Breakthrough Clinical Results
Ocugen, Inc. announced the first patient has been dosed in its Phase 2/3 GARDian3 clinical trial for OCU410ST, a novel modifier gene therapy for Stargardt disease. This follows encouraging Phase 1 results showing a 48% slower lesion growth and a statistically significant improvement in visual acuity. The Phase 2/3 trial will enroll 51 participants, with the primary objective of evaluating atrophic lesion size reduction. Ocugen plans to submit a Biologics License Application (BLA) for OCU410ST in 2027.
Key Highlights
- First patient dosed in Phase 2/3 GARDian3 clinical trial for OCU410ST.
- Phase 1 trial showed 48% slower lesion growth and improved visual acuity.
- Phase 2/3 trial to enroll 51 participants with Stargardt disease.
- BLA submission planned for 2027.
Incidence and Prevalence
Global Epidemiology of Stargardt Disease
The global prevalence of Stargardt disease (STGD1), an autosomal recessive form of juvenile macular degeneration, is not specifically documented in the available data. However, several regional studies provide insights into its epidemiological patterns.
A French study examining a population of nearly 4 million inhabitants over eighteen years (1972-1989) found that Stargardt's disease detection typically occurred before the age of 20. This study estimated a global prevalence for all inherited retinal dystrophies of 1:1,490, which translated to approximately 33,800 cases in France and more than 300,000 patients affected by disabling hereditary retinal dystrophies in the European Community. However, these figures represent all inherited retinal dystrophies rather than Stargardt disease specifically.
In an Indian cohort study, the median age at onset of Stargardt disease was 14 years (Range: 5-49 years), with a median age at presentation of 22 years (Range: 6-55 years). Most patients in this cohort reported at a younger age compared to other populations. Regarding genetic findings, ABCA4 gene mutation was detected in over 80% of patients (44 individuals), while others had variants in PROM1, CNGB3, and PDE6A/TULP1 genes, and 2 had no known variants. Two recurrent variants (c.5882G>A and c.859-9T>C) were associated with later onset of the disease.
A Russian cohort study from 2017 documented genetic variations in 51 patients from 10 ethnic groups. ABCA4 variations were found in 70.5% of cases, with ten novel ABCA4 variations detected. Most of the known variations identified were also found in European and American Stargardt disease populations. Multiple ABCA4 variations, ABCA4 + RDH12, and ABCA4 + BEST1 variations were observed, with disease severity proportionate to the variation burden.
The genetic basis of Stargardt disease shows great heterogeneity, with the condition primarily caused by mutations in the ABCA4 gene on chromosome 1. Stargardt's disease has been mapped to chromosome 1p21-p13 in the genetic interval defined by loci D1S424 and D1S236. Previous research has suggested that Stargardt's disease is genetically homogeneous.
Mutations in the ABCA4 gene have also been attributed to some cases of cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration, highlighting the complex genetic landscape of retinal disorders.
Economic Burden
Economic Burden of Treating Stargardt Disease in USA and Europe
Based on the available research, there appears to be a significant gap in the published literature regarding the economic burden specifically associated with treating Stargardt macular dystrophy in the United States and European healthcare systems.
Current PubMed-indexed studies have not adequately quantified the direct healthcare costs or indirect societal costs related to the management of this form of juvenile macular degeneration (also known as STGD1 or fundus flavimaculatus).
While there is substantial economic research on age-related macular degeneration (AMD) and its variants, the specific financial impact of treating Stargardt disease remains underdocumented in both North American and European contexts.
This represents an important knowledge gap in understanding the full economic implications of this rare genetic condition on healthcare systems and affected individuals. Future research should address this gap by conducting comprehensive cost analyses that consider:
- Direct medical costs including diagnostics, genetic testing, specialist consultations, and supportive therapies
- Indirect costs such as productivity losses, caregiver burden, and quality of life impacts
- Long-term economic consequences given the typically early onset and progressive nature of Stargardt disease
Healthcare policy makers and insurance providers would benefit from more robust economic data to inform coverage decisions and resource allocation for this patient population.
Study Design Parameters
Study Design Parameters and Endpoints in Key Stargardt Disease Trials
Study Designs
- A retrospective clinic-based cross-sectional study was conducted with 405 patients with Stargardt's disease
- A prospective explorative study conducted between September 2019 and August 2020 included participants with Stargardt disease with moderate to severe visual impairment and a relatively preserved peripheral visual field
- One study involved genealogical characterization and clinical examination of family members with autosomal dominant Stargardt-like macular dystrophy
- Mutation screening of the ELOVL4 gene was performed in a four-generation family study
Key Endpoints
- Best-corrected visual acuity (BCVA) was a primary endpoint in multiple studies
- Stage of Stargardt's disease based on the extent and appearance of fundus flecks
- Appearance of the macula at initial and most recent visits
- Central macular atrophy with or without flecks was assessed in affected individuals
- DNA sequence analysis to confirm diagnosis of autosomal dominant Stargardt-like macular dystrophy
- Fundus autofluorescence (excitation 488 nm) was used to assess retinal pigment epithelial (RPE) atrophy
- Progression of atrophy was measured using Euclidean distance mapping to calculate velocity of lesion border progression
Visual Acuity Measurements
- Early Treatment Diabetic Retinopathy Study (ETDRS) letters used to measure visual acuity
- LogMAR (logarithm of minimum angle of resolution) measurements used in some studies
- Threshold of 20/200 or better VA in at least one eye was an important benchmark
- 20/400 or better VA was another threshold used to evaluate disease progression
- Median visual acuity decline was measured at -0.03 Snellen decimal per year
Findings from Key Trials
- At initial visit, 199 patients were identified as having stage 1 Stargardt's disease, of whom 97.5% maintained 20/200 or better VA in at least one eye
- 185 patients were identified as having stage 2 or stage 2-3 Stargardt's disease, of whom 83.2% maintained 20/200 VA or better
- Patients with stage 1 were more likely to maintain 20/200 or better VA compared with patients with stage 2/stage 2-3 Stargardt's disease (chi2(1) = 21.25, P<0.001)
- 99% of stage 1 patients and 94.1% of stage 2/stage 2-3 patients maintained 20/400 or better VA in at least one eye (chi2(1) = 5.72, P = 0.017)
- Median growth of atrophy was 0.590 mm/year for definitely decreased autofluorescence
- Time-to-event analysis showed a median duration of 15.4 years from onset to foveal involvement
Assistive Technology Evaluation
- Head-mounted displays (AceSight, eSight 3, IrisVision Live, and Jordy) were tested in Stargardt patients
- The Canadian Occupational Performance Measure was used for evaluation
- Distance visual acuity and reading distance improved with all head-mounted displays
- eSight and IrisVision improved near visual acuity
Drug used in other indications
OCU410ST (AAV5-hRORA) Clinical Trials Beyond Stargardt Disease
Based on a comprehensive review of available information, there is insufficient data to determine what other indications OCU410ST (AAV5-hRORA) is being trialed for beyond Stargardt disease.
The gene therapy product OCU410ST, which utilizes an Adeno-Associated Virus serotype 5 vector carrying the human RAR-related Orphan Receptor A gene, may still be in early development stages for indications beyond Stargardt disease, or such trials may not be publicly registered at this time.
Similarly, without confirmed additional indications, there are no intervention models, dosing regimens, or administration protocols to report for OCU410ST in conditions other than Stargardt disease.
For patients and clinicians interested in this therapeutic approach, it would be advisable to:
- Monitor clinical trial registries for updates on OCU410ST development
- Consult with specialists in retinal diseases for the latest information
- Follow publications from the developing company for announcements of expanded indications
As gene therapy for ocular conditions continues to advance, new applications for promising candidates like OCU410ST may emerge in the treatment landscape for inherited retinal diseases and other ophthalmologic conditions.