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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Obesity, Genetic Obesity

Intervention / Treatment
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* Drug: Setmelanotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanocortin-4 Receptor Pathway, Genetic Obesity, Hunger, Hyperphagia, POMC, PCSK1, LEPR, SH2B1, NCOA1 (SRC1)