POMC/PCSK1, LEPR, SRC1, SH2B1, and PCSK1 N221D Gene Defects in the Melanocortin-4 Receptor Pathway
Conditions
Sponsors
Rhythm Pharmaceuticals Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients must have a pre-identified: • Heterozygous genetic variant in the POMC gene or PCSK1 gene (Sub-study 035a), • Heterozygous genetic variant in the LEPR gene (Sub-study 035b), • Homozygous, heterozygous, or compound heterozygous variant in the SRC1 gene (Sub-study 035c), • Homozygous, heterozygous, or compound heterozygous variant in SH2B1 gene, or chromosomal 16p11.2 deletion encompassing the SH2B1 gene (Sub-study 035d), • Heterozygous N221D variant in the PCSK1 gene (Sub-study 035e). For POMC, PCSK1, LEPR, SRC1 and SH2B1 gene variants, to be considered for inclusion, the variant must either: • Be categorized by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP)/International Organisation for Standardization (ISO) 15189 -certified laboratory using ACMG criteria as a) pathogenic; or b) likely pathogenic; or c) VUS OR • Be an N221D variant of the PCSK1 gene If a patient has composite heterozygous variants eligible for the study, she/he will be accounted for in the higher category based on ACMG classification. • For example, if a patient is a composite heterozygous for POMC pathogenic variant, and LEPR VUS, the patient will be categorized as POMC pathogenic (Sub-study 035a). If the 2 variants have the same ACMG classification, adjudication will be assigned to the less prevalent gene sub-study. For example: • If a patient is a composite heterozygous for LEPR VUS and SRC1 VUS, the patient will be categorized as SRC1 (Sub-study 035c). • If a patient is a composite heterozygous for SH2B1 VUS and SRC1 VUS, the patient will be assigned to SRC1 (Sub-study 035c). The final sub-study assignment will follow this hierarchy: deletion (of the 16p11.2 including SH2B1) > pathogenic > likely pathogenic > VUS > RISK. Patients that harbor RISK variants are not eligible with the exception of PCSK1 N221D If a patient has 2 or more variants with 2 or more of the same P/LP ACMG classification, adjudication will be assigned following this hierarchy based on predicted prevalence: 1) SH2B1 deletion, 2) SRC1-P/LP, 3) SH2B1-P/LP, 4) POMC-P/LP, 5) PCSK1-P/LP, 6) LEPR-P/LP. If a patient has 2 or more variants with 2 or more of the same VUS ACMG classification, adjudication will be assigned following this hierarchy based on predicted prevalence: 1) PCSK1-VUS, 2) LEPR-VUS, 3) SRC1-VUS, 4) SH2B1-VUS, 5) POMC-VUS, 6) PCSK1-p.N221D. 2. Between 6 and 65 years of age at the time of provision of informed consent/assent. 3. Obesity, with reported onset in childhood, and BMI > or =30 kg/m2 for patients > or =18 years of age or BMI =95th percentile for age and gender for patients 6 to 17 years of age, based on the United States (US) CDC criteria, at screening. 4. Patient and/or parent or guardian is able to communicate well with the Investigator, understand and comply with the requirements of the study (including once daily [QD] injection regimen and all other study procedures), and is able to understand and sign the written informed consent/assent. Patients who are unable to comply with all study procedures due to cognitive limitations or any other reason should not be enrolled into the study. 5. Patient and/or parent or guardian reports that the patient experienced childhood obesity, defined as the patient and/or parent or guardian reporting that the patient was significantly overweight prior to the age of 6 years old. Are the trial subjects under 18? yes Number of subjects for this age range: 150 F.1.2 Adults (18-64 years
Exclusion criteria
Exclusion criteria: 1. Bariatric surgery or procedure (e.g., gastric bypass/band/sleeve, duodenal switch, gastric balloon, intestinal barrier, etc.) within the last 6 months. All patients with a history of bariatric surgery or procedures must be discussed with, and receive approval from, the Sponsor prior to enrollment. 2. Weight loss >2% in the previous 3 months. NOTE: Dietary and/or exercise regimens, with or without the use of medications, supplements or herbal treatments associated with weight loss (e.g., orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion, Glucagon-like peptide-1 [GLP-1] receptor agonists, etc.) are allowed if: • the regimen and/or dose has been stable for at least 3 months prior to randomization • the patient has not experienced weight loss >2% during the previous 3 months, AND • the patient intends to keep the regimen and/or dose stable throughout the course of the study. 3. Documented diagnosis of any psychiatric disorder(s) that the Investigator believes will interfere significantly with study compliance. 4. Clinically significant depression or suicidality as defined by: any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) during Screening, any suicide attempt during the patient’s lifetime, or any suicidal behavior in the last month, or a Patient Health Questionnaire-9 (PHQ-9) score of > or = 15 during Screening. 5. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility. 6. HbA1c >10% at Screening. 7. History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). 8. Estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2 at Screening. 9. History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism. 10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by the Investigator during Screening. Any concerning lesions identified during Screening will be biopsied and results known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient may need to be excluded from the study. 11. Patient is, in the opinion of the Investigator, not suitable to participate in the study. 12. Participation in any clinical study with an investigational drug/device within 3 months or 5 half-lives, whichever is longer, prior to the first day of dosing. 13. Previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide. 14. Significant hypersensitivity to any excipient in the study drug. 15. If female, pregnant or breastfeeding, or planning or desiring to become pregnant during the duration of the trial. 16. Patients with the following mutations: biallelic BBS (and/or clinical diagnosis of Bardet-Biedl syndrome [BBS]) or biallelic ALMS1.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of setmelanotide on changes in body weight.;Secondary Objective: Key: • To evaluate the efficacy of setmelanotide based on the portion of patients with a clinically meaningful decrease in body weight defined as > or =5% decrease from baseline • To evaluate the efficacy of setmelanotide on changes in body weight in adult patients with obesity • To evaluate changes in hunger score in response to setmelanotide from baseline to 52 weeks of treatment • To evaluate the efficacy of setmelanotide on the portion of patients with at least 10% decrease in body weight Other: • To evaluate the efficacy of setmelanotide on changes in BMI in pediatric patients with obesity • To evaluate change in waist circumference in response to setmelanotide from baseline to 52 weeks of treatment • To evaluate the safety and tolerability of setmelanotide • To evaluate quality of life parameters following treatment with setmelanotide • To evaluate the ability of an initial response to setmelanotide (defining a responder population) to predict long-term benefit.;Primary end point(s): The difference in mean change in body weight from baseline at 52 weeks in patients treated with setmelanotide compared to placebo, assessed as percent change from baseline body mass index (BMI);Timepoint(s) of evaluation of this end point: 52 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary: • The proportion of patients who achieve at least 5% reduction in baseline BMI at 52 weeks, in patients treated with setmelanotide compared to placebo • The difference in mean change in body weight from baseline at 52 weeks in adult patients (age > or =18 years at baseline) treated with setmelanotide compared to placebo, assessed as percent change in baseline body weight • The difference in mean percent change in the weekly average most hunger score at 52 weeks in patients treated with setmelanotide compared to placebo, utilizing the Hunger Questions for Patients > or =12 years of Age • The proportion of patients who achieve at least 10% reduction in baseline BMI at 52 weeks, in patients treated with setmelanotide compared to placebo Other Secondary: • The difference in mean change in BMI from baseline at 52 weeks in pediatric patients (age or =5% body weight loss if >18 years of age, or a decrease in BMI by > or =3% if <18 years of age, after 12 weeks of therapy at 3.0 mg/day or at the maximally tolerated dose) as compared to the placebo group;Timepoint(s) of evaluation of this end point: 12 and 52 weeks | — |
Countries
Canada, China, France, Germany, Greece, Israel, Italy, Netherlands, Saudi Arabia, Spain, Turkey, United Kingdom, United States
Contacts
Public ContactClinical Operations
Rhythm Pharmaceuticals Inc.
Outcome results
None listed