Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Patients With Specific Gene Defects in the MC4R Pathway

Study Overview
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Brief Summary
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A trial to compare the weekly and daily formulations of setmelanotide in patients with genetic defects in the melanocortin-4 receptor pathway.

Detailed Description
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This study is designed to compare the safety, pharmacokinetics, and efficacy of weekly and daily formulations of setmelanotide in patients with obesity associated with biallelic or heterozygous POMC (pro-opiomelanocortin), PCSK1 (proprotein convertase subtilisin/kexin Type 1), LEPR (leptin receptor) genetic variants, and patients with Bardet-Biedl Syndrome (BBS).

Official Title
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A Phase 3, Randomized, Double-Blind Trial of Two Formulations of Setmelanotide (Daily and Weekly) With a Crossover to Open-Label Once Weekly Setmelanotide in Patients With Specific Gene Defects in the Melanocortin-4 Receptor Pathway Who Are Currently on a Stable Dose of the Once Daily Formulation

Conditions
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Bardet-Biedl Syndrome, POMC Deficiency

Intervention / Treatment
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* Drug: Setmelanotide 20mg weekly
* Drug: Placebo daily
* Drug: Setmelanotide 30mg weekly
* Drug: Setmelanotide 2mg daily
* Drug: Setmelanotide 3mg daily
* Drug: Placebo weekly


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Biallelic or heterozygous POMC/PCSK1 or LEPR (PPL) genetic variants or Bardet-Biedl syndrome (BBS), for which they are being treated with QD setmelanotide. 6 years or older at screening. Taking the setmelanotide QD formulation for at least 6 months in the RM-493-022 study with acceptable safety and tolerability, and dose level. Patient and/or parent or guardian is able to communicate well with the Investigator, to understand and comply with the requirements of the study and is able to understand and sign the written informed consent/assent. Use of a highly effective form of contraception throughout the study and for 90 days following the study. Key Exclusion Criteria: HbA1C >9.0% at screening. Anti-obesity medications within 3 months prior to starting the Run-in Period. History of significant liver disease or liver injury. Glomerular filtration rate <30 mL/min. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions. Major psychiatric disorders. Any suicidal ideation or behavior, or any lifetime history of a suicide attempt. Significant hypersensitivity to any excipient in the study drug. Inability to comply with the QW and QD injection regimens. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing, with the exception of a setmelanotide clinical trial. Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 6 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Setmelanotide subcutaneous injection Weekly 20 mg<br>Patients on 2mg setmelanotide daily will be randomized 1:1 to receive setmelanotide either QD or QW during the double blind period, and all will be assigned to this arm in the open label period. | Drug: Setmelanotide 20mg weekly<br>* 1:1 randomization in the double blind period, followed by open label<br>|
| Experimental: Setmelanotide subcutaneous injection Weekly 30 mg<br>Patients on 3mg setmelanotide daily will be randomized 1:1 to receive setmelanotide either QD or QW during the double blind period, and all will be assigned to this arm in the open label period. | Drug: Setmelanotide 30mg weekly<br>* 1:1 randomization in the double blind period, followed by open label<br>|
| Experimental: Setmelanotide subcutaneous injection Daily 2 mg<br>Patients on 2mg setmelanotide daily will be randomized 1:1 to receive setmelanotide either QD or QW during the double blind period. | Drug: Setmelanotide 2mg daily<br>* 1:1 randomization in the double blind period<br>|
| Experimental: Setmelanotide subcutaneous injection Daily 3 mg<br>Patients on 3mg setmelanotide daily will be randomized 1:1 to receive setmelanotide either QD or QW during the double blind period. | Drug: Setmelanotide 3mg daily<br>* 1:1 randomization in the double blind period<br>|
| Placebo Comparator: Placebo subcutaneous injection Daily<br>Patients will be randomized 1:1 to receive either QD or QW placebo during the double blind period (and setmelanotide in the other formulation). | Drug: Placebo daily<br>* 1:1 randomization in the double blind period<br>|
| Placebo Comparator: Placebo subcutaneous injection Weekly<br>Patients will be randomized 1:1 to receive either QD or QW placebo during the double blind period (and setmelanotide in the other formulation). | Drug: Placebo weekly<br>* 1:1 randomization in the double blind period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) | Comparison of steady-state PK parameter (Cmax) between weekly and daily formulations | 27 weeks | 
| Time to maximum plasma concentration (Tmax) | Comparison of steady-state PK parameter (Tmax) between weekly and daily formulations | 27 weeks | 
| Trough plasma concentration (Ctrough) | Comparison of steady-state PK parameter (Ctrough) between weekly and daily formulations | 27 weeks | 
| Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) | Comparison of steady-state PK parameter (AUC0-tau) between weekly and daily formulations | 27 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events and serious adverse events | Number of adverse events and serious adverse events throughout the trial | 27 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