The efficacy of LUXTURNA in pediatric and adult patients with biallelic RPE65 mutation-associated retinal dystrophy was evaluated in an open-label, two-center, randomized trial (Study 2). Of the 31 enrolled subjects, 21 subjects were randomized to receive subretinal injection of LUXTURNA. One subject discontinued from the study prior to treatment. Ten subjects were randomized to the control (non-intervention) group. One subject in the control group withdrew consent and was discontinued from the study. The nine subjects who were randomized to the control group were crossed over to receive subretinal injection of LUXTURNA after one year of observation. The average age of the 31 randomized subjects was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). The 31 randomized subjects included 13 males and 18 females. Sixty-eight percent (68%) of the subjects were White, 16% were Asian, 10% were American Indian or Alaska Native, and 6% were Black or African-American. Bilateral subretinal injections of LUXTURNA were administered sequentially in two separate surgical procedures with an interval of 6 to 18 days.

The efficacy of LUXTURNA was established on the basis of multi-luminance mobility testing (MLMT) score change from Baseline to Year 1. The MLMT was designed to measure changes in functional vision, as assessed by the ability of a subject to navigate a course accurately and at a reasonable pace at different levels of environmental illumination. The MLMT was assessed using both eyes and each eye separately at one or more of seven levels of illumination, ranging from 400 lux (corresponding to a brightly lit office) to 1 lux (corresponding to a moonless summer night). Each light level was assigned a score code ranging from 0 to 6. A higher score indicated that a subject was able to pass the MLMT at a lower light level. A score of -1 was assigned to subjects who could not pass MLMT at a light level of 400 lux. The MLMT of each subject was videotaped and assessed by independent graders. The MLMT score was determined by the lowest light level at which the subject was able to pass the MLMT. The MLMT score change was defined as the difference between the score at Baseline and the score at Year 1. A positive MLMT score change from Baseline to Year 1 visit indicated that the subject was able to complete the MLMT at a lower light level.

Additional clinical outcomes were also evaluated, including full-field light sensitivity threshold (FST) testing, visual acuity, and visual fields.

Table 2 summarizes the median MLMT score change from Baseline to Year 1 in the LUXTURNA treatment group as compared to the control group. A median MLMT score change of 2 was observed in the LUXTURNA treatment group, while a median MLMT score change of 0 was observed in the control group, when using both eyes or the first-treated eye. An MLMT score change of two or greater is considered a clinically meaningful benefit in functional vision.

Table 3 shows the number and percentage of subjects with different magnitudes of MLMT score change using both eyes at Year 1. Eleven of the 21 (52%) subjects in the LUXTURNA treatment group had an MLMT score change of two or greater, while one of the ten (10%) subjects in the control group had an MLMT score change of two.

Figure 6 shows MLMT performance of individual subjects using both eyes at Baseline and at Year 1.

Figure 6. MLMT Score Using Both Eyes at Baseline and Year 1 for Individual Subjects (Study 2)

Note for Figure 6: *subjects who were withdrawn or discontinued. The open circles are the baseline scores. The closed circles are the Year 1 scores. The numbers next to the solid circle represent score change at Year 1. The horizontal lines with arrows represent the magnitude of the score change and its direction. Arrows pointing towards the right represent improvement. The top section shows the results of the 21 subjects in the treatment group. The bottom section shows the results of the 10 subjects in the control group. Subjects in each group are chronologically organized by age, with the youngest subject at the top and the oldest subject at the bottom.

Analysis of white light FST testing showed statistically significant improvement from Baseline to Year 1 in the LUXTURNA treatment group compared to the control group. The change in visual acuity from Baseline to Year 1 was not significantly different between the LUXTURNA and control groups.

Figure 7 shows the effect of LUXTURNA over the two-year period in the LUXTURNA treatment group, as well as the effect in the control group after crossing over to receive subretinal injection of LUXTURNA. A median MLMT score change of two was observed for the LUXTURNA treatment group at Day 30, and this effect was sustained over the remaining follow-up visits throughout the two-year period. For the control group, a median MLMT score change of 0 was observed at all four follow up visits during the first year. However, after crossing-over to receive subretinal injection of LUXTURNA, the subjects in the control group showed a similar response to LUXTURNA as compared to the subjects in the LUXTURNA treatment group.

Figure 7. MLMT Time-Course over Two Years: Using Both Eyes (Study 2)

Note for Figure 7: Each box represents the middle 50% of distribution of MLMT score change. Vertical dotted lines represent additional 25% above and below the box. The horizontal bar within each box represents the median. The dot within each box represents the mean. The solid line connects the mean MLMT score changes over visits for the treatment group, including five visits during the first year and one visit at Year 2 (marked as x365). The dotted line connects the mean MLMT score change over visits for the control group, including five visits during the first year without receiving LUXTURNA, and four visits within the second year (marked as x30, x90, x180, and x365) after cross-over at Year 1 to receive LUXTURNA.