Hypothalamic Obesity, Prader-Willi Syndrome, PWS
Conditions
Keywords
melanocortin 4 receptor (MC4R), MC4R agonism, obesity
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 MC4R Pathway Impairment
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.
Interventions
DRUGPart 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)
DRUGPart 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)
DRUGPart C: RM-718
Multiple ascending doses of RM-718
DRUGPart D: RM-718
Multiple ascending doses of RM-718
Sponsors
Rhythm Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Study Parts A and B are blinded. Study Parts C and D are open-label.
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
Yes
Inclusion 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. 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/
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| Cmax measurement 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). | Maximum concentration measurement of RM-718 in plasma |
| Cmin measurement 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). | Minimum plasma concentration of RM-718 reached during dosing interval |
| Tmax measurement 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). | Time it takes for RM-718 to reach the maximum concentration (Cmax) |
| Tmin measurement 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). | Time at which the lowest concentration value of RM-718 is observed |
| Ctrough measurement 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). | Observed pre-dose plasma concentration of RM-718 |
| Cavg measurement 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). | Average concentration of RM-718 during a dosing interval in steady state |
| t1/2 measurement 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). | Terminal elimination half-life of RM-718 in plasma |
| λz measurement 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). | Estimate of the terminal elimination rate constant of RM-718 |
| CL/F measurement 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). | Clearance of RM-718 following extravascular administration |
| Vz/F measurement 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). | Volume of distribution of RM-718 following extravascular administration |
| Accumulation ratio of RM-718 | Week 1 to Week 4 (AUC on Week 4/AUC on Week 1) (Parts B, C) | Ratio of accumulation of RM-718 under steady state conditions |
| AUCtau measurement 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). | Area under the concentration versus time curve during a dosing interval |
| 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) | up to 168 hours post-dose on Day 8 and up to 168 hours post-dose on Day 29 | Observed pre-dose plasma concentration of RM-718 |
| 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) | Baseline to Week 26 | Change in body mass as measured by dual-energy x-ray |
| Change from baseline in BMI (Part C only) | Baseline to Week 16 | — |
Countries
United States
Contacts
Primary ContactRhythm Clinical Trials
Backup ContactPhysician Inquiry Clinical Trials
Outcome results
None listed