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

Retinitis Pigmentosa Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05203939
• Other study ID #: OCU400-101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 24, 2022
• Est. completion date: December 2024

Study information

• Verified date: October 2023
• Source: Ocugen
• Contact: Murthy Chavali, PhD
• Phone: 405-714-4198
• Email: murthy.chavali[@]ocugen.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

3 adult LCA patients with CEP290 mutations and 3 pediatric subjects with RP and LCA, will be enrolled in the Phase 2 portion.

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 124
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

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 subjects in Cohort 1-3, BCVA = 20/50 or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in study eye.

4. Unable to perform a Multi-Luminance Mobility Testing (MLMT) using study eye 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.

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 3.5 (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. Any contraindications for subretinal injection.

3. Any intraocular surgery within 6 months.

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

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. Previous treatment with a gene-therapy or cell therapy product.

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

4. Any contraindications for subretinal injection.

5. Breast-feeding, pregnancy, or inability to practice strict contraception within the Treatment Observation Period for subjects of childbearing potential.

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

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 3.5 (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. Any contraindications for subretinal injection.

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

4. Breast-feeding, pregnancy, or inability to practice strict contraception within the Treatment Observation Period for subjects of childbearing potential.

Related Conditions & MeSH terms

• Blindness
• Leber Congenital Amaurosis
• Retinitis
• Retinitis Pigmentosa

Intervention

Drug:
• OCU400 Low Dose
subretinal injection of up to 1.66 × 10^10 vg/mL
• OCU400 Med Dose
subretinal injection of upto 3.33 × 10^10 vg/mL
• OCU400 High Dose
subretinal injection of upto 1.66 × 10^11 vg/mL

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Ocugen

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)
Other	Changes in ellipsoid zone width/length on wide-field 45° 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)
Other	Contrast sensitivity	Contrast sensitivity will be conducted using Pelli-Robson chart.	1 year (Changes from baseline)
Other	Full Field Light Stimulation Threshold (FST)	FST will be completed at scheduled times throughout the study period	1 year (Changes from baseline)
Other	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)
Other	Vision on Quality of Life	The National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ25) and the Michigan Retinal Degeneration Questionnaire (MRDQ) questionnaires will be administered to assess the impact of vision on quality of subject's life.	1 year (Changes from baseline)
Other	Full Field Electroretinogram	The International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines will be followed for conducting ff-ERG (Full-field Electroretinography)	1 year (Changes from baseline)
Other	Wide-field fundus autofluorescence (wf-FAF)	The intensity of FAF will be evaluated using 55° posterior pole scanning.	1 year (Changes from baseline)
Primary	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
Primary	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
Primary	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	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)
Secondary	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)
Secondary	Slit-lamp biomicroscopy	Changes in visual function.	1 year (Changes from baseline)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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

External Links

•   Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa