Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa

Mean change in BCVA in study eye from baseline to month 12 as assessed by E-ETDRS in ITT population. A letter score is used to compare change over time, with a higher number of letters representing better visual function, and a lower number of letters representing worse visual function. For example, 85 letters is equivalent to 20/20 visual acuity and 5 letters is equivalent to 20/800 visual acuity. A change value is derived for each subject by taking the letter score at 12 months and subtracting the letter score at baseline. A mean of all change values is then calculated for each arm.

Time frame: 12 months

Population: ITT: All randomized subjects who provide any post-randomization data. One subject received a 4.0 x 10e6 dose prior to a protocol amendment that excluded this dose level; this subject is not included in these analyses. Also, of the 83 remaining subjects to be enrolled and randomized, 80 completed the study.

Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. For example, if a subject's CS peak appears to be at 2.0 CPD, then additional testing occurs at 1.0 and 4.0 CPD. RP patients have suppressed CS curves and the most common pattern widths are at 0.5, 1.0, 2.0, and 4.0 CPD. Severely impaired subjects (e.g., BCVA \< 20/400) usually have flat curves with low values (e.g., 1.28), while in mildly impaired RP subjects the values can be higher (e.g., 7.12), but are rarely near normal. These data represent mean change in CS from baseline to 12 months, with greater values representing greater improvement in visual function.

Time frame: 12 months

Population: mITT: all randomized subjects who provide any post-randomization data, excluding subjects with missing baseline or who are below the limit of detection (LOD) at baseline; shown here are subjects who could be assessed at a pattern width of 1.0 CPD, which applies to the largest number of participating subjects as compared to the other CPD pattern widths.

Mean change in total area (degrees squared) of all islands of vision from baseline to 12 months.

Time frame: 12 months

Population: mITT: all randomized subjects who provide any post-randomization data, excluding subjects with missing baseline or who are below the limit of detection (LOD) at baseline.

The LLMT identifies the performance of RP patients as they walk along an indoor pathway of arrows and obstacles at varying lighting levels. The Critical Illumination Level (CIL) is the light level below which the patient has a markedly slower pace and more errors than all light levels above (brighter than) that point. The LLMT uses light levels that go from very dim (0.12 lux) to a bright indoor room (500 lux), with evenly spaced increments that increase light by doubling the brightness of the room from the prior level. These evenly spaced light levels have been converted to a scale score to enable easier calculation of change scores. The dimmest light level of 0 lux (completely dark room) corresponds to a scale score of 13, whereas the brightest light level of 500 lux corresponds to a scale score of 0. A positive scale score change from baseline to 12 months represents improvement in low light vision, whereas a negative scale score change represents a decline in low light vision.

Time frame: 12 months

Population: Modified ITT: all randomized subjects who provide any post-randomization data, excluding subjects with missing baseline

The VA LV VFQ-48 (VFQ) is used to capture changes in patients' self-reporting of their difficulty with reading, mobility and performing other daily living activities affected by visual impairment. There are 4 scales on the VFQ including Visual Information, Reading, Visual Motor, and Mobility. A fifth value, Visual Ability, is an aggregate score of the 4 scales, measured in units called logits, and is calculated for each person based on item weighting using Raasch analysis. Visual Ability is used broadly to represent changes in subject-reported outcomes from visit to visit. Higher positive values on the Visual Ability score represent better function and less impairment, whereas lower or negatives scores represent worse function or more impairment. Change in the Visual Ability scale on the VFQ is calculated by taking a subject's score at 12 months and subtracting from it the baseline score.

Time frame: 12 months

Population: mITT: all randomized subjects who provide any post-randomization data, excluding subjects with missing baseline.

Assessed by treatment emergent adverse events, immunogenicity and safety visual assessments

Time frame: 12 months

Population: Safety population: all subjects who receive any study treatment (including sham); subjects who did not complete may not have data at 12-month time point

Mean change in BCVA in study eye from baseline to month 12 as assessed by E-ETDRS in the Per Protocol (PP) population (N=76). The PP population excludes seven subjects with major protocol violations, including two subjects who received a different treatment than the group to which they were randomized, four subjects with preexisting ophthalmic conditions meeting exclusion criteria (three glaucoma and one amblyopia), and one subject who experienced an intraocular lens subluxation (i.e., the displacement of a replacement lens following previous cataract surgery - unrelated to study drug) and could not perform endpoint testing at 12 months. Refer to Outcome Measure #1 for more information on how change in BCVA from baseline to month 12 is assessed.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study

Mean change in BCVA from Baseline to month 12 as assessed by E-ETDRS in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55). The work undertaken to understand what contributed to variability in measurements in the Phase 2b study, combined with the available published literature, has led to the identification of the characteristics of individuals who provide inconsistent/unreliable data. One such characteristic is found in subjects in whom there is a substantial BCVA disparity of more than 15 letters between their study (worse) eye and fellow (better) eye. This disparity has the potential to lead to variable testing results due to the brain's un-suppression of the image from their worse-seeing eye under clinical study monocular test conditions where their dominant eye is covered. Refer to Outcome Measure #1 for more information on how change in BCVA from baseline to month 12 is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study

Mean change in BCVA in study eye from baseline to month 12 as assessed by E-ETDRS in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye and with the ability to maintain fixation at baseline (N=42). Beyond the BCVA disparity characteristic described in the previous post-hoc outcome measures, another characteristic that was found to lead to high degrees of testing variability was the inability to maintain fixation as assessed by a fixation score of 1 on kinetic visual field testing. This inability was due to either an atypical form of RP which caused the development of a central scotoma (blind spot), or the absence of remaining central visual field. These individuals tended to have extremely variable results that were dependent upon their ability to use unsteady peripheral eccentric viewing to perform the clinical endpoint tests. Refer to Outcome Measure #1 for more information on how change in BCVA from baseline to month 12 is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study

Mean change in BCVA in study eye from baseline to month 12 as assessed by E-ETDRS in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21). Central foveal thickness, as measured by optical coherence tomography (OCT), is believed to be an anatomical marker representing the number of surviving foveal cones. A thicker central fovea corresponds to more surviving cone photoreceptors which are available to be up-regulated. Refer to Outcome Measure #1 for more information on how change in BCVA from baseline to month 12 is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population With ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness

Mean change in total area (degrees squared) of all islands of vision from baseline to 12 months in the Per Protocol (PP) Population (N=76). Refer to Outcome Measure #7 for background information on the PP population.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study.

Mean change in total area (degrees squared) of all islands of vision from baseline to 12 months in the Per Protocol (PP) Population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55). Refer to Outcome Measure #12 for background information on this analysis population.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study

Mean change in total area (degrees squared) of all islands of vision from baseline to 12 months in the Per Protocol (PP) Population with a study eye that is ≤15 letters worse than the fellow eye and with the ability to maintain fixation at baseline (N=42). Refer to Outcome Measure #16 for background information on this analysis population.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study

Mean change in total area (degrees squared) of all islands of vision from baseline to 12 months in the Per Protocol (PP) Population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at bbaseline (N=21). Refer to Outcome Measure #24 for background information on this analysis population.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness

The LLMT identifies the performance of RP patients as they walk along an indoor pathway of arrows and obstacles at varying lighting levels. The Critical Illumination Level (CIL) is the light level below which the patient has a markedly slower pace and more errors than all light levels above (brighter than) that point. The LLMT uses light levels that go from very dim (0.12 lux) to a very bright (500 lux), with evenly spaced increments that increase light by doubling the brightness of the room from the prior level. These evenly spaced light levels have been converted to a scale score to enable easier calculation of change scores. The dimmest level of 0 lux corresponds to a scale score of 13, whereas the brightest level of 500 lux corresponds to a scale score of 0. A positive scale score change from baseline to 12 months represents improvement, whereas a negative scale score change represents a decline. Refer to Outcome Measure #7 for background information on the PP population.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study, of which 66 posted a measurable CIL value at both baseline and 12 months. Missing values were not imputed for purposes of the PP Population analyses.

The LLMT identifies the performance of RP patients as they walk along an indoor pathway of arrows and obstacles at varying lighting levels. The Critical Illumination Level (CIL) is the light level below which the patient has a markedly slower pace and more errors than all light levels above (brighter than) that point. The LLMT uses light levels that go from very dim (0.12 lux) to very bright (500 lux), with evenly spaced increments that increase light by doubling the brightness of the room from the prior level. These evenly spaced light levels have been converted to a scale score to enable easier calculation of change scores. The dimmest level of 0 lux corresponds to a scale score of 13, whereas the brightest level of 500 lux corresponds to a scale score of 0. A positive scale score change from baseline to 12 months represents improvement, whereas a negative scale score change represents a decline. Refer to Outcome Measure #12 for background information on this analysis population.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study, of which 46 posted a measurable CIL value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

The LLMT identifies the performance of RP patients as they walk along an indoor pathway of arrows and obstacles at varying lighting levels. The Critical Illumination Level (CIL) is the light level below which the patient has a markedly slower pace and more errors than all light levels above (brighter than) that point. The LLMT uses light levels that go from very dim (0.12 lux) to very bright (500 lux), with evenly spaced increments that increase light by doubling the brightness of the room from the prior level. These evenly spaced light levels have been converted to a scale score to enable easier calculation of change scores. The dimmest level of 0 lux corresponds to a scale score of 13, whereas the brightest level of 500 lux corresponds to a scale score of 0. A positive scale score change from baseline to 12 months represents improvement, whereas a negative scale score change represents a decline. Refer to Outcome Measure #16 for background information on this analysis population.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study, of which 38 posted a measurable CIL value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

The LLMT identifies the performance of RP patients as they walk along an indoor pathway of arrows and obstacles at varying lighting levels. The Critical Illumination Level (CIL) is the light level below which the patient has a markedly slower pace and more errors than all light levels above (brighter than) that point. The LLMT uses light levels that go from very dim (0.12 lux) to very bright (500 lux), with evenly spaced increments that increase light by doubling the brightness of the room from the prior level. These evenly spaced light levels have been converted to a scale score to enable easier calculation of change scores. The dimmest level of 0 lux corresponds to a scale score of 13, whereas the brightest level of 500 lux corresponds to a scale score of 0. A positive scale score change from baseline to 12 months represents improvement, whereas a negative scale score change represents a decline. Refer to Outcome Measure #24 for background information on this analysis population.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness - all 21 subjects from this population completed the study, of which 20 posted a measurable CIL value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

The VA LV VFQ-48 (VFQ) is used to capture changes in patients' self-reporting of their difficulty with reading, mobility and performing other daily living activities affected by visual impairment. There are 4 scales on the VFQ including Visual Information, Reading, Visual Motor, and Mobility. The data shown in this outcome measure is focused on the fourth scale, Mobility, and is measured in units called logits. Higher positive values on the Mobility score represent better function and less impairment, whereas lower or negatives scores represent worse function or more impairment. Change in the Mobility scale on the VFQ is calculated by taking a subject's score at 12 months and subtracting from it the baseline score.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study

The VA LV VFQ-48 (VFQ) is used to capture changes in patients' self-reporting of their difficulty with reading, mobility and performing other daily living activities affected by visual impairment. There are 4 scales on the VFQ including Visual Information, Reading, Visual Motor, and Mobility. The data shown in this outcome measure is focused on the fourth scale, Mobility, and is measured in units called logits. Higher positive values on the Mobility score represent better function and less impairment, whereas lower or negatives scores represent worse function or more impairment. Change in the Mobility scale on the VFQ is calculated by taking a subject's score at 12 months and subtracting from it the baseline score.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study. Missing values were not imputed for purposes of this analysis.

The VA LV VFQ-48 (VFQ) is used to capture changes in patients' self-reporting of their difficulty with reading, mobility and performing other daily living activities affected by visual impairment. There are 4 scales on the VFQ including Visual Information, Reading, Visual Motor, and Mobility. A fifth value, Visual Ability, is an aggregate score of the 4 scales, measured in units called logits, and is calculated for each person based on item weighting using Raasch analysis. Visual Ability is used broadly to represent changes in subject-reported outcomes from visit to visit. Higher positive values on the Visual Ability score represent better function and less impairment, whereas lower or negatives scores represent worse function or more impairment. Change in the Visual Ability scale on the VFQ is calculated by taking a subject's score at 12 months and subtracting from it the baseline score. Refer to Outcome Measure #7 for background information on the PP population.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study

Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. The data shown here are for mean change from baseline to 12 months in the peak of the CS curve in the Per Protocol (PP) population (N=76). Refer to Outcome Measure #7 for background information on the PP population. Refer to Outcome Measure #2 for more information on how change in CS from baseline to month 12 is assessed.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study, of which 65 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of the PP Population analyses.

Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. The data shown here are for mean change from baseline to 12 months in the peak of the CS curve in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55). Refer to Outcome Measure #12 for background information on this analysis population. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study, of which 45 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. The data shown here are for mean change from baseline to 12 months in the peak of the CS curve in the PP Population with a study eye that is ≤15 letters worse than the fellow eye and with the ability to maintain fixation at Baseline (N=42). Refer to Outcome Measure #16 for background information on this analysis population. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study, of which 37 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. The data shown here are for mean change from baseline to 12 months in the peak of the CS curve in the Per Protocol (PP) Population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21). Refer to Outcome Measure #24 for background information on this analysis population. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness - all 21 subjects from this population completed the study, of which 19 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population (N=76), with a responder being defined as someone who gains at least 100% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to month 12 is assessed.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study, of which 65 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of the PP Population analyses.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55), with a responder being defined as someone who gains at least 100% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study, of which 45 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline and with the ability to maintain fixation at Baseline (N=42), with a responder being defined as someone who gains at least 100% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study, of which 37 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) Population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21), with a responder being defined as someone who gains at least 100% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness - all 21 subjects from this population completed the study, of which 19 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population (N=76), with a responder being defined as someone who gains at least 10 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. The PP population excludes seven subjects with major protocol violations, including two subjects who received a different treatment than the group to which they were randomized, four subjects with preexisting ophthalmic conditions meeting exclusion criteria (three glaucoma and one amblyopia), and one subject who experienced an intraocular lens subluxation (i.e., the displacement of a replacement lens following previous cataract surgery - unrelated to study drug) and could not perform endpoint testing at 12 months.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55), with a responder being defined as someone who gains at least 10 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. The work undertaken to understand what contributed to variability in measurements in the Phase 2b study, combined with the available published literature, has led to the identification of the characteristics of individuals who provide inconsistent/unreliable data. One such characteristic is found in subjects in whom there is a substantial BCVA disparity of more than 15 letters between their study (worse) eye and fellow (better) eye. This disparity has the potential to lead to variable testing results due to the brain's un-suppression of the image from their worse-seeing eye under clinical study monocular test conditions where their dominant eye is covered.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye and with the ability to maintain fixation at baseline (N=42), with a responder being defined as someone who gains at least 10 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. Beyond the BCVA disparity characteristic described in the previous post-hoc outcome measures, another characteristic that was found to lead to high degrees of testing variability was the inability to maintain fixation as assessed by a fixation score of 1 on kinetic visual field testing. This inability was due to either an atypical form of RP which caused the development of a central scotoma (blind spot), or the absence of remaining central visual field. These individuals tended to have extremely variable results that were dependent upon their ability to use unsteady peripheral eccentric viewing to perform the clinical endpoint tests.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21), with a responder being defined as someone who gains at least 10 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. Central foveal thickness, as measured by optical coherence tomography (OCT), is believed to be an anatomical marker representing the number of surviving foveal cones. A thicker central fovea corresponds to more surviving cone photoreceptors which are available to be up-regulated.

Time frame: 12 months

Population: Per Protocol (PP) Population With ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness

Comparison of responder rates across treatment groups in the Per Protocol (PP) population (N=76), with a responder being defined as someone who gains at least 13 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. The PP population excludes seven subjects with major protocol violations, including two subjects who received a different treatment than the group to which they were randomized, four subjects with preexisting ophthalmic conditions meeting exclusion criteria (three glaucoma and one amblyopia), and one subject who experienced an intraocular lens subluxation (i.e., the displacement of a replacement lens following previous cataract surgery - unrelated to study drug) and could not perform endpoint testing at 12 months.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55), with a responder being defined as someone who gains at least 13 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. The work undertaken to understand what contributed to variability in measurements in the Phase 2b study, combined with the available published literature, has led to the identification of the characteristics of individuals who provide inconsistent/unreliable data. One such characteristic is found in subjects in whom there is a substantial BCVA disparity of more than 15 letters between their study (worse) eye and fellow (better) eye. This disparity has the potential to lead to variable testing results due to the brain's un-suppression of the image from their worse-seeing eye under clinical study monocular test conditions where their dominant eye is covered.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye and with the ability to maintain fixation at baseline (N=42), with a responder being defined as someone who gains at least 13 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. Beyond the BCVA disparity characteristic described in the previous post-hoc outcome measures, another characteristic that was found to lead to high degrees of testing variability was the inability to maintain fixation as assessed by a fixation score of 1 on kinetic visual field testing. This inability was due to either an atypical form of RP which caused the development of a central scotoma (blind spot), or the absence of remaining central visual field. These individuals tended to have extremely variable results that were dependent upon their ability to use unsteady peripheral eccentric viewing to perform the clinical endpoint tests.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21), with a responder being defined as someone who gains at least 13 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. Central foveal thickness, as measured by optical coherence tomography (OCT), is believed to be an anatomical marker representing the number of surviving foveal cones. A thicker central fovea corresponds to more surviving cone photoreceptors which are available to be up-regulated.

Time frame: 12 months

Population: Per Protocol (PP) Population With ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness

Comparison of responder rates across treatment groups in the Per Protocol (PP) population (N=76), with a responder being defined as someone who gains at least 150% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to month 12 is assessed.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study, of which 65 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of the PP Population analyses.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55), with a responder being defined as someone who gains at least 150% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study, of which 45 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline and with the ability to maintain fixation at Baseline (N=42), with a responder being defined as someone who gains at least 150% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study, of which 37 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) Population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21), with a responder being defined as someone who gains at least 150% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness - all 21 subjects from this population completed the study, of which 19 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population (N=76), with a responder being defined as someone who gains at least 15 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. The PP population excludes seven subjects with major protocol violations, including two subjects who received a different treatment than the group to which they were randomized, four subjects with preexisting ophthalmic conditions meeting exclusion criteria (three glaucoma and one amblyopia), and one subject who experienced an intraocular lens subluxation (i.e., the displacement of a replacement lens following previous cataract surgery - unrelated to study drug) and could not perform endpoint testing at 12 months.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55), with a responder being defined as someone who gains at least 15 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. The work undertaken to understand what contributed to variability in measurements in the Phase 2b study, combined with the available published literature, has led to the identification of the characteristics of individuals who provide inconsistent/unreliable data. One such characteristic is found in subjects in whom there is a substantial BCVA disparity of more than 15 letters between their study (worse) eye and fellow (better) eye. This disparity has the potential to lead to variable testing results due to the brain's un-suppression of the image from their worse-seeing eye under clinical study monocular test conditions where their dominant eye is covered.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye and with the ability to maintain fixation at baseline (N=42), with a responder being defined as someone who gains at least 15 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. Beyond the BCVA disparity characteristic described in the previous post-hoc outcome measures, another characteristic that was found to lead to high degrees of testing variability was the inability to maintain fixation as assessed by a fixation score of 1 on kinetic visual field testing. This inability was due to either an atypical form of RP which caused the development of a central scotoma (blind spot), or the absence of remaining central visual field. These individuals tended to have extremely variable results that were dependent upon their ability to use unsteady peripheral eccentric viewing to perform the clinical endpoint tests.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21), with a responder being defined as someone who gains at least 15 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. Central foveal thickness, as measured by optical coherence tomography (OCT), is believed to be an anatomical marker representing the number of surviving foveal cones. A thicker central fovea corresponds to more surviving cone photoreceptors which are available to be up-regulated.

Time frame: 12 months

Population: Per Protocol (PP) Population With ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness

Comparison of responder rates across treatment groups in the Per Protocol (PP) population (N=76), with a responder being defined as someone who gains at least 200% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to month 12 is assessed.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study, of which 65 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of the PP Population analyses.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55), with a responder being defined as someone who gains at least 200% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study, of which 45 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline and with the ability to maintain fixation at Baseline (N=42), with a responder being defined as someone who gains at least 200% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study, of which 37 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) Population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21), with a responder being defined as someone who gains at least 200% in Peak CS from baseline to month 12. Assessment of the ability to detect changes in shades of grey, as measured with a vertical striped pattern that varies in width (cycles per degree or CPD); CS thresholds are created by taking the mean of multiple trials at each pattern width. A CS curve is created using a minimum of three pattern widths, one at the subject's peak or highest sensitivity, and then one larger and smaller pattern width on either side of the peak. Refer to Outcome Measure #2 for more information on how change in CS from baseline to 12 months is assessed.

Time frame: 12 months

Population: Per Protocol (PP) Population ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness - all 21 subjects from this population completed the study, of which 19 posted a measurable CS value at both baseline and 12 months. Missing values were not imputed for purposes of this analysis.

Comparison of responder rates across treatment groups in the Per Protocol (PP) population (N=76), with a responder being defined as someone who gains at least 20 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. The PP population excludes seven subjects with major protocol violations, including two subjects who received a different treatment than the group to which they were randomized, four subjects with preexisting ophthalmic conditions meeting exclusion criteria (three glaucoma and one amblyopia), and one subject who experienced an intraocular lens subluxation (i.e., the displacement of a replacement lens following previous cataract surgery - unrelated to study drug) and could not perform endpoint testing at 12 months.

Time frame: 12 months

Population: Per Protocol (PP) population - 74 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye at baseline (N=55), with a responder being defined as someone who gains at least 20 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. The work undertaken to understand what contributed to variability in measurements in the Phase 2b study, combined with the available published literature, has led to the identification of the characteristics of individuals who provide inconsistent/unreliable data. One such characteristic is found in subjects in whom there is a substantial BCVA disparity of more than 15 letters between their study (worse) eye and fellow (better) eye. This disparity has the potential to lead to variable testing results due to the brain's un-suppression of the image from their worse-seeing eye under clinical study monocular test conditions where their dominant eye is covered.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes - 54 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye and with the ability to maintain fixation at baseline (N=42), with a responder being defined as someone who gains at least 20 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. Beyond the BCVA disparity characteristic described in the previous post-hoc outcome measures, another characteristic that was found to lead to high degrees of testing variability was the inability to maintain fixation as assessed by a fixation score of 1 on kinetic visual field testing. This inability was due to either an atypical form of RP which caused the development of a central scotoma (blind spot), or the absence of remaining central visual field. These individuals tended to have extremely variable results that were dependent upon their ability to use unsteady peripheral eccentric viewing to perform the clinical endpoint tests.

Time frame: 12 months

Population: Per Protocol (PP) Population with ≤15 letter baseline BCVA disparity between eyes and ability to maintain fixation - 41 subjects from this population completed the study

Comparison of responder rates across treatment groups in the Per Protocol (PP) population with a study eye that is ≤15 letters worse than the fellow eye, the ability to maintain fixation, and with at least 130µm of central foveal thickness (as measured in the central subfield region) remaining at baseline (N=21), with a responder being defined as someone who gains at least 20 letters in BCVA (assessed by E-ETDRS) from baseline to month 12. Central foveal thickness, as measured by optical coherence tomography (OCT), is believed to be an anatomical marker representing the number of surviving foveal cones. A thicker central fovea corresponds to more surviving cone photoreceptors which are available to be up-regulated.

Time frame: 12 months

Population: Per Protocol (PP) Population With ≤15 Letter Baseline BCVA Disparity Between Eyes, Ability to Maintain Fixation, and \>130µm Central Foveal Thickness