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

NCT05093634 | Active Not Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: RM-493-035
• Study Type: interventional
• Target: 296
• Locations: 10 countries
• Sites: 56

Brief Summary

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.

Conditions

Obesity; Genetic Obesity

Keywords

Melanocortin-4 Receptor Pathway; Genetic Obesity; Hunger; Hyperphagia; POMC; PCSK1; LEPR; SH2B1; NCOA1 (SRC1)

Outcome Measures

Primary Outcomes (1)

• Difference in mean change in body weight in patients treated with setmelanotide compared to placebo, assessed as percent change in BMI

  Baseline to 52 weeks

Secondary Outcomes (4)

• The proportion of patients who achieve at least 5% reduction in BMI in patients treated with setmelanotide compared to placebo

  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

  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

  Baseline to 52 weeks

• The proportion of patients who achieve at least 10% reduction in BMI in patients treated with setmelanotide compared to placebo

  Baseline to 52 weeks

Study Arms (4)

POMC or PCSK1 variant

EXPERIMENTAL

1:1 Randomization

Drug: Setmelanotide; Drug: Placebo

LEPR variant

EXPERIMENTAL

1:1 Randomization

Drug: Setmelanotide; Drug: Placebo

NCOA1 (SRC1) variant

EXPERIMENTAL

1:1 Randomization

Drug: Setmelanotide; Drug: Placebo

SH2B1 variant

EXPERIMENTAL

1:1 Randomization

Drug: Setmelanotide; Drug: Placebo

Interventions

Setmelanotide DRUG

Subcutaneous Injection

LEPR variant; NCOA1 (SRC1) variant; POMC or PCSK1 variant; SH2B1 variant

Placebo DRUG

Subcutaneous Injection

LEPR variant; NCOA1 (SRC1) variant; POMC or PCSK1 variant; SH2B1 variant

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:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Rhythm Pharmaceuticals, Inc.: lead

Study Sites (56)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

HonorHealth Bariatric Center

Scottsdale, Arizona, 85258, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Yale Center for Clinical Investigation

New Haven, Connecticut, 06519, United States

Location

Advent Health

Altamonte Springs, Florida, 32701, United States

Location

InQuest Medical Research

Suwanee, Georgia, 30024, 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, 48126-2619, United States

Location

Mayo Clinic

Rochester, Minnesota, 55902, United States

Location

St. Luke's Hospital

Chesterfield, Missouri, 63017, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63130, United States

Location

University of Buffalo

Buffalo, New York, 14260, United States

Location

Metropolitan Hospital Center

New York, New York, 10029, United States

Location

Mount Sinai Hospital

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, 10306, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Geisinger Clinic

Danville, Pennsylvania, 17822, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

UPMC Montefiore

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt University School of Medicine

Nashville, Tennessee, 37232, United States

Location

Texas Tech

Amarillo, Texas, 79106, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Biopharma Informatic

Houston, Texas, 77084, United States

Location

Rio Grande Valley Endocrine Center

McAllen, Texas, 78503, United States

Location

Endocrine Associates of Dallas and Plano

Plano, Texas, 75093, United States

Location

MultiCare Health System Institute for Research and Innovation

Tacoma, Washington, 98405, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

Marshfield Clinic Research Foundation, a Division of Marshfield Clinic, Inc

Marshfield, Wisconsin, 54449, United States

Location

University of Alberta - Alberta Diabetes Institute (ADI)

Edmonton, Alberta, T6G 2E1, Canada

Location

GH Est Hopital Femme Mere Enfant

Lyon, 69677, France

Location

Hu Pitie Salpetriere Aphp

Paris, 75651, France

Location

Hopital Armand Trousseau

Paris, 75771, France

Location

Centre Hospitalier Universitaire (CHU) de Bordeaux

Pessac, 33604, France

Location

Hôpital Félix Guyon Bellepierre

Saint-Denis, 97400, France

Location

Charite - Universitatsmedizin Berlin

Berlin, 10117, Germany

Location

Endokrinologikum Frankfurt

Frankfurt, 60596, Germany

Location

Universitaetsklinikum Leipzig

Leipzig, 04103, Germany

Location

Universitaetsklinikum Ulm

Ulm, 89075, Germany

Location

University of Patras School of Medicine

Rio, 26504, Greece

Location

Hasharon Hospital

Petah Tikva, 49372, Israel

Location

Chaim Sheba MC, Safra Children's Hospital

Ramat Gan, 52621, Israel

Location

Erasmus Medisch Centrum

Rotterdam, 3015 GD, Netherlands

Location

University of Puerto Rico

San Juan, 00925-253, Puerto Rico

Location

Hospital Sant Joan de Deu, Barcelona

Barcelona, 08950, Spain

Location

Hospital Fundación Jimenez Díaz

Madrid, 28040, Spain

Location

Hospital Universitario Virgen de la Victoria de Málaga

Málaga, 29010, Spain

Location

Hospital General de Valencia

Valencia, 46014, Spain

Location

Bristol Royal Hospital for Children

Bristol, BS2 8AE, United Kingdom

Location

University of Cambridge

Cambridge, CB2 0QQ, United Kingdom

Location

Aintree University Hospital

Liverpool, L9 7AL, United Kingdom

Location

London Medical - The London Diabetes Centre

London, NW1 2PG, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, WC1E6JF, United Kingdom

Location

MeSH Terms

Conditions

Obesity; Hyperphagia

Interventions

setmelanotide

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Digestive

Study Officials

• David Meeker, MD

  Rhythm Pharmaceuticals, Inc.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2021
• First Posted: October 26, 2021
• Study Start: December 10, 2021
• Primary Completion: December 22, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: February 10, 2026

Record last verified: 2026-02

Locations

CA (1); NL (1); FR (5); ES (4); IL (2); US (32); DE (4); GB (5); PR (1); GR (1)