Clinical trial NCT06239116: A Study of RM-718 in Healthy Subjects and in Patients With HO
Official title: A Study of RM-718 Weekly Formulation in Healthy Subjects With Obesity and in Patients With Hypothalamic Obesity (HO)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Hypothalamic Obesity
Keywords: melanocortin 4 receptor (MC4R)
MC4R agonism
obesity
Lead sponsor: Rhythm Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2024-02-02
Enrollment: 120
Sex: ALL
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 hypothalamic obesity (HO).

Detailed description: This is a first-in-human and first-in-patient, 3-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), and MAD of RM-718 in patients 12 to 65 years of age with HO (Part C). 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. 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, and 16 weekly doses of open-label RM-718 in Part C. Study drug (RM-718 or placebo) doses are administered weekly via subcutaneous injection.

Eligibility criteria: 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.

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.

Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Parts A, B, C: Safety and Tolerability Assessed by Number of Study Participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: 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 and Part C cohorts)
Secondary outcomes:
measure: AUCtau measurement of RM-718
timeFrame: 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).
measure: Cmax measurement of RM-718
timeFrame: 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).
measure: Cmin measurement of RM-718
timeFrame: 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).
measure: Tmax measurement of RM-718
timeFrame: 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).
measure: Tmin measurement of RM-718
timeFrame: 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).
measure: Ctrough measurement of RM-718
timeFrame: 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).
measure: Cavg measurement of RM-718
timeFrame: 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).
measure: t1/2 measurement of RM-718
timeFrame: 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).
measure: λz measurement of RM-718
timeFrame: 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).
measure: CL/F measurement of RM-718
timeFrame: 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).
measure: Vz/F measurement of RM-718
timeFrame: 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).
measure: Accumulation ratio of RM-718
timeFrame: Week 1 to Week 4 (AUC on Week 4/AUC on Week 1) (Parts B, C)
measure: Change from baseline in BMI (Part C only)
timeFrame: Baseline to Week 16
measure: Mean change in weight (Part C only)
timeFrame: Baseline to Week 16
measure: Mean change in waist circumference (Part C only)
timeFrame: Baseline to Week 16
measure: Mean change in weekly average of the daily most hunger score in patients ≥12 years of age (Part C only)
timeFrame: Baseline to Week 16
measure: Mean change in weekly average of the Symptoms of Hyperphagia composite score (Part C only)
timeFrame: Baseline to Week 16
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Pediatric Endocrinology
state: Alabama
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: San Antonio
country: United States
facility: Worldwide Clinical Trials
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Pediatric Endocrine Clinic
state: Utah
Study officials:
affiliation: Rhythm Pharmaceuticals, Inc.
name: David Meeker
role: STUDY_CHAIR
References: