A Study of RM-718 in Healthy Subjects and Patients With MC4R Pathway Impairment

A Study of RM-718 Weekly Formulation in Healthy Subjects With Obesity and in Patients With Obesity Due to MC4R Impairment

The purpose of this study is to evaluate the safety, tolerability, and PK of RM-718 in healthy subjects with obesity and in patients with MC4R Pathway Impairment

Study Overview

• Status: Recruiting
• Conditions: Prader-Willi Syndrome; Hypothalamic Obesity; PWS
• Intervention / Treatment: Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Drug: Part B: RM-718 or placebo (matched to specific RM-718 dose cohort); Drug: Part C: RM-718; Drug: Part D: RM-718

Detailed Description

This is a first-in-human and first-in-patient, 4-part study that includes the evaluation of safety, tolerability, and PK of: single ascending doses (SAD) of RM-718 weekly (RM-718) in healthy subjects 18 to 55 years of age with obesity (Part A), multiple ascending doses (MAD) of RM-718 in healthy subjects 18 to 55 years of age with obesity (Part B), MAD of RM-718 in patients 12 to 65 years of age with HO (Part C), and MAD of RM-718 in patients with PWS (Part D). Cohorts in Parts A and B are double-blind, placebo-controlled, and randomized 2:1 (4 subjects receive RM-718, 2 subjects receive placebo). Part C evaluates open-label dose escalation in patients 12 to 65 years of age with HO. Part D evaluates open-label dose escalation in patients 12 to 65 years of age. Study participants will receive: 1 weekly dose of either RM-718 or placebo in Part A, 4 weekly doses of either RM-718 or placebo in Part B,16 weekly doses of open-label RM-718 in Part C, and 26 weekly doses of RM-718 in Part D. Study drug (RM-718 or placebo) doses are administered weekly via subcutaneous injection.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Physician Inquiry Clinical Trials; Phone Number: (857) 264-4280; Email: clinicaltrials@rhythmtx.com
• Study Contact Backup: Name: Rhythm Clinical Trials; Phone Number: (857) 264-4280; Email: clinicaltrials@rhythmtx.com

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • UAB Pediatric Endocrinology (Part C and Part D)
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Ann and Robert H. Lurie Children's Hospital of Chicago (Part C and Part D)
  • Massachusetts
    • Boston, Massachusetts, United States, 021115
      • Recruiting
      • Boston Children's Hospital (Part C only)
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital (Part C and Part D)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center (Part C only)
  • Texas
    • San Antonio, Texas, United States, 78217
      • Completed
      • Worldwide Clinical Trials (Part A and Part B)
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • University of Utah Pediatric Endocrine Clinic (Part C and Part D)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Key Inclusion Criteria:

Parts A and B:

• Male and female subjects in good health aged 18-55 years of age at Screening.
• Body mass index (BMI) ≥30 kg/m2.
• Subjects who are medically healthy with normal or clinically insignificant screening results.
• Subjects must use a highly effective form of contraception and follow the study contraception requirements.
• Ability to communicate well with the Investigator, understand and comply with the requirements of the trial, and understand English and sign the written informed consent.

Part C:

• Male and female patients with HO, aged 12-65 years of age at Screening.

• Patient has documented evidence of acquired HO defined as:

  • Diagnosis of craniopharyngioma or other brain lesion affecting the hypothalamic region and has undergone surgery, or chemotherapy, or radiation therapy involving the hypothalamus at least 6 months before Screening, OR
  • Documented injury to the hypothalamus at least 6 months before Screening for which surgery/radiation is not indicated.
• Weight gain associated with the hypothalamic injury either before or following therapy (surgery and/or following chemotherapy or radiotherapy), and a BMI of ≥30 kg/m2 for patients ≥18 years of age or BMI ≥95th percentile for age and sex for patients 12 to <18 years of age.
• Patients must use a highly effective form of contraception and follow the study contraception requirements.
• Ability to communicate with the Investigator, understand and comply with the requirements of the trial, and understand and sign the written informed consent and assent (for patients aged <18 years), and informed consent for a parent or guardian of any patient <18.

Part D:

• Confirmed diagnosis of PWS as determined by the Investigator at the time of Screening.
• Age ≥12 to 65, inclusive, at the time of signing Informed Consent and/or Assent.
• BMI ≥30 kg/m2 for patients ≥18 years of age or BMI ≥95th Percentile for age and sex for patients <18 years of age based on the US CDC criteria.
• Able to meet contraception requirements.

Key Exclusion Criteria:

Parts A and B

• Any clinically significant abnormalities on screening laboratories or physical examination as determined by the Investigator.
• Active or history of any significant medical condition such as and including renal, hepatic, pulmonary, gastrointestinal, cardiovascular, genitourinary, endocrine, immunologic, metabolic, neurologic or hematological disease.
• Obesity due to genetic, syndromic, or endocrine etiologies.
• History of renal transplant, end stage renal disease.
• Diagnosis of severe psychiatric disorders.
• Current, clinically significant pulmonary, cardiac, metabolic, or oncologic disease considered severe enough to interfere with the trial and/or confound the results.
• Cigarette smoking or dependence on caffeine, alcohol or drugs; unable or unwilling to abstain completely from caffeine, alcohol and related substances for 24 hours prior to and after study visits.
• History of recent surgery (within 60 days of Screening).
• Participation in any clinical trial with an investigational drug/device within 3 months or 5 half-lives, whichever is longer, prior to the first trial dose.
• Pregnant and/or breastfeeding or desiring to become pregnant during this trial.

Part C

• Diagnosis of Prader-Willi syndrome (PWS) or Rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, neuroendocrine tumor syndrome (ROHHADNET).
• Weight loss >2% in the previous 3 months for patients aged ≥18 years or >2% reduction in BMI for patients aged 12 to <18 years and/or anti-obesity medications for the treatment of obesity.
• Bariatric surgery or procedure within the last 2 years.
• Diagnosis of severe psychiatric disorders; any suicidal ideation, attempt or behavior.
• Current, clinically significant pulmonary, cardiac, metabolic, or oncologic disease considered severe enough to interfere with the trial and/or confound the results.
• History of renal transplant, end stage renal disease.
• Participation in any clinical trial with an investigational drug/device within 3 months or 5 half-lives, whichever is longer, prior to the first trial dose, or previous participation in a trial with setmelanotide.
• Pregnant and/or breastfeeding or desiring to become pregnant during this trial.
• Obesity attributable to other genetic or syndromic conditions (eg, PPL [pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), leptin receptor (LEPR), collectively], Bardet-Biedl syndrome [BBS]) prior to the hypothalamic injury.

Part D

• Weight loss >2% in the previous 3 months for patients aged ≥18 years or >2% reduction in BMI for patients aged 12 to <18 years or therapies for the treatment of obesity or hyperphagia.
• Metabolic and bariatric surgery (MBS) or procedure within last 6 months.
• Diagnosis of severe psychiatric disorders; any suicidal ideation, attempt or behavior.
• Current, clinically significant pulmonary, cardiac, metabolic, or oncologic disease considered severe enough to interfere with the trial and/or confound the results.
• Pregnant and/or breastfeeding or desiring to become pregnant during this 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: Parallel Assignment
• Masking: Triple

Number of Arms

17

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RM-718 (Cohort A1); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort A2); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort A3); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort A4); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort A5); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort A6); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort B2); Multiple ascending doses of RM-718 (4) or placebo (2)	Drug: Part B: RM-718 or placebo (matched to specific RM-718 dose cohort); Multiple ascending doses of RM-718 or placebo (matched to specific RM-718 Part B dose cohorts)
Experimental: RM-718 (Cohort B3); Multiple ascending doses of RM-718 (4) or placebo (2)	Drug: Part B: RM-718 or placebo (matched to specific RM-718 dose cohort); Multiple ascending doses of RM-718 or placebo (matched to specific RM-718 Part B dose cohorts)
Experimental: RM-718 (Cohort B4); Multiple ascending doses of RM-718 (4) or placebo (2)	Drug: Part B: RM-718 or placebo (matched to specific RM-718 dose cohort); Multiple ascending doses of RM-718 or placebo (matched to specific RM-718 Part B dose cohorts)
Experimental: RM-718 (Cohort B5); Multiple ascending doses of RM-718 (4) or placebo (2)	Drug: Part B: RM-718 or placebo (matched to specific RM-718 dose cohort); Multiple ascending doses of RM-718 or placebo (matched to specific RM-718 Part B dose cohorts)
Experimental: RM-718 (Cohort C1); Multiple ascending doses of RM-718 (30)	Drug: Part C: RM-718; Multiple ascending doses of RM-718
Experimental: RM-718 (Cohort B6); Multiple ascending doses of RM-718 (4) or placebo (2)	Drug: Part B: RM-718 or placebo (matched to specific RM-718 dose cohort); Multiple ascending doses of RM-718 or placebo (matched to specific RM-718 Part B dose cohorts)
Experimental: RM-718 (Cohort A7); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort A8); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort A9); Single dose of RM-718 (4) or placebo (2)	Drug: Part A: RM-718 or placebo (matched to specific RM-718 dose cohort); Single ascending dose of RM-718 or placebo (matched to specific RM-718 Part A dose cohort)
Experimental: RM-718 (Cohort B1); Multiple ascending doses of RM-718 (4) or placebo (2)	Drug: Part B: RM-718 or placebo (matched to specific RM-718 dose cohort); Multiple ascending doses of RM-718 or placebo (matched to specific RM-718 Part B dose cohorts)
Experimental: RM-718 (Cohort D1); Multiple ascending doses of RM-718 (up to 30)	Drug: Part D: RM-718; Multiple ascending doses of RM-718

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Parts A, B, C, D: Safety and Tolerability Assessed by Number of Study Participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	From Day 1 through the Safety-Follow-up call (up to Day 43 for all Part A cohorts, up to Day 70 for all Part B cohorts, up to Day 140 for Part C cohort, up to Day 210 for Part D cohort)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUCtau measurement of RM-718	Area under the concentration versus time curve during a dosing interval	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
Cmax measurement of RM-718	Maximum concentration measurement of RM-718 in plasma	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
Cmin measurement of RM-718	Minimum plasma concentration of RM-718 reached during dosing interval	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
Tmax measurement of RM-718	Time it takes for RM-718 to reach the maximum concentration (Cmax)	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
Tmin measurement of RM-718	Time at which the lowest concentration value of RM-718 is observed	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
Ctrough measurement of RM-718	Observed pre-dose plasma concentration of RM-718	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
Cavg measurement of RM-718	Average concentration of RM-718 during a dosing interval in steady state	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
t1/2 measurement of RM-718	Terminal elimination half-life of RM-718 in plasma	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
λz measurement of RM-718	Estimate of the terminal elimination rate constant of RM-718	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
CL/F measurement of RM-718	Clearance of RM-718 following extravascular administration	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
Vz/F measurement of RM-718	Volume of distribution of RM-718 following extravascular administration	up to 168 hours post-dose on Day 1 (Parts A, B and C) and 168 hours post-dose on Day 22 (Parts B and C).
Accumulation ratio of RM-718	Ratio of accumulation of RM-718 under steady state conditions	Week 1 to Week 4 (AUC on Week 4/AUC on Week 1) (Parts B, C)
Change from baseline in BMI (Part C only)		Baseline to Week 16
Mean change in weight (Part C only)		Baseline to Week 16
Mean change in waist circumference (Part C only)		Baseline to Week 16
Mean change in weekly average of the daily most hunger score in patients ≥12 years of age (Part C only)		Baseline to Week 16
Mean change in weekly average of the Symptoms of Hyperphagia composite score (Part C only)		Baseline to Week 16
Ctrough measurement of RM-718 (Part D)	Observed pre-dose plasma concentration of RM-718	up to 168 hours post-dose on Day 8 and up to 168 hours post-dose on Day 29
Change from baseline in BMI (Part D)		Baseline to Week 26
Mean change in weight (Part D)		Baseline to Week 26
Mean change in waist circumference (Part D)		Baseline to Week 26
Mean change in the weekly average of the Prader-Willi Syndrome Food Problem Diary (PWS-FPD) total score (Part D)		Baseline to Week 26
Mean change in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score (Part D)		Baseline to Week 26
Change in total body mass (Part D)	Change in body mass as measured by dual-energy x-ray	Baseline to Week 26

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2024
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: January 25, 2024
• First Submitted That Met QC Criteria: January 25, 2024
• First Posted (Actual): February 2, 2024

Study Record Updates

• Last Update Posted (Actual): December 22, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: obesity; melanocortin 4 receptor (MC4R); MC4R agonism
• Additional Relevant MeSH Terms: Urogenital Diseases; Imprinting Disorders; Neurologic Manifestations; Endocrine System Diseases; Nervous System Diseases; Nutrition Disorders; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genetic Diseases, Inborn; Overnutrition; Body Weight; Neurobehavioral Manifestations; Gonadal Disorders; Congenital Abnormalities; Abnormalities, Multiple; Overweight; Intellectual Disability; Disorders of Sex Development; Urogenital Abnormalities; Chromosome Disorders; Gonadal Dysgenesis; Hypogonadism; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Prader-Willi Syndrome; Sexual Infantilism
• Other Study ID Numbers: RM-718-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes