Phase 2 Trial to Evaluate Safety and Efficacy of Setmelanotide (RM-493) in Obese Participants With Prader-Willi Syndrome

A Phase 2, Randomized, Double-Blind, Placebo-controlled Pilot Study to Assess the Effects of RM-493, a Melanocortin 4 Receptor (MC4R) Agonist, in Obese Subjects With Prader-Willi Syndrome (PWS) on Safety, Weight Reduction, and Food-Related Behaviors

The purpose of this study was to evaluate the effects of a once daily subcutaneous injectable formulation of setmelanotide in obese participants with Prader-Willi syndrome on tolerability, weight loss, and hyperphagia-related behavior. The study drug (setmelanotide and placebo) was administered in a blinded fashion.

Inclusion Criteria:

1. PWS due to chromosome 15 micro-deletion, maternal uniparental disomy, or imprinting defect, confirmed by fluorescent in situ hybridization, chromosomal microarray, and/or methylation studies. Obese male or female participants weighing at least 50 kilograms (kg) with body mass index (BMI) ≥ 27 kilogram per square meter (kg/m²)

2. Age 16-65 years

3. If a participant has diagnosis of type 2 diabetes, following criteria must be met:

   1. hemoglobin A1C (HbA1c) < 7.5% not being managed with insulin. Participants taking glucagon-like peptide-1 (GLP-1) analogues (exenatide or liraglutide) must have been on stable dose for greater than 3 months.
   2. Fasting plasma glucose < 140 milligrams per deciliter (mg/dL)
   3. No history of ketoacidosis or hyperosmolar coma

4. Vital signs must be within the following ranges and stable.

   1. Systolic blood pressure, 90-150 millimeter of mercury (mm Hg)
   2. Diastolic blood pressure, 50-90 mm Hg
   3. Pulse rate, 40-100 beats per minute (bpm)

5. Stable body weight at home for approximately 2 months (self or guardian-reported loss/gain within ± 5%).

6. Blood pressure (≤ 150/90 mmHg); may include stable dose (≥ 30 days of use) of up to two anti-hypertensive medications that are intended to remain on a stable dose during the protocol

7. Parent or guardian is able to communicate well with the investigator, to understand and comply with the requirements of the study, and be able to understand and sign the written informed consent. Due to the significant intellectual disability with PWS, assent is to be provided by the participant who cannot consent for himself or herself.

8. Results of screening clinical laboratory tests (complete blood count with differential and platelets and chemistry profile) must be within normal range or, if outside of the normal range, must be accepted by the investigator and sponsor as not clinically significant.

9. Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months (and confirmed with a screening follicle-stimulating hormone (FSH) level in the post-menopausal lab range), do not require contraception during the study. All other females of child-bearing potential must agree to use contraception as outlined in the protocol.

10. Males with female partners of childbearing potential must agree to a double barrier method if they become sexually active during the study and for 90 days following the study. Male participants must not donate sperm for 90 days following their participation in the study.

11. Participants must be on a stable dose of any allowed chronic concomitant medications while participating in the study.

Exclusion Criteria:

1. Recent use (within 3 month) of weight loss agents including herbal medication.
2. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) disorders which the investigator believes will interfere significantly with study compliance.
3. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
4. Any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS).
5. Clinically significant illness in the 8 weeks before screening.
6. History of clinically significant bleeding disorders.
7. Current, clinically significant liver, renal, pulmonary, cardiac, oncologic, or gastrointestinal disease.
8. Diagnosis of type 1 diabetes mellitus or other active endocrine disorders (e.g., Cushing syndrome, or thyroid dysfunction except if on adequate thyroid or glucocorticoid replacement supplement).
9. Cardiovascular disease event including history of congestive heart failure, coronary artery disease, myocardial infarction, second degree or greater heart block or prolonged QT syndrome.
10. Blood pressure > 150/90 mm Hg.
11. Liver disease or liver injury as indicated by abnormal liver function tests, aspartate aminotransferase, alkaline phosphatase, or serum bilirubin (> 1.5 x upper limit of normal for any of these tests) or history of hepatic cirrhosis.
12. History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine, blood urea nitrogen, or urinary constituents (e.g., albuminuria) or moderate to severe renal dysfunction as defined by the Cockcroft-Gault equation (< 50 mL/min).
13. History or close family history (parents or siblings) of melanoma.
14. Oculocutaneous albinism (occurs at approximately 1% in PWS).
15. Significant dermatologic findings as part of the Screening comprehensive skin evaluation performed by the dermatologist.
16. Significant history of abuse of drugs or solvents in the year before screening or a positive Drugs of Abuse (DOA) test at screening.
17. History of alcohol abuse in the past year before screening or currently drinks in excess of 21 units per week (3 servings or units/day).
18. Caffeine consumption exceeding 6 cups of caffeinated tea/coffee (or equivalent) per day.
19. Participant is, in the opinion of the Investigator, not suitable to participate in the study.
20. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
21. Positive history for human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C tests or tuberculosis.
22. Serious adverse reaction or significant hypersensitivity to any drug.
23. Clinically significant blood loss or blood donation > 500 milliliters (mL) within 3 months.
24. Inadequate venous access.
25. History of low blood counts or recurring infections.