Cystinosis, Genetic Disease, Nonsense Mutation
Conditions
Keywords
aminoglycoside, translational read-through, cystinosis, nonsense mutation
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)
Interventions
DRUGELX-02
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).
Sponsors
Eloxx Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must meet all of the following criteria to participate in this study: 1. 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) 2. A diagnosis of nephropathic cystinosis and biallelic CTNS mutations, including at least one nonsense mutation 3. 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 4. 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 5. 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: 1. 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 2. Concomitant use of cysteamine bitartrate from 7 days prior to baseline until 7 days following final administration ELX-02 3. 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 4. Patients without documented prior aminoglycoside exposure who have a mitochondrial mutation that has been shown to increase sensitivity to aminoglycosides 5. Known relevant allergy or hypersensitivity to aminoglycosides
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum observed plasma concentration (Cmax) | Day 1 of treatment periods 1, 2, and 3 | Full PK profile 12 blood samples over 24 hours |
| 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) | Day 1 of treatment periods 1, 2, and 3 | Full PK profile 12 blood samples over 24 hours |
| Renal clearance on Day 1 (Ae24h/plasma AUC0-24h) | Day 1 of treatment periods 1, 2, and 3 | 6 urine collections over 24 hours |
| Observed plasma concentration at 1 hour post dose (C1h) | Days 1, 2, 5, and 7 of treatment periods 1-2; Days 1, 2, 5, 7, 10, and 14 of treatment period 3 | Sparse sampling, blood sampling only, pre-dose and 1 hour post dose |
| Amount of ELX-02 excreted in urine from 0 to 24 hours (Ae24h) | Day 1 of treatment periods 1, 2, and 3 | 6 urine collections over 24 hours |
Secondary
| Measure | 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 |
Countries
Canada
Outcome results
None listed