040, Spain

Location

Hospital General de Valencia

Valencia, 46014, Spain

Location

Bristol Royal Hospital for Children

Bristol, United Kingdom

Location

University of Cambridge

Cambridge, United Kingdom

Location

London Medical - The London Diabetes Centre

London, NW1 2PG, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, WC1E 6JF, United Kingdom

Location

Related Publications (2)

• Trapp CM, Censani M. Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity. Curr Opin Endocrinol Diabetes Obes. 2023 Apr 1;30(2):136-140. doi: 10.1097/MED.0000000000000798. Epub 2023 Feb 1.

  PMID: 36722447 DERIVED

• 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.

  PMID: 35797460 DERIVED

MeSH Terms

Interventions

setmelanotide

Results Point of Contact

• Title: Rhythm Pharmaceuticals, Inc.
• Organization: Rhythm Clinical Trials

clinicaltrials@rhythmtx.com

857-264-4280

Study Officials

• David Meeker, MD

  Rhythm Pharmaceuticals, Inc.

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Stage 1 of the trial is open-label. Participants who were eligible to enter Stage 2 of the trial were randomized in a blinded manner at the Stage 2 Entry Visit in a 2:1 ratio to receive either setmelanotide or placebo.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2021
• First Posted: July 15, 2021
• Study Start: November 30, 2021
• Primary Completion: August 4, 2023
• Study Completion: September 30, 2024
• Last Updated: July 2, 2025
• Results First Posted: October 24, 2024

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (21); DE (3); GR (1); ES (4); CA (1); IL (1); NL (1); GB (4)