Study of setmelanotide in patients with obseity with specific genetic defects

Phase 1

Conditions: Specific Gene Defects in the Melanocortin-4 Receptor Pathway, responsible for improper functions of certainmessenger materials in the body. E.g Melanocyte-Stimulating Hormone (MSH)
Therapeutic area: Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]

Registration Number: EUCTR2021-002855-12-NL

Lead Sponsor: Rhythm Pharmaceuticals Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 165

Inclusion Criteria

1. Patients must have a pre-identified genetic variant in an established MC4R pathway gene that contributes to obesity.
2. Patients between the ages of 6 and 65, inclusive, at the time of signing Informed Consent or Assent.
3. Patients with obesity, defined as BMI =40 kg/m2 for patients =18 years of age or BMI =97th percentile for age and gender for
patients 6 to <18 years of age based on the United States (US) Centers for Disease Control and Prevention criteria.
4. Patient and/or parent or guardian is able to communicate well with the Investigator, to understand and
comply with the requirements of the trial (including the 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.
5. 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 8.9.7:
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) and 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 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.
6. Symptoms or behaviors of hyperphagia persistent during the patient’s life, including manifestations in childhood, as determined by the Investigator at screening.
Are the trial subjects under 18? yes
Number of subjects for this age range: 50
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 115
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion Criteria

1. Patients with the following genetic variants: biallelic Bardet-Biedl Syndrome (BBS); biallelic Alström Syndrome 1 (ALMS1); homozygous, heterozygous, or compound heterozygous variants in MC4R, pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), leptin receptor (LEPR), nuclear receptor coactivator 1 (NCOA1; steroid receptor coactivator-1 [SRC1]) or SRC homology 2 B adapter protein 1 (SH2B1) genes as well as 16p11.2 chromosomal deletions that include the SH2B1 gene.
2. 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.)
3. Bariatric surgery or procedure (e.g., gastric bypass/band/sleeve, duodenal switch, gastric balloon, intestinal barrier, etc.) within the last 6 months.
4. 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.
5. 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, any suicidal behavior in the last month, or a Patient Health Questionnaire-9 (PHQ-9) score of =15 during Screening process.
6. 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.
7. Significant features of, or meeting the diagnostic criteria for, a genetic syndrome that is associated with obesity.
8. Glycated hemoglobin (HbA1C) >10.0% at Screening.
9. 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
10. 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 for calculation of GFR.
11. History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
Note: If the type of skin cancer in patient’s or close family history is not known, then the patient should not be enrolled into the trial.
12. 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. If any concerning lesions are identified during Screening, the patient should be referred to a dermatologist. Any concerning lesions identified during Screening will be biopsied and results known to be benign prior to enrollment. If the

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the proportion of patients with obesity with genetic variants in a specific gene in the melanocortin-4 receptor (MC4R) pathway who achieve a clinically meaningful reduction in body weight in response to setmelanotide at the end of open-label treatment;Secondary Objective: To evaluate change in weight parameters and hunger in response to setmelanotide in patients with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment;Primary end point(s): The proportion of patients by genotype who demonstrate a significant clinically meaningful response (defined below) to setmelanotide at the end of Stage 1:<br>- For all patients: achieving a =5% reduction in BMI from Baseline;Timepoint(s) of evaluation of this end point: 40 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Mean change and percent change in BMI from Baseline to end of Stage 1 in all patients and patients =18 years old, per gene<br>- Mean change and percent change in body weight from Baseline to end of Stage 1 in patients =18 years old, per gene<br>- Mean change in BMI Z-score from Baseline to end of Stage 1 in patients <18 years old, per gene<br>- Mean percent change in the weekly average of the daily maximal hunger score from Baseline to end of Stage 1 in patients =12 years old, per gene<br>- The proportion of patients =12 years old, per gene, who achieve a =2-point reduction (improvement) from Baseline to end of Stage 1 in the weekly average of the daily maximal hunger score.;Timepoint(s) of evaluation of this end point: 40 weeks