The Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa and Leber Congenital Amaurosis

To assess the safety of unilateral subretinal administration of OCU400 in patients with retinitis pigmentosa associated with NR2E3 and RHO mutations and in patients with LCA due to mutation(s) in CEP290 gene (LCA10).

This is a multicenter, open-label, dose ranging study in three subgroups of subjects with three consecutive cohorts. A total of 18 RP subjects with at least 6 subjects from each of the following subgroups will be selected: Biallelic autosomal recessive NR2E3 mutations Autosomal dominant NR2E3 mutation Autosomal dominant RHO mutations For the Phase I portion of the study, the 3+3 design for sequential dose escalating cohorts will be used with scheduled 3 dosing levels between 9 and 18 subjects will be used to follow the design. The following algorithm will be followed: Cohort 1 Low Dose: 3+3 subjects will receive subretinal injection of OCU400 low dose concentration (1.66 x 1010 vg/mL. The sentinel subject will receive subretinal injection of up to 200 µL (3.33 x 109 vg/eye) in low dose. Based on safety outcome in the first subject, dose volume will further be increased up to 300 µL (5.0x 109 vg/eye) in the subsequent subjects. 1 of 3 results will occur from the first 3 subjects: If none of the first 3 subjects on low dose concentration (1.66 x 1010 vg/mL) are determined by the DSMB to have dose-limiting toxicity, then the dose will be escalated for the next cohort. If 2 or more of the first 3 subjects on low dose concentration (1.66 x 1010 vg/mL) are determined by the DSMB to have dose-limiting toxicity, then the dose will be de-escalated for the next cohort. If exactly 1 of the first 3 subjects on low dose concentration (1.66 x 1010 vg/mL) is determined by the DSMB to have dose-limiting toxicity, then 3 additional patients will be enrolled on low dose concentration (1.66 x 1010 vg/mL) at up to 300 uL dose volume. If none of the 3 additional patients are determined by the DSMB to have dose-limiting toxicity, then the dose will be escalated for the next cohort. If 1 or more of the 3 additional patients are determined by the DSMB to have dose-limiting toxicity, then the dose will be de-escalated for the next cohort. Cohort 2 Medium Dose: 3+3 subjects will receive subretinal injection of up to 300μl OCU400 medium dose concentration (3.33 x 1010 vg/mL) following the same algorithm as Cohort 1. Cohort 3 High Dose: 3+3 subjects who will receive subretinal injection of up to 300μl OCU400 high dose concentration (1.66 x 1011 vg/mL) following the same algorithm as Cohort 1. Thus, under this design there will be 9 subjects enrolled subjects if there are no dose-limiting toxicities and up to 18 under the condition that exactly 1 of the first 3 of every cohort is determined to have a dose-limiting toxicity. Following the Phase 1 portion of the study, if less than 18 subjects were used to follow the 3+3 design and no dose limited toxicities occurred, then the remaining maximum of 9 subjects will be enrolled in the last safe dosing level to provide additional sample for exploring efficacy of the Phase 2 portion of the study. Three additional LCA patients with CEP290 mutation will be enrolled in the Phase 2 portion of the study in parallel with 9 patients with RP due to NR2E3 and RHO mutations. For the Phase 2 portion, patients will receive a subretinal injection of up to 300μl OCU400 at the last safe dose level determined from the Phase 1 portion of the study. The study for an individual subject will consist of the following periods: A Screening Period of up to 3 months (90 days) A Baseline Period of up to 14 days A Treatment Observation Period of 1 year during which Study Drug will be administered once to the treated eye on Day 0 The assessments and measurements will be performed according to the Schedule of Procedures Following the 12 months post-dose visit in the Treatment Observation Period, at End of Study, subjects will be encouraged to enroll in an extension study (OCU400-102) to assess the safety of OCU400 administered in the contralateral eye. Those who does not enroll in OCU400-102, will be enrolled in a Long-Term Safety Follow-up (LTSFU) extension study (OCU400-103) for an additional 4 years. Sample Size Justification: The trial will enroll up to 21 patients (18 RP and 3 LCA) in both Phase 1 and Phase 2 components. The sample size was estimated based on a minimum number necessary to obtain a preliminary clinical assessment regarding OCU400's safety profile. The limited number for LCA patients is necessitated by the rarity of patients with LCA10.