Summary

Eligibility
for people ages 18 years and up (full criteria)
Location
at La Jolla, California and other locations
Dates
study started
estimated completion

Description

Summary

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).

Official Title

Phase 1/2 Study to Assess the Safety and Efficacy of Ocu400 for Retinitis Pigmentosa Associated With Nr2e3 and Rho Mutations and Leber Congenital Amaurosis With Mutation(S) in Cep290 Gene

Details

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.

Keywords

Retinitis Pigmentosa, Leber Congenital Amaurosis, NR2E3, Rhodopsin, Enhanced S-cone syndrome, Cep290, Blindness, Retinitis, OCU400 Low Dose, OCU400 Mid Dose, OCU400 High Dose

Eligibility

For people ages 18 years and up

Diagnosis and main criteria for inclusion:

Subjects meeting all inclusion criteria and none of the exclusion criteria are eligible for study participation.

Inclusion Criteria for RP:

Males or females ≥18 years of age at the time of informed consent.

Confirmed genetic diagnosis of biallelic autosomal recessive NR2E3 mutations for Subgroup 1, autosomal dominant NR2E3 mutation for Subgroup 2, or autosomal dominant RHO mutations for Subgroup 3.

For the sentinel subject of Cohort 1-3, BCVA ≤ 20/160 in the study eye or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in the study eye.

For non-sentinel subjects, BCVA ≤ 20/50 or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in the study eye.

Able to perform a multi-luminance mobility testing (MLMT) using study eye, but unable to pass the MLMT at 1 lux, the lowest luminance level tested.

Subject eligibility for NR2E3 and RHO subgroups who pass the MLMT at 1 lux may be assessed on a case-by-case basis by Ocugen following a review of the results of screening assessments.

Exclusion Criteria for RP:

The subject lacks evidence of the outer nuclear layer, i.e., containing the nuclei of the retinal photoreceptors as determined by spectral-domain optical coherence tomography (SD-OCT).

Considered unsuitable for any reason that may either place the subject at increased risk during participation or interfere with the interpretation of the study outcomes by the Investigator, or the Sponsor after reviewing medical, ocular, and psychiatric history, clinical examination, and laboratory evaluation, as determined by the Investigator, i.e., inability to fixate, high myopia ≥10 diopters, glaucoma, medium haze, other retinal pathologies, and > 3-fold elevation of liver enzymes or > 2-fold elevation of serum creatinine, etc.

Previous treatment with a gene therapy or cell therapy product.

Previous treatment with any investigational drug or device within one year.

Any contraindications for subretinal injection.

Cataract surgery within 3 months. YAG capsulotomy within 1 month. Any other intraocular surgery within 6 months.

Breastfeeding, pregnancy, sperm donation, or inability to practice strict contraception within the Treatment Observation Period.

Any medical condition with a life expectancy < 6 years.

Inclusion Criteria for LCA:

Males or females at least 18 years of age at the time of informed consent.

Clinical diagnosis of LCA and confirmed genetic diagnosis of CEP290 mutation.

Best corrected visual acuity (BCVA) is equal to or worse than LogMAR +0.7 but equal to or better than LogMAR 3.5 in the study eye.

Detectable outer nuclear layer in the macular region as determined by spectral-domain optical coherence tomography (SD-OCT).

Exclusion Criteria for LCA:

Any symptom of central nervous system involvement/disease that would impact the ability to measure visual function

Considered unsuitable for any reason that may either place the patient at increased risk during participation or interfere with the interpretation of the study safety and efficacy outcomes by the Investigator, after reviewing medical, ocular, and psychiatric history, clinical examination, and laboratory evaluation, as determined by the Investigator, i.e., high myopia ≥10 diopters, glaucoma, insufficient ocular media clarity and pupil dilation, other retinal pathologies, unstable systemic disease, etc.

Previous treatment with a gene therapy or cell therapy product.

Previous treatment with any investigational drug or device within one year.

Any contraindications for subretinal injection.

Any intraocular surgery within 6 months.

Active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis)

Breastfeeding, pregnancy, sperm donation, or inability to practice strict contraception within the Treatment Observation Period.

Locations

  • Ocugen Site 5 - University of California, San Diego (UCSD) - Shiley Eye Institute accepting new patients
    La Jolla California 92093 United States
  • Ocugen Site 2 - Casey Eye Institute - OHSU accepting new patients
    Portland Oregon 97239 United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Ocugen
Links
Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa
ID
NCT05203939
Phase
Phase 1/2 research study
Study Type
Interventional
Participants
Expecting 21 study participants
Last Updated