A Phase 2 Study of ELX-02 in Patients With Nephropathic Cystinosis

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2 open label study to evaluate the safety, tolerability, PK, and PD of multiple dose levels of SC administered ELX-02 in patients with cystinosis with nonsense mutation in at least one allele. Six patients will be enrolled in the trial. The study will comprise of the following periods for each patient: A screening period of up to 6 weeks A total treatment period of 4 weeks A safety follow-up period of 4 weeks after the last treatment Each patient will receive three escalating doses as follows: Treatment period 1: ELX-02 0.5 mg/kg SC daily for 7 days (total dose not to exceed 3.5 mg/kg for this week; the daily dose will be individualized to achieve the target weekly exposure of about 47.5 µg*h/mL) Treatment period 2: ELX-02 1.0 mg/kg SC daily for 7 days (total dose not to exceed 7.0 mg/kg for this week; the daily dose will be individualized to achieve the target weekly exposure of about 95 µg*h/mL) Treatment period 3: ELX-02 2.0 mg/kg SC daily for 14 days (total dose not to exceed 14 mg/kg for these two weeks; the daily dose will be individualized to achieve the target weekly exposure of about 190 µg*h/mL)

Official Title
-----------------
A Phase 2, Single Center, Open-Label, Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Daily Subcutaneously Administered ELX-02 in Patients With Nephropathic Cystinosis Bearing One or More CTNS Gene (Cystinosin) Nonsense Mutations

Conditions
-----------------
Genetic Disease, Nonsense Mutation, Cystinosis

Intervention / Treatment
-----------------
* Drug: ELX-02


Participation Criteria
=================
Eligibility Criteria
-----------------
Patients must meet all of the following criteria to participate in this study: Male or female patients who, at the time of screening, are 18 years of age or older (Cohort 1) or ≥12 years of age (Cohort 2) A diagnosis of nephropathic cystinosis and biallelic CTNS mutations, including at least one nonsense mutation Patients should have a mild to moderate disease estimated glomerular filtration rate ≥40 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula Body mass index of 19.0 to 30.0 kg/m2. Patients with a lower BMI may be entered into the study at the discretion of the Investigator following consultation with the Sponsor Renal transplant permitted with stable graft function (serum creatinine) for 3 months prior to Screening Patients with any of the following characteristics/conditions will not be included in the study: Participation in clinical study including administration of any investigational drug or device in the last 30 days or 5 half-lives (whichever is longer) prior to investigational product dosing in the current study Concomitant use of cysteamine bitartrate from 7 days prior to baseline until 7 days following final administration ELX-02 An average systolic blood pressure and/or diastolic blood pressure ≥95th percentile for sex, age, and height on 3 or more occasions during the screening period Patients without documented prior aminoglycoside exposure who have a mitochondrial mutation that has been shown to increase sensitivity to aminoglycosides Known relevant allergy or hypersensitivity to aminoglycosides

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ELX-02<br>Eukaryotic ribosomal selective glycoside (ERSG) | Drug: ELX-02<br>* ELX-02 is a small molecule, new chemical entity being developed for the treatment of genetic diseases caused by nonsense mutations. ELX-02 is a eukaryotic ribosomal selective glycoside (ERSG).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AEs associated with different dose levels of ELX-02 |  | From the time of first dosing through the follow-up visit, an average of approximately 10 weeks | 
| Area under the plasma concentration curve from time zero to 24 hours (AUC0-24h) | Full PK profile 12 blood samples over 24 hours | Day 1 of treatment periods 1, 2, and 3 | 
| Maximum observed plasma concentration (Cmax) | Full PK profile 12 blood samples over 24 hours | Day 1 of treatment periods 1, 2, and 3 | 
| Observed plasma concentration at 1 hour post dose (C1h) | Sparse sampling, blood sampling only, pre-dose and 1 hour post dose | Days 1, 2, 5, and 7 of treatment periods 1-2; Days 1, 2, 5, 7, 10, and 14 of treatment period 3 | 
| Amount of ELX-02 excreted in urine from 0 to 24 hours (Ae24h) | 6 urine collections over 24 hours | Day 1 of treatment periods 1, 2, and 3 | 
| Renal clearance on Day 1 (Ae24h/plasma AUC0-24h) | 6 urine collections over 24 hours | Day 1 of treatment periods 1, 2, and 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline in WBC cystine levels |  | Screening; Days 1, 2, 5, and 7 of treatment periods 1-2; Days 1, 2, 5, 7, 10, and 14 of treatment period 3, and 4-week safety follow-up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
aminoglycoside, translational read-through, cystinosis, nonsense mutation