The Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa and Leber Congenital Amaurosis
a study on Retinitis Pigmentosa Leber Congenital Amaurosis Blindness
Summary
- Eligibility
- for people ages 6 years and up (full criteria)
- Location
- at La Jolla, California and other locations
- Dates
- study startedestimated 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 two subgroups of subjects with three consecutive cohorts.
A total of 18 adult RP subjects with at least 9 adult subjects from each of the following subgroups will be selected:
Biallelic autosomal recessive NR2E3 mutations or autosomal dominant NR2E3 mutations
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 adult subjects enrolled 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 adult subjects were used to follow the 3+3 design and no dose limited toxicities occurred, then the remaining maximum of 9 adult 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 adult LCA patients with CEP290 mutations will be enrolled in the Phase 2 portion of the study in parallel with 9 adult patients with RP due to NR2E3 and RHO mutations.
A total of 3 additional pediatric subjects with RP or LCA, including 1 subject from each of the following subgroups, will also be enrolled in the Phase 2 portion:
RP: Biallelic autosomal recessive NR2E3 mutations or autosomal dominant NR2E3 mutation
RP: Autosomal dominant RHO mutations
LCA: Autosomal recessive CEP290 mutations
For the Phase 2 portion, adult 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.
Following DSMB confirmation, pediatric dosing will be initiated at a de-escalated dose of one step lower than the determined MTD in the adult subject population (i.e. if the MTD in the adult population is the high dose, 1.66 x 1011 vg/mL, then the pediatric subjects will receive the medium dose concentration of 3.33 x 1010 vg/mL). This de-escalated dose will be administered as a precautionary measure due to the pediatric population potentially being more prone to a greater inflammatory response and in consideration of OCU400 being the first modifier gene therapy to be administered in pediatric subjects with retinal dystrophy.
After the first two pediatric subjects receive the medium dose, 3.33 x 1010 vg/mL, and DSMB reviews safety data, the third pediatric subject may be considered for the higher MTD determined in adult subjects of 1.66 x 1011 vg/mL.
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
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 do 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 24 patients (18 adult RP, 3 adult LCA, 2 pediatric RP, and 1 pediatric 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 and was chosen per FDA's recommendation to include 3 subjects.
Keywords
Retinitis Pigmentosa, Leber Congenital Amaurosis, NR2E3, Rhodopsin, Enhanced S-cone syndrome, Cep290, Blindness, Retinitis, OCU400 Low Dose, OCU400 Mid Dose, OCU400 High Dose, OCU400
Eligibility
For people ages 6 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 Adult RP:
Males or females ≥18 years of age at the time of informed consent.
Confirmed genetic diagnosis of biallelic autosomal recessive NR2E3 mutations or autosomal dominant NR2E3 mutation for Subgroup 1 or autosomal dominant RHO mutations for Subgroup 2.
For the sentinel subject of Cohort 1-3, BCVA ≤ 20/160 in study eye or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in study eye.
For non-sentinel subject, BCVA ≤ 20/50 or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in 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 review of results of screening assessments.
Exclusion Criteria for Adult RP:
Subject lacks evidence of 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.
Breast-feeding, pregnancy, sperm donation or inability to practice strict contraception within the Treatment Observation Period.
Any medical condition with life expectancy < 6 years.
Inclusion Criteria for Adult 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) 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 Adult 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)
Breast-feeding, pregnancy, sperm donation or inability to practice strict contraception within the Treatment Observation Period.
Inclusion Criteria for Pediatric RP:
Males or females 6 - 17 years of age (inclusive) at the time of parental permission and/or assent, whichever is applicable.
Confirmed genetic diagnosis of biallelic autosomal recessive NR2E3 mutations or autosomal dominant NR2E3 mutation for Subgroup 1 or autosomal dominant RHO mutations for Subgroup 2.
BCVA ≤ 20/50 or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in 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 review of results of screening assessments
Exclusion Criteria for Pediatric RP:
Subject lacks evidence of 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.
Breast-feeding, pregnancy, or inability to practice strict contraception within the Treatment Observation Period for subjects of childbearing potential.
Active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis)
Any medical condition with life expectancy < 6 years.
Inclusion Criteria for Pediatric LCA:
Males or females 6 - 17 years of age (inclusive) at the time of parental permission and/or assent, whichever is applicable.
Clinical diagnosis of LCA and confirmed genetic diagnosis of CEP290 mutation.
Best corrected visual acuity (BCVA) 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 Pediatric 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 subject 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)
Breast-feeding, pregnancy, or inability to practice strict contraception within the Treatment Observation Period for subjects of childbearing potential.
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 24 study participants
- Last Updated
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