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

Официальное название

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

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат 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)
• Препарат 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)
• Препарат Part C: RM-718
  Multiple ascending doses of RM-718
• Препарат Part D: RM-718
  Multiple ascending doses of RM-718

Первичные конечные точки

• 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) [Срок оценки: 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)]

Вторичные конечные точки (12)

• AUCtau measurement of RM-718 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Week 1 to Week 4 (AUC on Week 4/AUC on Week 1) (Parts B, C)]

Критерии участия

Критерии включения

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.

Критерии исключения

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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 7 центров

• UAB Pediatric Endocrinology (Part C and Part D) — Birmingham
• Ann and Robert H. Lurie Children's Hospital of Chicago (Part C and Part D) — Chicago
• Boston Children's Hospital (Part C only) — Boston
• Brigham and Women's Hospital (Part C and Part D) — Boston
• Vanderbilt University Medical Center (Part C only) — Nashville
• Worldwide Clinical Trials (Part A and Part B) — San Antonio
• University of Utah Pediatric Endocrine Clinic (Part C and Part D) — Salt Lake City

Идентификаторы

NCT: NCT06239116 · RM-718-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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