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

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

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

Study Overview

• Status: Completed
• Conditions: Bardet-Biedl Syndrome; POMC Deficiency
• Intervention / Treatment: Drug: Setmelanotide 20mg weekly; Drug: Setmelanotide 30mg weekly; Drug: Setmelanotide 2mg daily; Drug: Setmelanotide 3mg daily; Drug: Placebo daily; Drug: Placebo weekly

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2E1
      • Alberta Health Services
• Germany
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum
• Netherlands
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus MC
• Puerto Rico
  • Rio Piedras, Puerto Rico, 00935
    • UPR Medical Sciences Campus
• United Kingdom
  • Cambridge, United Kingdom, CA2 0QQ
    • Addenbrooke's Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Honor Health Research Institute
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Setmelanotide subcutaneous injection Weekly 20 mg; 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; 1:1 randomization in the double blind period, followed by open label
Experimental: Setmelanotide subcutaneous injection Weekly 30 mg; 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; 1:1 randomization in the double blind period, followed by open label
Experimental: Setmelanotide subcutaneous injection Daily 2 mg; 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; 1:1 randomization in the double blind period
Experimental: Setmelanotide subcutaneous injection Daily 3 mg; 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; 1:1 randomization in the double blind period
Placebo Comparator: Placebo subcutaneous injection Daily; 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; 1:1 randomization in the double blind period
Placebo Comparator: Placebo subcutaneous injection Weekly; 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; 1:1 randomization in the double blind period

What is the study measuring?

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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2021
• Primary Completion (Actual): October 19, 2023
• Study Completion (Actual): October 19, 2023

Study Registration Dates

• First Submitted: July 27, 2021
• First Submitted That Met QC Criteria: January 3, 2022
• First Posted (Actual): January 18, 2022

Study Record Updates

• Last Update Posted (Actual): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Hyperphagia; Hunger; Melanocortin-4 Receptor Pathway; Genetic Obesity
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Hypothalamic Diseases; Eye Diseases, Hereditary; Abnormalities, Multiple; Ciliopathies; Retinitis Pigmentosa; Bardet-Biedl Syndrome; Laurence-Moon Syndrome; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; alpha-MSH
• Other Study ID Numbers: RM-493-037

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No