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

A 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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Retinitis Pigmentosa; Leber Congenital Amaurosis
• Intervention / Treatment: Drug: OCU400 Low Dose; Drug: OCU400 Med Dose; Drug: OCU400 High Dose; Drug: OCU400 Second Eye Dosing

Detailed Description

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 an additional 2 years.

Participants from the Phase 1/2 study who previously received the investigational product (OCU400) in one eye may be eligible to receive OCU400 in the untreated fellow eye, provided they meet the inclusion/exclusion criteria and have completed week 48 follow up visit.

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. Enrollment for this study has closed.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85020
      • Associated Retina Consultants
  • California
    • La Jolla, California, United States, 92093
      • Ocugen Site 5 - University of California, San Diego (UCSD) - Shiley Eye Institute
  • Florida
    • Miami, Florida, United States, 33136
      • Ocugen Site 3 - Bascom Palmer Eye Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Ocugen Site 6 - Emory University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Ocugen Site 2 - Casey Eye Institute - OHSU
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Ocugen Site 8 - Mid Atlantic Retina - Wills Eye Hospital
  • Texas
    • Dallas, Texas, United States, 75231
      • Ocugen Site 1 - Retina Foundation of the Southwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (Low Dose); Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation or RHO mutations subgroup	Drug: OCU400 Low Dose; subretinal injection of up to 1.66×10E10 vg/mL
Experimental: Cohort 2 (Mid Dose); Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation or RHO mutations subgroup	Drug: OCU400 Med Dose; subretinal injection of up to 3.33×10E10 vg/mL
Experimental: Cohort 3 (High Dose); Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation, RHO mutations subgroup	Drug: OCU400 High Dose; subretinal injection of up to 1.66×10E11 vg/mL
Experimental: Pediatric Arm; Pediatric subjects will receive the medium dose concentration	Drug: OCU400 Med Dose; subretinal injection of up to 3.33×10E10 vg/mL
Experimental: Phase 2 (High and Medium Dose); Following DSMB confirmation, adult RP subjects with Biallelic autosomal recessive NR2E3 mutations, autosomal dominant NR2E3 mutations, Autosomal dominant RHO mutations will receive a high dose concentration of OCU400 or LCA patients with CEP290 mutation will receive a medium dose concentration of OCU400.	Drug: OCU400 Med Dose; subretinal injection of up to 3.33×10E10 vg/mL; Drug: OCU400 High Dose; subretinal injection of up to 1.66×10E11 vg/mL
Experimental: Adult Arm; Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation, RHO mutations subgroup will receive a high dose concentration of OCU400 and LCA patients with CEP290 will receive a medium dose concentration of OCU400	Drug: OCU400 Med Dose; subretinal injection of up to 3.33×10E10 vg/mL; Drug: OCU400 High Dose; subretinal injection of up to 1.66×10E11 vg/mL
Experimental: Second Eye Dosing; Eligible RP participants will be dosed in the untreated fellow eye with a therapeutic dose used in Phase 3 study of OCU400 (1.0x10E11vg/mL in 250 μl ) and will be followed for an additional 48 weeks.	Drug: OCU400 Second Eye Dosing; subretinal injection of 1.0x10E11vg/mL in 250 μl
No Intervention: 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 earliest timepoint on or after the date of their diagnosis of RP or LCA. Subjects will be seen up to a total of four times during the 12 months of the Observational Period, at baseline, 3 months, 6 months and 12 months. A total of up to 100 subjects will be enrolled in the study, including: Approximately 76 newly enrolled subjects consisting of 50 adult RP subjects, 6 adult LCA subjects, 20 pediatric RP/LCA subjects. Up to 24 subjects that reconsent from the OCU400-101 study (subjects from OCU400-101 will provide data on their untreated eye)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study Drug-related adverse events (SDAE)	Counts, frequencies and percentages of SDAEs. SDAE is a primary adverse event of interest and defined as AEs and SAEs that are direct subjects to the Study Drug only.	1 year
Treatment-Emergent adverse events (TEAEs)	Counts, frequencies and percentages TEAEs. TEAEs are defined as an event that was not present prior to administration of the dose of study drug and present after the dose, or if it represents the exacerbation of an event that was present prior to the dose.	1 year
Serious adverse events (SAEs)	Counts, frequencies and percentages of SAEs including Resulted in Death, Life-threatening, Hospitalization, Disabling/incapacitating, Congenital anomaly or birth defect and medically significant AEs ( AE that did not meet any of the above criteria but could have jeopardized the subject and might have required medical or surgical intervention to prevent one of the outcomes listed above).	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best-corrected visual acuity (BCVA)	Measured as the ETDRS letter score on the EVA tester or E-ETDRS charts. Electronic ETDRS Visual Acuity Testing Protocol will be followed (confidential).	1 year (Changes from baseline)
Low-luminance visual acuity (LLVA)	Electronic Visual Acuity Tester (EVA) and a Sponsor specific Low-Luminance lens will be used. Early Treatment of Diabetic Retinopathy Study (ETDRS) will also be accepted as a backup.	1 year (Changes from baseline)
Slit-lamp biomicroscopy	Changes in visual function.	1 year (Changes from baseline)
Intraocular pressure (IOP)	IOP measurement by applanation or rebound tonometry. Confirmation with Goldmann tonometer if IOP reading is outside the normal range (8-21mmHg).	1 year (Changes from baseline)
Indirect ophthalmoscopy	If visual acuity is so poor that the participant is unable to count fingers or perceive hand motion, light perception will be tested with the indirect ophthalmoscope as the light source.	1 year (Changes from baseline)
anti-AAV5 (anti Adeno-associated virus type 5)	Blood samples will be collected for the assessment. These samples will be analyzed using validated assays at a bioanalytical laboratory.	1 year
anti-hNR2E3 antibodies (hNR2E3 gene)	Blood samples will be collected for the assessment. These samples will be analyzed using validated assays at a bioanalytical laboratory.	1 year
T-cell response	Blood samples will be collected for the assessment. These samples will be analyzed using validated assays at a bioanalytical laboratory.	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multi-luminance mobility testing (MLMT)	Subjects will navigate a standardized mobility maze under set conditions as specified times during the study. The mobility testing will follow a standardized administration and data acquisition protocol and may only be administered by site staff certified in the methodology.	1 year (Changes from baseline)
Contrast sensitivity	Contrast sensitivity will be conducted using Pelli-Robson chart.	1 year (Changes from baseline)
Wide-field fundus autofluorescence (wf-FAF)	The intensity of FAF will be evaluated using 55° posterior pole scanning.	1 year (Changes from baseline)
Full Field Light Stimulation Threshold (FST)	FST will be completed at scheduled times throughout the study period	1 year (Changes from baseline)
Changes in ellipsoid zone width/length on wide-field 20° SD-OCT	Ellipsoid zone area/outer segment length will be determined by Spectral Domain Optical Coherence Tomography (SD-OCT) using standardized systems and acquisition protocols.	1 year (Changes from baseline)
Photopic Static Visual Fields	The Octopus 900 will be used with a standardized white-on-white full field and a blue-on-yellow with full field	1 year (Changes from baseline)
Vision on Quality of Life	The National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ25) and the Michigan Retinal Degeneration Questionnaire (MRDQ) questionnaires (for RP Adult subjects only) will be administered to assess the impact of vision on quality of subject's life.	1 year (Changes from baseline)
Full Field Electroretinogram	The International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines will be followed for conducting ff-ERG (Full-field Electroretinography) for RP subjects only.	1 year (Changes from baseline)

Collaborators and Investigators

• Sponsor: Ocugen
• Investigators: Study Chair: Huma Qamar, MD, MPH, CMI, Ocugen

Publications and helpful links

General Publications

• Li S, Datta S, Brabbit E, Love Z, Woytowicz V, Flattery K, Capri J, Yao K, Wu S, Imboden M, Upadhyay A, Arumugham R, Thoreson WB, DeAngelis MM, Haider NB. Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa. Gene Ther. 2021 May;28(5):223-241. doi: 10.1038/s41434-020-0134-z. Epub 2020 Mar 2.

Helpful Links

• Retina World Congress 2024- Meeting Abstract. Title: Safety and Efficacy Results from a Phase 1/2 Clinical Trial of OCU400 Modifier Gene Therapy for Treatment of Retinitis Pigmentosa
• ARVO Annual Meeting 2024- Meeting Abstract: Title: OCU400 Nuclear Hormone Receptor-Based Gene Modifier Therapy: Safety and Efficacy from Phase 1/2 Clinical Trial for Retinitis Pigmentosa Associated with NR2E3 and RHO Mutations
• International Conference on Ophthalmology and Vision Science, Canada- Meeting Abstract: Title: Evaluation of Safety and Efficacy of OCU400 Gene Therapy for Retinitis Pigmentosa: Phase 1/2 Study Results
• American Academy of Ophthalmology (AAO) Annual Meeting- Title: Safety and Efficacy of OCU400 Gene Modifier Therapy for Retinitis Pigmentosa: Phase 1/2 Study Updates

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2022
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: November 16, 2021
• First Submitted That Met QC Criteria: January 10, 2022
• First Posted (Actual): January 24, 2022

Study Record Updates

• Last Update Posted (Actual): August 6, 2025
• Last Update Submitted That Met QC Criteria: August 1, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: NR2E3; Rhodopsin; Enhanced S-cone syndrome; Cep290
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, Inborn; Eye Diseases; Eye Diseases, Hereditary; Vision Disorders; Sensation Disorders; Retinal Diseases; Retinal Dystrophies; Retinal Degeneration; Retinitis; Retinitis Pigmentosa; Blindness; Leber Congenital Amaurosis
• Other Study ID Numbers: OCU400-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No