Clinical trial NCT02896192: Setmelanotide for the Treatment of Early-Onset Pro-Opiomelanocortin (POMC) Deficiency Obesity
Official title: An Open-Label, 1-Year Trial, Including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Early Onset POMC Deficiency Obesity Due to Bi-Allelic Loss-of-Function POMC or PCSK1 Genetic Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pro-opiomelanocortin (POMC) Deficiency Obesity
Keywords: POMC deficiency obesity
PCSK1 deficiency obesity
Setmelanotide
RM-493
Obesity
Melanocortin 4 receptor
MC4R pathway
Lead sponsor: Rhythm Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2016-09-12
Enrollment: 15
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
Primary purpose: TREATMENT

Brief summary: To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with pro-opiomelanocortin (POMC) deficiency or proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency obesity due to rare biallelic or loss-of function mutations at the end of 1 year of treatment.


Eligibility criteria: Inclusion Criteria:

1. Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each allele) genetic status for either the POMC or PCSK1 genes, with the loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype.
2. Age 6 years and above.
3. If adult age ≥ 18 years, obesity with body mass index (BMI) ≥ 30 kilograms per square meter (kg/m\^2); if child or adolescent, obesity with BMI ≥ 95th percentile for age on growth chart assessment.
4. Study participant and/or 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/assent, after being informed about the study.
5. Female participants of child-bearing potential must agree to use contraception as outlined in the protocol. Female participants 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 follicular stimulating hormone \[FSH\] level in the post-menopausal lab range), or have delayed pubertal development and failure to have achieved menarche, do not require contraception during the study.
6. Male participants with female partners of childbearing potential must agree to a double barrier method if they become sexually active during the study. Male participants must not donate sperm during and for 90 days following their participation in the study.

Exclusion Criteria:

1. Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents, including herbal medications, that has resulted in weight loss or weight stabilization. Participants may be reconsidered approximately 1 month after cessation of such intensive regimens.
2. Prior gastric bypass surgery resulting in \>10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain.
3. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders (DSM-III) disorders that the investigator believes will interfere significantly with study compliance.
4. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
5. Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS). Any lifetime history of a suicide attempt, or any suicidal behavior in the last month.
6. Current, clinically significant pulmonary, cardiac, or oncologic disease.
7. History of significant liver disease or liver injury, or current liver assessment for a cause of abnormal liver tests (as indicated by abnormal liver function tests, alanine transaminase \[ALT\], aspartate transaminase \[AST\], alkaline phosphatase, or serum bilirubin \[\> 2.0 x upper limit of normal (ULN) for any of these tests\]) for an etiology other than non-alcoholic fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD, including diagnosed non-alcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic cirrhosis will be exclusionary, but the presence of NAFLD would not be exclusionary.
8. History or presence of impaired renal function as indicated by clinically significant abnormal creatinine, blood urea nitrogen (BUN), or urinary constituents (e.g., albuminuria) or moderate to severe renal dysfunction as defined by the Cockcroft Gault equation \< 30 mL/min.
9. History or close family history (parents or siblings) of skin cancer or melanoma, or participant history of ocular-cutaneous albinism.
10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions, determined as part of a screening comprehensive skin evaluation performed by a qualified dermatologist.
11. Participant is, in the opinion of the study investigator, not suitable to participate in the study.
12. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
13. Significant hypersensitivity to study drug.
14. Inability to comply with every day (QD) injection regimen.

Primary outcomes:
measure: Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)
timeFrame: Week 52
Secondary outcomes:
measure: Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)
timeFrame: Week 52
measure: Mean Percent Change From Baseline in Body Weight at Week 52
timeFrame: Baseline, Week 52
measure: Mean Percent Change From Baseline in Hunger Score (Worst "Most" Hunger in 24 Hours) at Week 52
timeFrame: Baseline, Week 52
measure: Percentage of Participants Who Achieved at Least 25% Improvement in Daily Hunger From Baseline
timeFrame: Baseline, Week 52
measure: Absolute Change From Baseline in Waist Circumference at Week 52
timeFrame: Baseline, Week 52
measure: Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period
timeFrame: Baseline, 8-week withdrawal period (up to ~Week 20)
measure: Absolute Score in Daily Hunger Reduction During the Double-Blind Placebo-Controlled Withdrawal Period
timeFrame: 8-week withdrawal period (up to ~Week 20)
measure: Mean Percent Change From Baseline in Body Mass Index (BMI) at Week 52
timeFrame: Baseline, Week 52
measure: Area Under the Curve (AUC) Change From Baseline in Oral Glucose, Assessed by the Oral Glucose Tolerance Test (OGTT)
timeFrame: Baseline, Week 52
measure: Change From Baseline in Serum Glucose at Week 52
timeFrame: Baseline, Week 52
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Honor Health Research Institute
state: Arizona
city: Gent
country: Belgium
facility: UZ Gent
city: Brampton
country: Canada
facility: Peel Memorial Hospital
state: Ontario
city: Paris
country: France
facility: Institute of Cardiometabolism and Nutrition / Hopital de la Pitié-Salpêtrière
city: Berlin
country: Germany
facility: Charité Campus Virchow-Klinikum / Institute for Experimental Pediatric Endocrinology
city: Madrid
country: Spain
facility: Hospital Universitario Niño Jesús
city: Cambridge
country: United Kingdom
facility: University of Cambridge Metabolic Research Laboratories
Study officials:
affiliation: Rhythm Pharmaceuticals, Inc.
name: David Meeker, MD
role: STUDY_CHAIR
References:
citation: Clement K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kuhnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020 Dec;8(12):960-970. doi: 10.1016/S2213-8587(20)30364-8. Epub 2020 Oct 30.