Alport Syndrome
Conditions
Keywords
Aminoglycoside, Nonsense Mutation, Translational read through
Brief summary
This is a Phase 2 open label pilot study to evaluate the safety and efficacy of subcutaneously administered ELX-02 in patients with X-linked or autosomal recessive Alport Syndrome with Col4A5 and Col4A3/4 nonsense mutation. In total, up to 8 participants, with a minimum of 3 adults, will be enrolled in the trial. The study will be comprised of the following periods for each participant: * a Screening period of up to 6 weeks (42 days) * a total Treatment Period of 8 weeks (60 days) * a safety/efficacy Follow-up Period of 12 weeks (90 days) after the last treatment The Treatment Period will be a treatment of ELX-02 0.75 mg/kg SC QD for 8 weeks.
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
6 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
* A confirmed diagnosis of X-linked or autosomal recessive Alport Syndrome with a documented nonsense mutation of Col4A5 in a male or nonsense mutation of Col4A3 or Col4A4 (male or female) * The nonsense mutation should be UAG or UGA * eGFR\>60 ml/min/1.73 m2 (based on CKD-EPI for ages ≥18 and Schwartz formula for participants \<18) * Urinary protein based on two spot urine collections \[urine protein/creatinine ratio (UPCR) ≥ 500 mg/g\] * Stable regimen of ACEi/ARB for at least 4 weeks before screening (unless there is a contraindication)
Exclusion criteria
* History of any organ transplantation * Mutation consistent with autosomal dominant Alport Syndrome * Liver disease characterized by cirrhosis or portal hypertension. Participants with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or a total bilirubin 3.0 times the upper limit of normal (ULN) will be excluded * History of congestive heart failure diagnosed clinically or with documented left ventricular ejection fraction (LVEF) ≤ 40% * History of dialysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events Associated With Administration of 0.75 mg/kg of ELX-02 Once Daily | From the time of first dosing through the end of the follow-up period, a total of 5 months | Treatment Emerging Adverse Events were defined as any adverse events with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. Severe Treatment Emerging Adverse Event is a Treatment Emerging Adverse Events with CTCAE Grade 3 or above. Related Treatment Emerging Adverse Events is defined as a Treatment Emerging Adverse Events with a certain, probable/likely, or possible relationship to the study drug. Serious Adverse Events were Adverse Events resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Treatment in Collagen IV Expression (Foot Process Width in Renal Biopsy) | Baseline to End of Treatment (at Day 60) | Collagen IV expression was assessed by measuring podocyte foot process width in renal biopsy specimens, using Transmission Electron Microscopy (TEM) method. Results are reported as percentage change from baseline to End of Treatment. Decrease values indicate kidney structural and morphological improvement. |
| Change From Baseline to End of Treatment in Collagen IV Expression (Filtration Slit Density in Renal Biopsy) | Baseline to End of Treatment (at Day 60) | Collagen IV expression was assessed by measuring filtration slit density in renal biopsy specimens, using 3D-Structured Illumination Microscopy method. Results are reported as change from baseline. Increase values indicate improvement and protein recovery. |
| Change From Baseline in Proteinuria | From screening assessment to end of study treatment, total of 3 timepoints for results at Baseline, Week 4 and End of Treatment at Day 60. | Change from baseline to End Of Treatment. Measurement of urine protein/ creatinine ratio (UPCR) in urine samples |
| Change From Baseline to End of Treatment in Collagen IV Expression (Combined Average of Alpha 3 and Alpha 4 Chains) | Baseline to End of Treatment (at Day 60) | Collagen IV expression was assessed by measuring the combined average of alpha 3 and alpha 4 chains, using Immunofluorescence method. Results are reported as percentage change from baseline to End of Treatment. Increase in Collagen IV expression indicate kidney structural improvement. |
Countries
Australia, United Kingdom
Participant flow
Recruitment details
A total of 3 subjects (two 12 years old and one 18 years old) were enrolled in this study.
Pre-assignment details
The study consisted of 3 periods for each subject; a screening period of 6 weeks, a treatment period of 8 weeks and a safety follow up period of 12 weeks after the last treatment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized Between 12 and 18 | 2 Participants |
| Age, Customized Between 18 and 30 | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United Kingdom | 3 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 |
Outcome results
None listed