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

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.

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.