X-linked Retinoschisis
Conditions
Keywords
XLRS, maculoschisis, retinal degeneration, RS1, adeno-associated virus, gene therapy, AAV
Brief summary
This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector expressing retinoschisin (rAAV2tYF-CB-hRS1) in patients with X-linked retinoschisis. Up to 27 participants will be enrolled and 3 dose levels will be evaluated in a dose escalation format.
Detailed description
This will be a non-randomized, open label, Phase 1/2 dose escalation study. Up to 27 participants will be enrolled. Each participant will receive the study agent by intravitreal injection in one eye on a single occasion. Enrollment will begin with the lowest dose and will proceed to higher doses only after review of safety data by a Data and Safety Monitoring Committee (DSMC). Participants in the dose escalation phase will be ≥ 18 years of age. After the maximum tolerated dose is identified individuals ≥ 6 years of age will be enrolled. Safety will be measured by the number and proportion of participants experiencing adverse events and immune response to RS1. Efficacy will be measured by evaluation of changes in visual function and schisis cavity size.
Interventions
BIOLOGICALrAAV2tYF-CB-hRS1
adeno-associated virus vector expressing retinoschisin
Sponsors
Beacon Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
include: 1. Retinal disease consistent with a diagnosis of XLRS and documented mutations in the RS1 gene 2. Male individual at least 18 years of age (dose escalation phase) or at least 6 years of age (maximum tolerated dose phase), 3. Able to perform tests of visual and retinal function, 4. Visual acuity specified for each group 5. Not treated with CAIs currently or within 3 months prior to study enrollment, 6. Have acceptable laboratory parameters.
Exclusion criteria
include: 1. Prior receipt of any AAV gene therapy product, 2. Pre-existing eye conditions that would preclude the planned intravitreal injection or interfere with interpretation of study endpoints or complications of vector administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Adverse Events | From Day 0 to Month 12 (12 months) | Number of participants with ocular adverse events, assessed by standard ophthalmic examination, including slit lamp biomicroscopy, tonometry, and indirect ophthalmoscopy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Best Corrected Visual Acuity (BCVA) | From Day 0 to Month 12 (12 Months) | Change in ETDRS (Early Treatment of Diabetic Retinopathy) Letter Score. Minimum value=0; Maximum value=100. Higher scores indicate better visual acuity. Change = 12 Mo value - Baseline value |
| Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT) | From Day 0 to Month 12 (12 months) | Change in cystic cavity volume (mm\^3), obtained from spectral domain optical coherence tomography (SD-OCT) of the retina, yielding volumetric measures of schisis cavity size and total cyst cavity. Change = 12 Mo value - Baseline value |
| Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses | From Day 0 to Month 12 (12 months) | Change in dark-adapted 3.0 B-wave amplitude (μV). Change = 12 Mo value - Baseline value |
Countries
United States
Participant flow
Recruitment details
No participants have completed the study at this time because the study is ongoing (overall status: active, not recruiting). All enrolled participants are in long term follow-up.
Participants by arm
| Arm | Count |
|---|---|
| rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye Group 1A/1B: Adult participants were administered a single intravitreal (IVT) injection of rAAV2tYF-CB-hRS1, once in the study eye, at a dose of 1 x 10\^11 vg/eye and followed for a minimum of 12 months after dose administration. | 6 |
| rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye Group 2/2A: Adult and pediatric participants were administered a single intravitreal (IVT) injection of rAAV2tYF-CB-hRS1, once in the study eye, at a dose of 3 x 10\^11 vg/eye and followed for a minimum of 12 months after dose administration. | 8 |
| rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye Group 3/4: Adult participants were administered a single intravitreal (IVT) injection of rAAV2tYF-CB-hRS1, once in the study eye, at a dose of 6 x 10\^11 vg/eye and followed for a minimum of 12 months after dose administration. | 13 |
| Total | 27 |
Baseline characteristics
| Characteristic | rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye | rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye | rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 5 Participants | 0 Participants | 6 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 13 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 5 Participants | 12 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 7 Participants | 12 Participants | 24 Participants |
| Region of Enrollment United States | 6 participants | 8 participants | 13 participants | 27 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 13 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 8 | 0 / 13 |
| other Total, other adverse events | 6 / 6 | 7 / 8 | 13 / 13 |
| serious Total, serious adverse events | 2 / 6 | 1 / 8 | 1 / 13 |
Outcome results
Primary
Number of Participants Experiencing Adverse Events
Number of participants with ocular adverse events, assessed by standard ophthalmic examination, including slit lamp biomicroscopy, tonometry, and indirect ophthalmoscopy.
Time frame: From Day 0 to Month 12 (12 months)
Population: All treated study participants with ocular treatment-emergent adverse events (TEAEs).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye | Number of Participants Experiencing Adverse Events | 6 Participants |
| rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye | Number of Participants Experiencing Adverse Events | 7 Participants |
| rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye | Number of Participants Experiencing Adverse Events | 12 Participants |
Secondary
Change From Baseline in Best Corrected Visual Acuity (BCVA)
Change in ETDRS (Early Treatment of Diabetic Retinopathy) Letter Score. Minimum value=0; Maximum value=100. Higher scores indicate better visual acuity. Change = 12 Mo value - Baseline value
Time frame: From Day 0 to Month 12 (12 Months)
Population: All treated study participants with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye | Change From Baseline in Best Corrected Visual Acuity (BCVA) | Baseline Letter Score (Study Eye) | 38.7 ETDRS Letter Score | Standard Deviation 16.82 |
| rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye | Change From Baseline in Best Corrected Visual Acuity (BCVA) | Month 12 Letter Score (Study Eye) | 39.5 ETDRS Letter Score | Standard Deviation 16.65 |
| rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye | Change From Baseline in Best Corrected Visual Acuity (BCVA) | Baseline Letter Score (Study Eye) | 56.3 ETDRS Letter Score | Standard Deviation 8.65 |
| rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye | Change From Baseline in Best Corrected Visual Acuity (BCVA) | Month 12 Letter Score (Study Eye) | 59.9 ETDRS Letter Score | Standard Deviation 10.29 |
| rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye | Change From Baseline in Best Corrected Visual Acuity (BCVA) | Baseline Letter Score (Study Eye) | 50.4 ETDRS Letter Score | Standard Deviation 18.93 |
| rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye | Change From Baseline in Best Corrected Visual Acuity (BCVA) | Month 12 Letter Score (Study Eye) | 51.4 ETDRS Letter Score | Standard Deviation 18.28 |
Secondary
Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses
Change in dark-adapted 3.0 B-wave amplitude (μV). Change = 12 Mo value - Baseline value
Time frame: From Day 0 to Month 12 (12 months)
Population: All treated study participants with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye | Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses | Baseline Dark Adapted 3.0 B-Wave Amplitude (μV) | 107.3 μV | Standard Deviation 50.09 |
| rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye | Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses | M12 Dark Adapted 3.0 B-Wave Amplitude (μV) | 92.8 μV | Standard Deviation 61.94 |
| rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye | Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses | Baseline Dark Adapted 3.0 B-Wave Amplitude (μV) | 206.0 μV | Standard Deviation 60.95 |
| rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye | Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses | M12 Dark Adapted 3.0 B-Wave Amplitude (μV) | 142.2 μV | Standard Deviation 62.77 |
| rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye | Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses | M12 Dark Adapted 3.0 B-Wave Amplitude (μV) | 164.0 μV | Standard Deviation 53.11 |
| rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye | Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses | Baseline Dark Adapted 3.0 B-Wave Amplitude (μV) | 169.9 μV | Standard Deviation 62.82 |
Secondary
Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT)
Change in cystic cavity volume (mm\^3), obtained from spectral domain optical coherence tomography (SD-OCT) of the retina, yielding volumetric measures of schisis cavity size and total cyst cavity. Change = 12 Mo value - Baseline value
Time frame: From Day 0 to Month 12 (12 months)
Population: All treated study participants with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye | Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT) | Baseline Cystic Cavity Volume (mm^3) (Study Eye) | 1.13 Cystic Cavity Volume (mm^3) | Standard Deviation 1.34 |
| rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye | Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT) | Month12 Cystic Cavity Volume (mm^3) (Study Eye) | 1.33 Cystic Cavity Volume (mm^3) | Standard Deviation 1.82 |
| rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye | Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT) | Baseline Cystic Cavity Volume (mm^3) (Study Eye) | 1.12 Cystic Cavity Volume (mm^3) | Standard Deviation 0.68 |
| rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye | Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT) | Month12 Cystic Cavity Volume (mm^3) (Study Eye) | 1.28 Cystic Cavity Volume (mm^3) | Standard Deviation 0.62 |
| rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye | Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT) | Baseline Cystic Cavity Volume (mm^3) (Study Eye) | 1.28 Cystic Cavity Volume (mm^3) | Standard Deviation 1.57 |
| rAAV2tYF-CB-hRS1 6 x 10^11 vg Per Eye | Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT) | Month12 Cystic Cavity Volume (mm^3) (Study Eye) | 1.04 Cystic Cavity Volume (mm^3) | Standard Deviation 1.64 |