EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R Pathway

February 6, 2026 updated by: Rhythm Pharmaceuticals, Inc.

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial: Multiple Independent Sub-studies of Setmelanotide in Patients With POMC/PCSK1, LEPR, NCOA1(SRC1), or SH2B1 Gene Variants in the Melanocortin-4 Receptor Pathway

The protocol describes a randomized, double-blind, placebo-controlled trial with independent sub-studies of setmelanotide in patients with obesity and at least one of the specific gene variants in the Melanocortin-4 Receptor pathway:

  • POMC or PCSK1 (Sub-study 035a)
  • LEPR (Sub-study 035b)
  • SRC1 (Sub-study 035c)
  • SH2B1 (Sub-study 035d)

The objectives and endpoints are identical for these sub-studies.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

296

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T6G 2E1
        • University of Alberta - Alberta Diabetes Institute (ADI)
  • France
      • Lyon, France, 69677
        • GH Est Hopital Femme Mere Enfant
      • Paris, France, 75651
        • Hu Pitie Salpetriere Aphp
      • Paris, France, 75771
        • Hôpital Armand Trousseau
      • Pessac, France, 33604
        • Centre Hospitalier Universitaire (CHU) de Bordeaux
      • Saint-Denis, France, 97400
        • Hôpital Félix Guyon Bellepierre
  • Germany
      • Berlin, Germany, 10117
        • Charité - Universitätsmedizin Berlin
      • Frankfurt, Germany, 60596
        • Endokrinologikum Frankfurt
      • Leipzig, Germany, 04103
        • Universitaetsklinikum Leipzig
      • Ulm, Germany, 89075
        • Universitaetsklinikum Ulm
  • Greece
      • Rio, Greece, 26504
        • University of Patras School of Medicine
  • Israel
      • Petah Tikva, Israel, 49372
        • Hasharon Hospital
      • Ramat Gan, Israel, 52621
        • Chaim Sheba MC, Safra Children's Hospital
  • Netherlands
      • Rotterdam, Netherlands, 3015 GD
        • Erasmus Medisch Centrum
  • Puerto Rico
      • San Juan, Puerto Rico, 00925-253
        • University of Puerto Rico
  • Spain
      • Barcelona, Spain, 08950
        • Hospital Sant Joan de Deu, Barcelona
      • Madrid, Spain, 28040
        • Hospital Fundación Jiménez Díaz
      • Málaga, Spain, 29010
        • Hospital Universitario Virgen de la Victoria de Málaga
      • Valencia, Spain, 46014
        • Hospital General de Valencia
  • United Kingdom
      • Bristol, United Kingdom, BS2 8AE
        • Bristol Royal Hospital for Children
      • Cambridge, United Kingdom, CB2 0QQ
        • University of Cambridge
      • Liverpool, United Kingdom, L9 7AL
        • Aintree University Hospital
      • London, United Kingdom, NW1 2PG
        • London Medical - The London Diabetes Centre
      • London, United Kingdom, WC1E6JF
        • University College London Hospitals NHS Foundation Trust
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85016
        • Phoenix Children's Hospital
      • Scottsdale, Arizona, United States, 85258
        • HonorHealth Bariatric Center
    • California
      • Los Angeles, California, United States, 90027
        • Children's Hospital Los Angeles
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Children's Hospital Colorado
    • Connecticut
      • New Haven, Connecticut, United States, 06519
        • Yale Center for Clinical Investigation
    • Florida
      • Altamonte Springs, Florida, United States, 32701
        • Advent Health
    • Georgia
      • Suwanee, Georgia, United States, 30024
        • InQuest Medical Research
    • Massachusetts
      • Worcester, Massachusetts, United States, 01655
        • UMass Memorial Medical Center
    • Michigan
      • Ann Arbor, Michigan, United States, 48105
        • University of Michigan
      • Dearborn, Michigan, United States, 48126-2619
        • Metro Detroit Endocrinology Center
    • Minnesota
      • Rochester, Minnesota, United States, 55902
        • Mayo Clinic
    • Missouri
      • Chesterfield, Missouri, United States, 63017
        • St. Luke's Hospital
      • St Louis, Missouri, United States, 63130
        • Washington University in St. Louis
    • New York
      • Buffalo, New York, United States, 14260
        • University of Buffalo
      • New York, New York, United States, 10032
        • Columbia University
      • New York, New York, United States, 10029
        • Mount Sinai Hospital
      • New York, New York, United States, 10029
        • Metropolitan Hospital Center
      • Staten Island, New York, United States, 10306
        • Ten's Medical Center - Pediatric Endocrinology Clinic
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Cincinnati Children's Hospital Medical Center
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health & Science University
    • Pennsylvania
      • Danville, Pennsylvania, United States, 17822
        • Geisinger Clinic
      • Philadelphia, Pennsylvania, United States, 19104
        • Children's Hospital of Philadelphia
      • Pittsburgh, Pennsylvania, United States, 15213
        • UPMC Montefiore
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University School of Medicine
    • Texas
      • Amarillo, Texas, United States, 79106
        • Texas Tech
      • Houston, Texas, United States, 77030
        • Texas Children's Hospital
      • Houston, Texas, United States, 77084
        • Biopharma Informatic
      • McAllen, Texas, United States, 78503
        • Rio Grande Valley Endocrine Center
      • Plano, Texas, United States, 75093
        • Endocrine Associates of Dallas and Plano
    • Washington
      • Tacoma, Washington, United States, 98405
        • MultiCare Health System Institute for Research and Innovation
    • West Virginia
      • Morgantown, West Virginia, United States, 26506
        • West Virginia University
    • Wisconsin
      • Marshfield, Wisconsin, United States, 54449
        • Marshfield Clinic Research Foundation, a Division of Marshfield Clinic, Inc

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients must have a pre-identified:

    • Heterozygous genetic variant in the POMC gene or PCSK1 gene
    • Heterozygous genetic variant in the LEPR gene
    • Homozygous, heterozygous, or compound heterozygous variant in the NCOA1 (SRC1)
    • Homozygous, heterozygous, or compound heterozygous variant in SH2B1 gene, or chromosomal 16p11.2 deletion encompassing the SH2B1 gene
  • Between 6 and 65 years of age at the time of provision of informed consent/assent
  • Obesity, defined as BMI ≥30 kg/m2 for patients ≥18 years of age or BMI ≥95th percentile for age and gender for patients 6 up to 17 years of age
  • Patient 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
  • Patient and/or parent or guardian reports that patient experienced childhood obesity, defined as the patient and/or parent or guardian reporting that the patient was significantly overweight during childhood
  • Agree to use a highly effective form of contraception throughout the study and for 90 days following the study
  • Reported history of lifestyle intervention of diet and exercise
  • Reported history of hyperphagia

Key Exclusion Criteria:

  • Weight loss of 2% or greater in the previous 3 months
  • Recent history of bariatric surgery
  • Significant psychiatric disorder(s)
  • Suicidal ideation, attempt or behavior
  • Clinically significant pulmonary, cardiac, endocrine/metabolic, hepatic or oncologic disease
  • Glycated hemoglobin (HbA1C) >10% at Screening
  • History of significant liver disease or severe kidney disease
  • History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism
  • Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion)
  • Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing
  • Previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide
  • Significant hypersensitivity to any excipient in the study drug
  • If female, pregnant or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: POMC or PCSK1 variant
1:1 Randomization
Drug: Placebo
Subcutaneous Injection
Drug: Setmelanotide
Subcutaneous Injection
Experimental: LEPR variant
1:1 Randomization
Drug: Placebo
Subcutaneous Injection
Drug: Setmelanotide
Subcutaneous Injection
Experimental: NCOA1 (SRC1) variant
1:1 Randomization
Drug: Placebo
Subcutaneous Injection
Drug: Setmelanotide
Subcutaneous Injection
Experimental: SH2B1 variant
1:1 Randomization
Drug: Placebo
Subcutaneous Injection
Drug: Setmelanotide
Subcutaneous Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Difference in mean change in body weight in patients treated with setmelanotide compared to placebo, assessed as percent change in BMI
Time Frame: Baseline to 52 weeks
Baseline to 52 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
The proportion of patients who achieve at least 5% reduction in BMI in patients treated with setmelanotide compared to placebo
Time Frame: Baseline to 52 weeks
Baseline to 52 weeks
The difference in mean change in body weight in adult patients treated with setmelanotide compared to placebo, assessed as percent change in baseline body weight
Time Frame: Baseline to 52 weeks
Baseline to 52 weeks
The difference in mean percent change in the weekly average most hunger score in patients treated with setmelanotide compared to placebo
Time Frame: Baseline to 52 weeks
Baseline to 52 weeks
The proportion of patients who achieve at least 10% reduction in BMI in patients treated with setmelanotide compared to placebo
Time Frame: Baseline to 52 weeks
Baseline to 52 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rhythm Pharmaceuticals, Inc.

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 10, 2021

Primary Completion (Actual)

December 22, 2025

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

September 30, 2021

First Submitted That Met QC Criteria

October 13, 2021

First Posted (Actual)

October 26, 2021

Study Record Updates

Last Update Posted (Actual)

February 10, 2026

Last Update Submitted That Met QC Criteria

February 6, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RM-493-035

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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