Early Onset Leptin Receptor (LEPR) Deficiency Obesity due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation
Conditions
Sponsors
Rhythm Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each allele) genetic status for either the LEPR 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 kg/m2; if child or adolescent, obesity with BMI = 95th percentile for age on growth chart assessment. 4. Study participant and/or parent or guardian can communicate well with the investigator, to understand and comply with the requirements of the study, and can 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 FSH level in the post-menopausal lab range), or 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 patients must not donate sperm during and for 90 days following their participation in the study. Are the trial subjects under 18? yes Number of subjects for this age range: 5 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 13 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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. Patients 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. Specifically, patients may be considered if surgery was not successful, or resulted in 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 patient 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. Any concerning lesions identified during the screening period 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. Volunteer 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. Previous history of significant hypersensitivity to exogenously injected peptides (e.g. urticaria, shortness of breath, or more severe responses inclu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in patients with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment. ;Secondary Objective: To assess the effect of setmelanotide, over one year, on: • Safety and tolerability of setmelanotide (including blood pressure [BP] and heart rate [HR]). • Hunger in patients = 12 year old • Percent change in body fat mass. • Glucose parameters: fasting glucose, glycated hemoglobin (HbA1c), oral glucose tolerate test (OGTT) with focus on parameters of insulin sensitivity. • Waist circumference. • During withdrawal from drug: reversal of weight and hunger reduction during the double-blind placebo- controlled withdrawal period. ;Primary end point(s): The primary endpoint is the proportion of patients in the full analysis set (FAS) who meet the =10% weight loss threshold (responders) after ~1 year of treatment, compared to the proportion from historical data (at most 5% responders in the null population). ;Timepoint(s) of evaluation of this end point: End of 1 year treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Supporting secondary, tertiary and exploratory endpoints will include: The safety and tolerability of setmelanotide QD SC injection will be assessed by the frequency and severity of adverse events (AEs) as well as changes in physical examinations, electrocardiograms (ECGs), vital signs (including resting BP and HR), laboratory evaluations, monitoring for changes in neurocognition in patients =16 years of age, and injection site reactions. Assessemnt of Hunger, Body composition, waist circumference, Glucose parameters, PK (adult an adolescent patients). Potential improvements in lipids (fasting cholesterol and triglycerides) as well as glucose parameters as measured by fasting glucose, HbA1c and OGTT with focus on parameters of insulin sensitivity will be assessed over time. Several questionnaires will be utilized throughout the study to assess quality of life (IWQOL-Lite and PedsQL) along with the SF-36 and SF-10 health survey. As required by Food and Drug Administration (FDA) for central nervous system (CNS)-active obesity medications, changes in depression/suicidality as assessed by the C- SSRS and PHQ-9 will be monitored over the entire course of the trial. Changes in pubertal development for those patients who have yet to reach Tanner Stage V will be assessed over the course of the study. ;Timepoint(s) of evaluation of this end point: Throughout the course of the study and end of approximately 1 year of treatment | — |
Countries
France, Germany, Netherlands, United Kingdom, United States
Contacts
Public ContactFred Fiedorek
Rhythm Pharmaceuticals, Inc.
Outcome results
None listed