OCU410ST for Stargardt Disease

(GARDian Trial)

Recruiting at 5 trial locations

Overseen By Charles Wykoff, MD, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ocugen

Must not be taking: Retroviral therapy

Disqualifiers: Gene therapy, Cell therapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests OCU410ST, a treatment using a harmless virus to deliver a helpful gene into the eye, for children and young adults with Stargardt disease. The gene helps manage fat buildup, stress, and inflammation in the eye.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on retroviral therapy, you may need to stop as it could interfere with the investigational product.

Is OCU410ST (AAV5-hRORA) safe for use in humans?

Research on similar AAV5-based treatments in nonhuman primates showed no significant safety concerns, with no gross pathology or harmful immune responses observed after injection. ^{1 2 3 4 5}

How is the treatment OCU410ST unique for Stargardt Disease?

OCU410ST is unique because it uses an adeno-associated virus (AAV) vector to deliver a gene therapy specifically targeting the genetic cause of Stargardt Disease, which is a novel approach compared to traditional treatments that do not address the underlying genetic mutations. ^{1 2 6 7 8}

Who Is on the Research Team?

Murthy Chavali, Ph.D

Principal Investigator

Ocugen., Inc.

Are You a Good Fit for This Trial?

This clinical trial is for individuals aged 18-65 with Stargardt Disease, specifically those who have a vision acuity of 50 letters or less on the ETDRS chart. Participants must have confirmed genetic mutations in ABCA4 and evidence of macular lesions consistent with the disease. They should also have some remaining retinal layer detectable by OCT imaging.

Inclusion Criteria

I have two harmful mutations in my ABCA4 gene.

Detectable outer nuclear layer (ONL) in the macular region tomography (SD-OCT)

I have a diagnosis of Stargardt Disease affecting my eyes.

Exclusion Criteria

I cannot have eye injections or be put under anesthesia due to health reasons.

I have never had gene or cell therapy before.

Concurrent retroviral therapy that would inactivate the investigational product

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Open-label, dose-ranging/dose escalation study with a 3+3 design enrolling up to 18 subjects

12 months

Multiple visits for dose administration and monitoring

Phase 2 Treatment

Randomized, dose-expansion cohort with subjects receiving subretinal injections of OCU410ST

12 months

Multiple visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular follow-up visits for safety and efficacy assessments

What Are the Treatments Tested in This Trial?

Interventions

• OCU410ST

Trial Overview The study tests OCU410ST's safety and effectiveness for treating Stargardt Disease. It's a two-phase trial involving up to 42 participants across multiple centers, aiming to see how well this treatment works and if it's safe.

How Is the Trial Designed?

Group I: Experimental: Phase1 Dose Escalation- Medium Dose (7.5×10E10 vg/mL): Experimental Treatment 1 Intervention

Medium Dose (7.5×10E10 vg/mL): Subjects will receive a subretinal injection of OCU410ST in the Medium dose concentration.

Group II: Experimental: Phase1 Dose Escalation- Low Dose (3.75×10E10 vg/mL): Experimental Treatment 1 Intervention

Low Dose (3.75×10E10 vg/mL): Subjects will receive a subretinal injection of 200 µL of OCU410ST in the low dose concentration.

Group III: Experimental: Phase1 Dose Escalation- High Dose (2.25×10E11 vg/mL): Experimental Treatment 1 Intervention

High Dose (2.25×10E11 vg/mL): Subjects will receive a subretinal injection of OCU410ST in the high dose concentration.

Group IV: Experimental: Phase 2 Dose Expansion: Dose 2 from Phase 1-Randomized Pediatric Arm Experimental Treatment 1 Intervention

Subjects will receive a subretinal injection of OCU410ST with Lower Dose than Maximum tolerated dose (MTD) from Phase 1

Group V: Experimental: Phase 2 Dose Expansion: Dose 2 from Phase 1-Randomized Adult Arm Experimental Treatment 1 Intervention

Subjects will receive a subretinal injection of OCU410ST with Lower Dose than Maximum tolerated dose (MTD) from Phase 1

Group VI: Experimental: Phase 2 Dose Expansion: Dose 1 from Phase 1-Randomized Pediatric Arm Experimental Treatment 1 Intervention

Subjects will receive a subretinal injection of OCU410ST with Maximum tolerated dose (MTD) from Phase 1.

Group VII: Experimental: Phase 2 Dose Expansion: Dose 1 from Phase 1-Randomized Adult Arm Experimental Treatment 1 Intervention

Subjects will receive a subretinal injection of OCU410ST with Maximum tolerated dose (MTD) from Phase 1.

Group VIII: No Intervention- Randomized Control Adult Arm Active Control 1 Intervention

No Intervention Control Arm: Subject will not receive any active study intervention

Group IX: No Intervention- Randomized Control Pediatric Arm Active Control 1 Intervention

No Intervention Control Arm: Subject will not receive any active study intervention

OCU410ST is already approved in United States, European Union for the following indications:

Approved in United States as OCU410ST for:

• None - Orphan Drug Designation granted for ABCA4-associated retinopathies including Stargardt, RP19, and CORD3

Approved in European Union as OCU410ST for:

• None - Orphan Medicinal Product Designation granted for ABCA4-associated retinopathies including Stargardt disease

Who Is Running the Clinical Trial?

Ocugen

Lead Sponsor

Trials

12

Recruited

1,100+

Published Research Related to This Trial

The study demonstrated that a hybrid AAV dual vector system effectively delivered the full-length ABCA4 gene in a mouse model of Stargardt disease, leading to proper localization of the ABCA4 protein in photoreceptor cells.

Treatment with this hybrid vector significantly reduced the accumulation of toxic lipofuscin compounds in the retina, indicating its potential as a safe and therapeutic approach for addressing the underlying cause of Stargardt disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual ABCA4-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease. Dyka, FM., Molday, LL., Chiodo, VA., et al.[2020]

In a study of 12 patients with recessive Stargardt disease (STGD1), a distinct phenotype was observed characterized by advanced outer retinal degeneration, leading to a pale fundus appearance due to scleral exposure after approximately 50 years of disease progression.

The patients exhibited severe visual impairment, with best-corrected visual acuity ranging from 20/400 to hand motion, and significant loss of outer retinal structures was confirmed through imaging techniques, indicating a severe impact on retinal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep Scleral Exposure: A Degenerative Outcome of End-Stage Stargardt Disease. Lee, W., Zernant, J., Nagasaki, T., et al.[2021]

The study enrolled 15 patients with Stargardt disease type 4, all carrying variants in the PROM1 gene, to investigate the natural history of the disease over a 2-year period with regular follow-ups.

At baseline, 34.5% of the patients' eyes showed areas of definitely decreased autofluorescence, indicating retinal damage, with an average lesion size of 3.2 mm², which will help in understanding disease progression and may inform future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Progression of the Stargardt Disease Type 4 (ProgStar-4) Study: Design and Baseline Characteristics (ProgStar-4 Report No. 1). Strauss, RW., Muñoz, B., Ahmed, MI., et al.[2018]

In a study of 12 subjects from two related families with Stargardt disease, significant clinical variation was observed, with different family members exhibiting distinct phenotypes and progression of the disease.

The findings suggest that Stargardt disease may have a grading pattern based on age-related changes in visual function, indicating a need for more parameters to classify the disease effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical polymorphism of stargardt disease in a large consanguineous tunisian family; implications for nosology. El Matri, L., Ouechtati, F., Chebil, A., et al.[2021]

The AAV5-hGRK1 vector effectively targets both rod and cone photoreceptors in nonhuman primates, demonstrating its potential for gene therapy in retinal diseases.

The study confirmed the safety of AAV5-hGRK1, with no significant pathology observed post-injection and undetectable neutralizing antibodies, indicating a favorable profile for clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The human rhodopsin kinase promoter in an AAV5 vector confers rod- and cone-specific expression in the primate retina. Boye, SE., Alexander, JJ., Boye, SL., et al.[2021]

In a study of 51 patients with early-onset Stargardt disease, the average age of onset was 7.2 years, and visual acuity declined significantly over time, with profound chorioretinal atrophy developing as the disease progressed.

Genetic screening revealed that 37 out of 44 patients had two mutations in the ABCA4 gene, indicating a strong genetic basis for this severe form of retinal degeneration, which often presents with minimal initial abnormalities on examination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early-onset stargardt disease: phenotypic and genotypic characteristics. Lambertus, S., van Huet, RA., Bax, NM., et al.[2022]

Dual AAV vectors have been developed to deliver the ABCA4 gene effectively, overcoming the packaging limitations of traditional AAV vectors, which can only hold about 5 kb of genetic material.

In tests on both mouse and pig photoreceptors, these dual AAV vectors successfully rescued the retinal phenotype in Abca4-/- mice, demonstrating their potential as a gene therapy for Stargardt disease (STGD1).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual AAV Vectors for Stargardt Disease. Trapani, I.[2019]

Over a nine-year study of a large Tunisian family with Stargardt disease, all seven patients progressed to the same advanced phenotype (phenotype 3), indicating a consistent and progressive nature of the disease despite initial phenotypic variations.

Genetic analysis revealed two mutations in the ABCA4 gene, but these variations did not affect the end-stage progression of the disease, suggesting that the severity of Stargardt disease may be more influenced by other factors than just specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic Progression of Stargardt Disease in a Large Consanguineous Tunisian Family Harboring New ABCA4 Mutations. Falfoul, Y., Habibi, I., Turki, A., et al.[2020]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Dual ABCA4-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Deep Scleral Exposure: A Degenerative Outcome of End-Stage Stargardt Disease. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

The Progression of the Stargardt Disease Type 4 (ProgStar-4) Study: Design and Baseline Characteristics (ProgStar-4 Report No. 1). [2018]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Clinical polymorphism of stargardt disease in a large consanguineous tunisian family; implications for nosology. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

The human rhodopsin kinase promoter in an AAV5 vector confers rod- and cone-specific expression in the primate retina. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Early-onset stargardt disease: phenotypic and genotypic characteristics. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Dual AAV Vectors for Stargardt Disease. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Phenotypic Progression of Stargardt Disease in a Large Consanguineous Tunisian Family Harboring New ABCA4 Mutations. [2020]