DAYBREAK: 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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A 2-stage (open-label run-in, followed by randomized, double-blind, placebo-controlled withdrawal) trial of setmelanotide in patients with obesity and specific gene defects variants in the melanocortin-4 receptor (MC4R) pathway.

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

Conditions
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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 genetic variant in an established MC4R pathway gene that contributes to obesity Age 6 to 65 years, inclusive Obesity, defined as BMI ≥40 kg/m2 for patients≥18 years of age or BMI ≥97th percentile for age and gender for patients 6 up to 17 years of age Study participant and/or parent or guardian is able to understand all study procedures and provide consent/assent Use of highly effective contraception Symptoms or behaviors of hyperphagia Exclusion Criteria: Patients with the following genetic variants: biallelic Bardet-Biedl Syndrome (BBS); biallelic Alström Syndrome 1 (ALMS1); homozygous, heterozygous, or compound heterozygous variants in MC4R, POMC, PCSK1, 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 include the SH2B1 gene Recent intensive diet and/or exercise regimen with or without the use of weight loss agents including herbal medications that has resulted in weight loss >2% within previous 3 months Bariatric surgery within the previous 6 months. Documented diagnosis of schizophrenia, bipolar disorder, personality disorder, major depressive disorder, or other psychiatric disorder(s) 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 patient'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 HbA1C >10.0% at Screening History of significant liver disease Glomerular filtration rate (GFR) <30 mL/min at Screening History or close family history of melanoma or patient 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 Patients 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 are breastfeeding or nursing

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: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Setmelanotide<br>Patients with specific gene variants in the MC4R pathway on setmelanotide | Drug: Setmelanotide<br>* Subcutaneous injection<br>|
| Placebo Comparator: Placebo<br>Patients with specific gene variants in the MC4R pathway on placebo | Drug: Placebo<br>* Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients by genotype who achieve MC4R pathway who achieve a ≥5% reduction in BMI | To evaluate the proportion of patients with obesity and genetic variants in the MC4R pathway who achieve a clinically meaningful reduction in body weight in response to setmelanotide | Baseline to End of Stage 1 (16 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change and percent change in BMI in all patients and patients ≥18 years old, per gene | To evaluate change in weight parameters in response to setmelanotide in patients with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment | Baseline to End of Stage 1 (16 weeks) | 
| Mean change and percent change in body weight in patients ≥18 years old, per gene | To evaluate change in weight parameters in response to setmelanotide in patients with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment | Baseline to End of Stage 1 (16 weeks) | 
| Mean change in BMI Z-score in patients <18 years old, per gene | To evaluate change in weight parameters in patients less than 18 years of age in response to setmelanotide in patients with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment | Baseline to End of Stage 1 (16 weeks) | 
| Mean percent change in the weekly average of the daily maximal hunger score in patients ≥12 years old, per gene | To evaluate change in hunger in response to setmelanotide in patients ≥12 years old with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment | Baseline to End of Stage 1 (16 weeks) | 
| The proportion of patients ≥12 years old, per gene, who achieve a ≥2 point reduction in the weekly average of the daily maximal hunger score | The proportion of patients ≥12 years old, per gene, who achieve a ≥2 point reduction (improvement) in the weekly average of the daily maximal hunger score | Baseline to End of Stage 1 (16 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanocortin-4 Receptor, Genetic Obesity, Leptin