Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants 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 participants with genetic defects in the melanocortin-4 receptor pathway.

Study Overview

• Status: Completed
• Conditions: Bardet-Biedl Syndrome; POMC Deficiency
• Intervention / Treatment: Drug: Setmelanotide 2 mg; Drug: Setmelanotide 2.5 mg; Drug: Setmelanotide 3 mg; Drug: Setmelanotide 20 mg; Drug: Setmelanotide 25 mg; Drug: Setmelanotide 30 mg

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 19
• 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 (NCT03013543) study with acceptable safety and tolerability, and dose level.
• Participant 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:

• Glycosylated hemoglobin (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 milliliter per minute (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

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Run-in Period: Setmelanotide 2 mg QD; Participants received subcutaneous (SC) injection of 2 mg setmelanotide once daily (QD) for 1 week in the run-in period.	Drug: Setmelanotide 2 mg; Administered as SC injection
Experimental: Run-in Period: Setmelanotide 2.5 mg QD; Participants received SC injection of 2.5 mg setmelanotide QD for 1 week in the run-in period.	Drug: Setmelanotide 2.5 mg; Administered as SC injection
Experimental: Run-in Period: Setmelanotide 3 mg QD; Participants received SC injection of 3 mg setmelanotide QD for 1 week in the run-in period.	Drug: Setmelanotide 3 mg; Administered as SC injection
Experimental: DB Period: Setmelanotide 20 mg QW; Participants who received 2 mg setmelanotide QD in the run-in period, received SC injection of 20 mg setmelanotide once weekly (QW) and placebo matched to setmelanotide QD for 13 weeks in the DB period.	Drug: Setmelanotide 20 mg; Administered as SC injection
Experimental: DB Period: Setmelanotide 25 mg QW; Participants who received 2.5 mg setmelanotide QD in the run-in period, received SC injection of 25 mg setmelanotide QW and placebo matched to setmelanotide QD for 13 weeks in the DB period.	Drug: Setmelanotide 25 mg; Administered as SC injection
Experimental: DB Period: Setmelanotide 3 mg QD; Participants who received 3 mg setmelanotide QD in the run-in period, received SC injection of 3 mg setmelanotide QD and placebo matched to setmelanotide QW for 13 weeks in the DB period.	Drug: Setmelanotide 3 mg; Administered as SC injection
Experimental: DB Period: Setmelanotide 30 mg QW; Participants who received 3 mg setmelanotide QD in the run-in period, received SC injection of 30 mg setmelanotide QW and placebo matched to setmelanotide QD for 13 weeks in the DB period.	Drug: Setmelanotide 30 mg; Administered as SC injection
Experimental: OL Period: Setmelanotide 20 mg QW; Participants who received 2 mg setmelanotide QD in the run-in period and 20 mg setmelanotide QW in the DB period, received SC injection of 20 mg setmelanotide QW for 13 weeks in the OL period.	Drug: Setmelanotide 20 mg; Administered as SC injection
Experimental: OL Period: Setmelanotide 25 mg QW; Participants who received 2.5 mg setmelanotide QD in the run-in period and 25 mg setmelanotide QW in the DB period, received SC injection of 25 mg setmelanotide QW for 13 weeks in the OL period.	Drug: Setmelanotide 25 mg; Administered as SC injection
Experimental: OL Period: Setmelanotide 30 mg QW; Participants who received 3 setmelanotide QD in the run-in period and 3 mg setmelanotide QD or 30 mg setmelanotide QW in the DB period, received SC injection of 30 mg setmelanotide QW for 13 weeks in the OL period.	Drug: Setmelanotide 30 mg; Administered as SC injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Drug Concentration (Cmax) of Setmelanotide After QD Administration in the Run-in Period	Maximum drug concentration determined directly from individual concentration-time data.	Pre-dose (0 hour) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose at Week -1
Cmax of Setmelanotide After QW Administration	Maximum drug concentration determined directly from individual concentration-time data. Data are reported by dose level (treatment regimen) in the OL Period and dosing sequence (QD-QD-QW or QD-QW-QW).	Pre-dose (0 hour) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours postdose at Week 14
Time to Maximum Plasma Concentration (Tmax) of Setmelanotide After QD Administration in the Run-in Period	Maximum drug concentration determined directly from individual concentration-time data.	Pre-dose (0 hour) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose at Week -1
Tmax of Setmelanotide After QW Administration	Maximum drug concentration determined directly from individual concentration-time data. Data are reported by dose level (treatment regimen) in the OL Period and dosing sequence (QD-QD-QW or QD-QW-QW).	Pre-dose (0 hour) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours postdose at Week 14
Mean Trough Plasma Concentration (Ctrough) of Setmelanotide After QD or QW Administration at Week 1	Ctrough is concentration at the end of the dosing interval, prior to subsequent dose administration. Data are reported by dose level (treatment regimen) in the DB Period and dosing sequence (QD-QD-QW or QD-QW-QW).	30 minutes predose at Week 1
Mean Setmelanotide Ctrough After QD or QW Administration at Week 5	Ctrough is concentration at the end of the dosing interval, prior to subsequent dose administration. Data are reported by dose level (treatment regimen) in the DB Period and dosing sequence (QD-QD-QW or QD-QW-QW).	30 minutes predose at Week 5
Mean Setmelanotide Ctrough After QD or QW Administration at Week 9	Ctrough is concentration at the end of the dosing interval, prior to subsequent dose administration. Data are reported by dose level (treatment regimen) in the DB Period and dosing sequence (QD-QD-QW or QD-QW-QW).	30 minutes predose at Week 9
Mean Setmelanotide Ctrough After QD or QW Administration at Week 18	Ctrough is concentration at the end of the dosing interval, prior to subsequent dose administration. Data are reported by dose level (treatment regimen) in the DB Period and dosing sequence (QD-QD-QW or QD-QW-QW).	30 minutes predose at Week 18
Mean Setmelanotide Ctrough After QD or QW Administration at Week 22	Ctrough is concentration at the end of the dosing interval, prior to subsequent dose administration. Data are reported by dose level (treatment regimen) in the DB Period and dosing sequence (QD-QD-QW or QD-QW-QW).	30 minutes predose at Week 22
Mean Setmelanotide Ctrough After QD or QW Administration at Week 27	Ctrough is concentration at the end of the dosing interval, prior to subsequent dose administration. Data are reported by dose level (treatment regimen) in the DB Period and dosing sequence (QD-QD-QW or QD-QW-QW).	30 minutes predose at Week 27
Area Under the Plasma Concentration-Time Curve Over the Dosing Interval (AUC0-tau) of Setmelanotide After QD Administration in the Run-in Period	AUC0-tau was recorded from collected blood samples.	Pre-dose (0 hour) and at 0.5, 1, 2, 3, 4, 6, and 8 hours postdose at Week -1
AUC0-tau of Setmelanotide After QD Administration in the Run-in Period	AUC0-tau was recorded from collected blood samples. Data are reported by dose level (treatment regimen) in the OL Period and dosing sequence (QD-QD-QW or QD-QW-QW).	Pre-dose (0 hour) and 0.5, 1, 2, 6, 8, 12, 24, 48, 72, 96, 120, and 168-hours postdose at Week 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence in a participant or clinical trial participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. The AEs reported after the start of the run-in period were considered TEAEs.	From first dose of study drug administration up to Week 30
Number of Participants With Injection Site Reactions (ISRs) From Baseline Through Week 13	The injection site evaluation included the identification of areas of erythema, edema, and induration, as well as the presence of localized pain, tenderness, and itching. Baseline was defined as the last available measurement prior to the first dose of setmelanotide or placebo. Injection site reactions frequency of once daily (QD) and once weekly (QW) were reported. Data are reported by dose level (treatment regimen) in the DB Period. Number of participants with injection site reactions according to severity were reported.	Baseline through Week 13
Number of Participants With ISRs From Week 14 Through Week 27	The injection site evaluation included the identification of areas of erythema, edema, and induration, as well as the presence of localized pain, tenderness, and itching. Injection site reactions frequency of QD and QW were reported. Data are reported by dose level (treatment regimen) in the OL Period. Number of participants with injection site reactions according to severity were reported.	Week 14 through Week 27

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 (Estimated): November 26, 2024
• Last Update Submitted That Met QC Criteria: November 15, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Hyperphagia; Hunger; Melanocortin-4 Receptor Pathway; Genetic Obesity
• Additional Relevant MeSH Terms: Ciliopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Eye Diseases; Eye Diseases, Hereditary; Congenital Abnormalities; Abnormalities, Multiple; Hypothalamic Diseases; 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