Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Setmelanotide in Obesity with POMC/PCSK1, LEPR, NCOA1, or SH2B1 Gene Variants
- Trial ID
- 2023-507634-24-00
- Protocol
- RM-493-035
- Sponsor
- Rhythm Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of setmelanotide on changes in body weight. This is clinically relevant as it addresses the improper function of certain messenger materials in the body that control body weight and hunger, which is a significant concern in patients with obesity due to specific genetic variants. Understanding the impact of setmelanotide on body weight can provide insights into potential therapeutic benefits for managing obesity in this population.
Secondary objectives include:
- Evaluating the efficacy of setmelanotide based on the portion of patients with a clinically meaningful decrease in body weight, defined as a ≥5% decrease from baseline.
- Assessing the efficacy of setmelanotide on changes in body weight in adult patients with obesity.
- Evaluating changes in hunger score in response to setmelanotide from baseline to 52 weeks of treatment.
- Assessing the efficacy of setmelanotide on the portion of patients with at least a 10% decrease in body weight.
- Evaluating the efficacy of setmelanotide on changes in BMI in pediatric patients with obesity.
- Assessing changes in waist circumference in response to setmelanotide from baseline to 52 weeks of treatment.
- Evaluating the safety and tolerability of setmelanotide.
- Assessing quality of life parameters following treatment with setmelanotide.
- Evaluating the ability of an initial response to setmelanotide (defining a responder population) to predict long-term benefit.
Participants
The clinical trial involves a total of **300 participants** who are being evaluated for the efficacy of setmelanotide on changes in body weight. The study population includes both **male and female subjects** aged between **6 and 65 years**. Participants are selected based on specific genetic criteria, including variants in the POMC, PCSK1, LEPR, NCOA1 (SRC1), and SH2B1 genes, which are associated with obesity and improper function of certain messenger materials in the body that control body weight and hunger. The trial includes individuals with a history of obesity onset in childhood, with a body mass index (BMI) of ≥30 kg/m² for those aged 18 and older, or a BMI ≥95th percentile for age and gender for those aged 6 to 17, according to US CDC criteria. Participants are required to have a reported history of lifestyle interventions involving diet and exercise, and symptoms or behaviors of **hyperphagia** persistent throughout their life. The trial population is considered vulnerable, and participants must be able to communicate effectively with the investigator and comply with trial requirements. The study does not exclude based on gender, and both male and female participants are included, with specific considerations for contraception and reproductive status as applicable.
Plans and Procedures
The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy of **setmelanotide** in patients with specific genetic variants affecting the melanocortin-4 receptor pathway, which are associated with improper function of certain messenger materials controlling body weight and hunger. The trial is structured into multiple independent sub-studies, each targeting different gene variants, including POMC, PCSK1, LEPR, NCOA1 (SRC1), and SH2B1. The primary objective is to assess the change in body weight over a 52-week period, with secondary endpoints including the proportion of patients achieving significant reductions in baseline BMI and changes in hunger scores.
Participants will be involved in the trial for a maximum of 52 weeks, with the study expected to conclude by December 31, 2026. The trial begins with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, genetic variant classification, and obesity history. Following successful screening, participants will be randomized to receive either setmelanotide or placebo. Study visits will occur regularly to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment.
Participants may be withdrawn from the study if they fail to comply with the trial procedures, experience adverse effects, or if the investigator deems it necessary for safety reasons. The trial is not categorized as low intervention, and the investigational product is administered as a solution for injection. The study is conducted under strict regulatory standards to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of **setmelanotide**, marketed under the name IMCIVREE, which is a **solution for injection**. This experimental medication is provided in a concentration of 10 mg/ml and is administered subcutaneously. The maximum daily dose is 3.0 mg, with a total maximum dose of 1092.0 mg over a treatment period of up to 52 weeks. The pharmaceutical form is a solution for injection, and the medication is produced by Rhythm Pharmaceuticals Netherlands B.V. The active substance, setmelanotide, is of chemical origin and is classified under the ATC code A08AA12. The study-specific labeling and additional modifications are detailed in the sIMPD.
In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled trial. The placebo is designed to match the experimental medication in appearance and administration route to maintain the study's blinding. The placebo is administered subcutaneously in the same manner as the active treatment, ensuring consistency in the administration process. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.
Efficacy
The efficacy of setmelanotide in this clinical trial will be assessed primarily by evaluating the difference in mean change in body weight from baseline at 52 weeks, compared to placebo. This will be measured as a percent change from baseline body mass index (BMI). Secondary endpoints include the proportion of patients achieving at least a 5% reduction in baseline BMI at 52 weeks, the difference in mean change in body weight from baseline in adult patients, and the difference in mean percent change in the weekly average most hunger score at 52 weeks. Additional secondary endpoints involve the proportion of patients achieving at least a 10% reduction in baseline BMI, changes in BMI Z-score for pediatric patients, and changes in waist circumference.
These efficacy parameters will be collected and analyzed at the 52-week mark, utilizing validated scales and patient-reported outcomes. The Hunger Questions for Patients aged 12 and above will be used to assess changes in hunger scores. The Impact of Weight on Quality of Life (IWQOL-Lite for adults and IWQOL-Kids-Parent Proxy for children) will be employed to evaluate changes in physical functioning and quality of life scores. The trial will also assess the overall safety and tolerability of setmelanotide in patients with genetic variants in the melanocortin-4 receptor (MC4R) pathway. The study is designed to provide comprehensive data on the efficacy of setmelanotide in reducing body weight and improving related health outcomes in the specified patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must have a pre-identified: •Heterozygous gene variant in the POMC gene or PCSK1 gene (Sub-study 035a), •Heterozygous gene variant in the LEPR gene (Sub-study 035b), •Homozygous, heterozygous, or compound heterozygous variant in the NCOA1 (SRC1) gene (Sub study 035c), •Homozygous, heterozygous, or compound heterozygous variant in the SH2B1 gene, or chromosomal 16p11.2 deletion encompassing the SH2B1 gene (Sub-study 035d), For POMC, PCSK1, LEPR, NCOA1 (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 (P); or b) Likely pathogenic (LP); or c) Variant of uncertain significance (VUS); or d) For POMC, PCSK1, and LEPR, in addition to P/LP, only the sub-category of VUS variants that are suspected to be pathogenic (VUS-SP) will be eligible for inclusion. If a patient has 2 or more variants eligible for the trial, she/he will be assigned to a sub-study according to the following 2 rules: 1) To the highest ACMG pathogenicity category according to the following hierarchy: P > LP > VUS-SP > VUS • For example, if a patient carries both a POMC Pathogenic (P) variant and a LEPR VUS SP variant, the patient will be assigned as a POMC Pathogenic (P) patient (Sub study 035a). 2) If the 2 variants have the same ACMG classification, the patient will be assigned to the sub-study with lower overall frequency of gene variants according to the following hierarchy (least frequent to most frequent): LEPR > POMC/PCSK1 > NCOA1 (SRC1) > SH2B1. • For example, if a patient carries both a LEPR Pathogenic (P) variant and a SH2B1 Pathogenic (P) variant, the patient will be assigned as a LEPR Pathogenic (P) patient (Sub-study 035b).
- Between 6 and 65 years of age at the time of provision of informed consent/assent.
- Obesity, with reported onset in childhood, and BMI ≥30 kg/m2 for patients ≥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.
- Patient and/or parent or guardian is able to communicate well with the Investigator, understand and comply with the requirements of the trial (including once daily [QD] injection regimen and all other trial procedures), and is able to understand and sign the written informed consent/assent. Patients who are unable to comply with all trial procedures due to cognitive limitations or any other reason should not be enrolled into the trial.
- 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 had obesity or was significantly overweight prior to the age of 6 years old.
- Patient must meet one of the following requirements: Female participants of childbearing potential, defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), must be confirmed non-pregnant and agree to use a highly effective form of contraception throughout the trial and for 90 days following the trial. Highly effective forms of contraception are detailed below and in Section 7.2.6: • Combined (estrogen and progestin) hormonal contraception associated with inhibition of ovulation (i.e., oral, intravaginal, or transdermal) • Progestin-only hormonal contraception associated with inhibition of ovulation (oral, implantable, or injectable) • Intrauterine device (IUD) • Intrauterine hormone-releasing system • Bilateral tubal occlusion • Vasectomy/vasectomized partner (provided that the vasectomized partner is the sole sexual partner of the female participant, and the vasectomized partner has received medical assessment of surgical success) • Sexual abstinence, only if it is the preferred and usual lifestyle of the patient Female participants of non-childbearing potential, defined as: permanently sterile (status post hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or post-menopausal for at least 12 months (and confirmed with a screening follicle-stimulating hormone level in the post-menopausal lab range) do not require contraception during the trial. Younger female patients who have not achieved sexual maturity at trial entry will be assessed for Tanner Staging and required to comply with contraception requirements at first menarche. Male participants with female partners of childbearing potential must agree to use a highly effective method of contraception if they become sexually active during the trial or within 90 days following their participation in the trial. Male patients must also not donate sperm during and for 90 days following their participation in the trial.
- Reported history of lifestyle intervention with diet and exercise.
- Symptoms or behaviors of hyperphagia persistent during the patient’s life, including manifestations in childhood, as determined by the Investigator at screening.
Exclusion Criteria
- 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.
- Weight loss >2% in the previous 3 months. Patients will not be excluded for using regimens for weight maintenance or to prevent weight gain, such as dietary and/or exercise regimens, or medications, supplements or herbal treatments (e.g., orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion, glucagon-like peptide 1 [GLP 1] receptor agonists, etc.), provided: • 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 trial.
- Documented diagnosis of current unstable major psychiatric disorder(s) (e.g., major depressive disorder, bipolar disorder, schizophrenia, etc.) or documented worsening psychiatric condition that required changes in treatment regimen within the previous 2 years, or other psychiatric-related risks that the Investigator believes may interfere with trial compliance or patient safety.
- 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 ≥15 during screening.
- Current, clinically significant pulmonary, cardiac, endocrine/metabolic, hepatic, or oncologic disease considered severe enough to interfere with the trial and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility.
- HbA1c >10% at screening.
- History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). (Patients with NAFLD or NASH will not be excluded based on this criterion.)
- Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at screening. In patients ≥18 years of age the Modification of Diet in Renal Disease (MDRD) Equation should be used to calculate eGFR. In patients <18 years of age the Bedside Schwartz Equation should be used to calculate eGFR.
- History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
- 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 trial.
- Patient is, in the opinion of the Investigator, not suitable to participate in the trial
- Participation in any clinical trial with an investigational drug/device within 3 months or 5 half-lives, whichever is longer, prior to the first day of dosing.
- Previously enrolled in a clinical trial involving setmelanotide or any previous exposure to setmelanotide.
- Hypersensitivity to the active substance or to any of the excipients of the investigational medicinal products (active and placebo).
- Females who are pregnant or breastfeeding, or planning or desiring to become pregnant during the duration of the trial.
- Patients with the following gene variants: biallelic BBS (and/or clinical diagnosis of Bardet-Biedl syndrome [BBS]), biallelic ALMS1, or any MC4R variants
- Legally protected persons per local regulations (e.g., those that fall under the L1121-6 article of the Public Health code in France) or other applicable local laws.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 15 Nov 2021 | 15 |
 Germany | Not Recruiting | 15 Nov 2021 | 25 |
 Greece | Not Recruiting | 15 Nov 2021 | 10 |
 The Netherlands | Not Recruiting | 15 Nov 2021 | — |
 Spain | Not Recruiting | 15 Nov 2021 | 10 |
| Netherlands | — | — | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Solution for Injection, subcutaneous Use | Placebo | N/A | — | — | — | N/A |
IMCIVREE 10 mg/ml solution for injection | Test | SOLUTION FOR INJECTION | SOLUTION FOR INJECTION | 3.0 | 52 | PRD10024904 |