study to assess the safety and efficacy of ocu400 for retinitis pigmentosa and leber congenital amaurosis

Conditions: Retinitis Pigmentosa; Leber Congenital Amaurosis

Summary: this is a phase 1/2 study to assess the safety and efficacy 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 (ocu400-101). to document prospective eye pathology in the above subjects investigators will also conduct a natural history study (ocu400-104)i this is a multicenter study, which will be conducted in two phases and will enroll up to a total of 24 subjects in the ocu400-101 and 100 subjects in the ocu400-104 study.

this study will be conducted in two phases enrolling up to 24 subjects. treated subjects will receive a single subretinal injection of ocu400 in the study eye. 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 from each of the following subgroups with biallelic autosomal recessive nr2e3 mutations, autosomal dominant nr2e3 mutations or autosomal dominant rho mutations will be selected for dose escalation. 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. up to 3 additional adult lca patients with cep290 mutations and at least 1 pediatric lca subject, will be enrolled in the phase 2 portion. sample size justification: the trial will enroll up to 24 patients (18 adult rp, up to 3 lca patients, and at least 1 pediatric lca patient) in both phase 1 and phase 2 components. participants who meet eligibility criteria, will be enrolled, and receive a single subretinal injection of ocu400 in one study eye. participants are considered to have completed this study if they complete the final eos visit week 48 (12 months following the ip dose). the study duration will be approximately 58 weeks for each participant and will be followed in long term safety follow up for additional 2 years. natural history study (ocu400-104, a prospective and retrospective natural history study of rp and lca): this is an observatory study for the prospective natural history of rp and lca in adult and pediatric subjects. the study will also collect and review retrospective data and ophthalmology examination of natural history and progression of disease for all subjects starting with the earliest timepoint on or after the date of their diagnosis of rp or lca.

Eligibility criteria:
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: 1. males or females ≥ 18 years of age at the time of informed consent. 2. 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. 3. 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. 4. 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. 5. 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. exclusion criteria for adult rp: 1. subject lacks evidence of outer nuclear layer. 2. 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. 3. previous treatment with a gene-therapy or cell therapy product. 4. previous treatment with any investigational drug or device within one year. 5. any contraindications for subretinal injection. 6. cataract surgery within 3 months. yag capsulotomy within 1 month. any other intraocular surgery within 6 months. 7. breast-feeding, pregnancy, sperm donation or inability to practice strict contraception within the treatment observation period. 8. any medical condition with life expectancy \< 6 years. inclusion criteria for adult lca: 1. males or females at least 18 years of age at the time of informed consent. 2. clinical diagnosis of lca and confirmed genetic diagnosis of cep290 mutation. 3. best corrected visual acuity (bcva) equal to or worse than logmar +0.7 but equal to or better than logmar 3.8 (light perception) in the study eye. 4. detectable outer nuclear layer in the macular region as determined by spectral-domain optical coherence tomography (sd-oct). exclusion criteria for adult lca: 1. any symptom of central nervous system involvement/disease that would impact the ability to measure visual function. 2. 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. 3. any contraindications for subretinal injection. 4. any intraocular surgery within 6 months. 5. active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis). 6. breast-feeding, pregnancy, sperm donation or inability to practice strict contraception within the treatment observation period. inclusion criteria for pediatric rp: 1. males or females 6 - 17 years of age (inclusive) at the time of parental permission and/or assent, whichever is applicable. 2. 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. 3. bcva ≤ 20/32 or visual field less than 20° in any meridian, as measured by a iii4e isopter or equivalent in study eye. 4. 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. exclusion criteria for pediatric rp: 1. subject lacks evidence of outer nuclear layer as determined by spectral-domain optical coherence tomography (sd-oct). 2. 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. 3. previous treatment with a gene-therapy or cell therapy product. 4. previous treatment with any investigational drug or device within one year. 5. any contraindications for subretinal injection. 6. cataract surgery within 3 months. yag capsulotomy within 1 month. any other intraocular surgery within 6 months. 7. breast-feeding, pregnancy, or inability to practice strict contraception within the treatment observation period for subjects of childbearing potential. 8. active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis). 9. any medical condition with life expectancy \< 6 years. inclusion criteria for pediatric lca: 1. males or females 6 - 17 years of age (inclusive) at the time of parental permission and/or assent, whichever is applicable. 2. clinical diagnosis of lca and confirmed genetic diagnosis of cep290 mutation. 3. best corrected visual acuity (bcva) equal to or worse than logmar +0.7 but equal to or better than logmar 3.8 (light perception) in the study eye. 4. detectable outer nuclear layer in the macular region as determined by spectral-domain optical coherence tomography (sd-oct). exclusion criteria for pediatric lca: 1. any symptom of central nervous system involvement/disease that would impact the ability to measure visual function. 2. 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. 3. any contraindications for subretinal injection. 4. any intraocular surgery within 6 months. 5. active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis). 6. breast-feeding, pregnancy, or inability to practice strict contraception within the treatment observation period for subjects of childbearing potential.

Keywords: nr2e3 rhodopsin enhanced s-cone syndrome cep290