Setmelanotide for the Treatment of Early-Onset Pro-Opiomelanocortin (POMC) Deficiency Obesity

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Pro-opiomelanocortin (POMC) Deficiency Obesity

Intervention / Treatment
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* Drug: Setmelanotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Age 6 years and above. 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. 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. 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. 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: 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. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain. 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. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15. 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. Current, clinically significant pulmonary, cardiac, or oncologic disease. 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. 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. History or close family history (parents or siblings) of skin cancer or melanoma, or participant history of ocular-cutaneous albinism. 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. Participant is, in the opinion of the study investigator, not suitable to participate in the study. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing. Significant hypersensitivity to study drug. Inability to comply with every day (QD) injection regimen.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Setmelanotide<br>Participants received titrated doses of setmelanotide once daily, by subcutaneous (SC) injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kilograms (kg) weight loss (or at least 5% weight loss if baseline body weight was <100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks ( 1 year) of treatment at a therapeutic dose. | Drug: Setmelanotide<br>* Once daily SC injection<br>* Other names: RM-493;Drug: Placebo<br>* Once daily SC injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort) | The percentage of participants who met the ≥ 10% weight loss threshold after approximately Week 52 ( 1 year) of treatment were analyzed. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort) | The percentage of participants who met the ≥ 10% weight loss threshold after approximately Week 52 ( 1 year) of treatment were analyzed. | Week 52 | 
| Mean Percent Change From Baseline in Body Weight at Week 52 | The mean percent change from baseline in body weight at 52 weeks was analyzed. | Baseline, Week 52 | 
| Mean Percent Change From Baseline in Hunger Score (Worst Most Hunger in 24 Hours) at Week 52 | The mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. | Baseline, Week 52 | 
| Percentage of Participants Who Achieved at Least 25% Improvement in Daily Hunger From Baseline | The percentage of participants (≥12 years of age) achieving a ≥25% improvement from baseline in hunger score at Week 52 (i.e., after treatment with setmelanotide for 52 weeks at the therapeutic dose) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. | Baseline, Week 52 | 
| Absolute Change From Baseline in Waist Circumference at Week 52 | Waist circumference (centimeters) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. Waist circumference was measured when participants were fasting at approximately the same time at each visit. The absolute change from baseline in waist circumference was assessed. | Baseline, Week 52 | 
| Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period | A comparison of weight change was evaluated during the 8 week placebo-controlled withdrawal period for each participant, during which each participant received 4 weeks of placebo and 4 weeks active therapy in a blinded fashion. | Baseline, 8-week withdrawal period (up to  Week 20) | 
| Absolute Score in Daily Hunger Reduction During the Double-Blind Placebo-Controlled Withdrawal Period | The absolute score in daily hunger during the double-blind placebo-controlled withdrawal period (≥12 Years of Age) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. Lower scores represent lower hunger, higher scores represent greater hunger. | 8-week withdrawal period (up to  Week 20) | 
| Mean Percent Change From Baseline in Body Mass Index (BMI) at Week 52 | The mean percent change from baseline in BMI was assessed. | Baseline, Week 52 | 
| Area Under the Curve (AUC) Change From Baseline in Oral Glucose, Assessed by the Oral Glucose Tolerance Test (OGTT) | The AUC change from baseline for the OGTT was assessed. The AUC was calculated by the linear trapezoidal method and includes pre-dose and post-dose assessments. At each visit, oral glucose was captured pre-meal, and post-meal at the following times: 30 minutes, 60 minutes, 90 minutes, and 120 minutes. OGTT was not performed for participants with a diagnosis of Type 1 or Type 2 diabetes. | Baseline, Week 52 | 
| Change From Baseline in Serum Glucose at Week 52 | Change from baseline in serum glucose at Week 52 was assessed. | Baseline, Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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POMC deficiency obesity, PCSK1 deficiency obesity, Setmelanotide, RM-493, Obesity, Melanocortin 4 receptor, MC4R pathway