Breakthrough Clinical Results
Ocugen, Inc. announced that the U.S. FDA has cleared an Investigational New Drug (IND) amendment to initiate a Phase 2/3 pivotal confirmatory clinical trial of OCU410ST, a modifier gene therapy for Stargardt disease. Positive Phase 1 data showed a favorable safety profile, slower lesion growth, and improved visual function. The Phase 2/3 trial will enroll 51 participants, with 34 receiving OCU410ST and 17 serving as controls. The primary objective is to evaluate the reduction in atrophic lesion size. Ocugen plans to submit a Biologics License Application (BLA) for OCU410ST in 2027.
Key Highlights
- FDA cleared IND amendment for Phase 2/3 trial of OCU410ST for Stargardt disease.
- Positive Phase 1 data showed favorable safety, slower lesion growth, and improved vision.
- Phase 2/3 trial will enroll 51 participants, evaluating lesion size reduction and visual acuity.
- BLA submission for OCU410ST is planned for 2027.
Incidence and Prevalence
Stargardt disease (STGD) is the most common inherited macular dystrophy, primarily affecting young adults. While several studies have investigated its incidence and prevalence, a definitive global estimate is challenging to pinpoint due to variations in study methodologies and populations. Furthermore, the available literature often focuses on specific regions or populations, making direct global comparisons difficult.
Incidence:
- A prospective epidemiological study conducted in the United Kingdom and published in 2017 estimated the annual incidence of STGD to be between 0.110 and 0.128 per 100,000 individuals. This study, conducted through the British Ophthalmological Surveillance Unit (BOSU), is notable for its prospective design, but its findings may not be directly generalizable to the global population due to potential variations in genetic predisposition and environmental factors.
Prevalence:
- Older estimates often cite a prevalence of approximately 1:8000-10,000, which translates to 10-12.5 per 100,000 individuals. However, these figures are based on earlier studies and may not reflect the current understanding of the disease.
Challenges in Estimating Global Burden:
- Variability in diagnostic criteria: The diagnosis of STGD can rely on a combination of clinical findings, imaging techniques (such as fundus autofluorescence), and genetic testing. Variations in the use and interpretation of these methods can affect prevalence and incidence estimates.
- Genetic heterogeneity: STGD is primarily associated with mutations in the ABCA4 gene, but the specific mutations and their prevalence can vary across different populations. This genetic heterogeneity makes it difficult to extrapolate findings from one population to another.
- Limited data from diverse populations: Many epidemiological studies on STGD have been conducted in high-income countries, with limited data available from low- and middle-income countries. This lack of representation from diverse populations hinders the development of accurate global estimates.
Future Directions:
To obtain more precise global estimates of STGD incidence and prevalence, future research should prioritize:
- Standardized diagnostic criteria: The development and adoption of standardized diagnostic criteria for STGD would improve the comparability of data across different studies and populations.
- Large-scale, multi-center studies: International collaborations and multi-center studies involving diverse populations are needed to capture the true global burden of STGD.
- Genetic screening and epidemiological studies in underrepresented populations: Increased efforts to conduct genetic screening and epidemiological studies in low- and middle-income countries would provide valuable data for understanding the global distribution of STGD.
In summary, while existing data provides a preliminary understanding of STGD incidence and prevalence, further research is needed to establish more accurate and representative global estimates. Standardized diagnostic criteria, large-scale studies, and increased representation from diverse populations are crucial for achieving this goal.
Study Design Parameters
Several studies have explored the progression of Stargardt disease and identified potential outcome measures for clinical trials. Here's a summary of study design parameters and endpoints used in key trials:
Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Studies:
- Objective: Document the natural course of Stargardt disease and identify appropriate outcome measures for clinical trials.
- Methods: Prospective, multicenter study using fundus autofluorescence imaging, optical coherence tomography (OCT), and microperimetry.
-
Endpoints:
-
Fundus autofluorescence: Measurement of areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF).
-
OCT: Assessment of ellipsoid zone (EZ) loss width and area.
-
Microperimetry: Evaluation of mean retinal sensitivity (MS) and the number of points with normal sensitivity, relative scotoma, or deep scotoma.
Progression of Stargardt Disease Study:
- Objective: Describe the yearly progression rate of atrophic lesions.
- Design: Multicenter retrospective cohort study.
- Participants: 251 patients with disease-causing variants in ABCA4, of which 215 had at least two gradable fundus autofluorescence images with atrophic lesions.
- Endpoint: Yearly rate of progression of atrophic lesions measured by fundus autofluorescence (DDAF and QDAF).
- Results: Mean progression of DDAF was 0.51 mm^2/year, and total decreased autofluorescence was 0.35 mm^2/year. Progression rates depended on initial lesion size.
Natural History Study of Stargardt Disease Type 4:
- Objective: Describe the design and baseline characteristics of patients with STGD4.
- Design: Multicenter, prospective natural history study.
- Participants: 15 patients with disease-causing variants in PROM1.
- Methods: Best-corrected visual acuity, OCT, fundus autofluorescence, mesopic and scotopic microperimetry.
- Endpoints: Area of DDAF, mean retinal sensitivity.
Study on Late-Onset Stargardt Disease:
- Objective: Describe the natural history and demonstrate the accuracy of retinal pigment epithelium (RPE) atrophy progression as an outcome measure.
- Design: Retrospective cohort study.
- Participants: 47 patients with late-onset Stargardt disease (age of onset 45 years).
- Endpoint: RPE atrophy progression measured on fundus autofluorescence and near-infrared reflectance imaging.
- Results: Mean RPE atrophy progression was 0.22 mm/year.
Study on EZ Loss in Childhood-Onset STGD1:
- Objective: Evaluate the reliability of EZ loss measurements from SD-OCT and track disease progression.
- Participants: 46 children with molecularly confirmed STGD1.
- Endpoint: Annual rate of EZ width and area loss measured by SD-OCT.
- Results: Mean annual rate of transverse EZ loss was 279.5 m/year, and mean rate of EZ area loss was 1.20 mm^2/year. Area of EZ loss was more sensitive than transverse EZ width loss.
Study on Impact of Decreased AF on Visual Acuity:
- Objective: Investigate the impact of decreased AF areas on visual acuity in recent-onset STGD1.
- Design: Prospective, international, multicenter observational study.
- Participants: 64 patients with recent-onset STGD1 (symptom onset 2 years before the first visit).
- Endpoints: Rate of change in visual acuity, rate of change of DDAF, QDAF, and total decreased AF area.
- Results: Visual acuity change was not significantly associated with changes in DDAF, QDAF, or total decreased AF area. DDAF growth rate depended on initial lesion size.
In summary, fundus autofluorescence, OCT, and microperimetry are key outcome measures used in Stargardt disease trials. DDAF area, EZ loss, and mean retinal sensitivity are frequently used quantitative endpoints. Visual acuity is also assessed, but its rate of change may not be directly correlated with changes in atrophic lesion size in recent-onset disease.
Drug used in other indications
OCU410ST, also known as sepofarsen, is primarily known for its trials in Stargardt disease (STGD1), a form of inherited macular degeneration. Specifically, it targets the common deep-intronic c.2991+1655A>G mutation in the CEP290 gene, which is associated with a form of Leber congenital amaurosis (LCA). LCA is also an inherited retinal dystrophy, but unlike Stargardt disease, it presents at birth or in early infancy.
Sepofarsen is an antisense oligonucleotide (ASO) designed to modulate pre-messenger RNA splicing. In the context of LCA caused by the c.2991+1655A>G mutation, sepofarsen aims to correct the aberrant splicing of the CEP290 gene, thereby restoring normal protein function and potentially improving vision.
The intervention model for trials involving sepofarsen typically involves intravitreal injections of the ASO. This delivery method allows the drug to reach the retina, where the CEP290 protein plays a crucial role in photoreceptor function. Clinical trials have demonstrated the safety and durability of sepofarsen, with early efficacy data suggesting potential visual improvements in some patients. However, further research is needed to fully assess the long-term efficacy and potential variability in clinical response, particularly in patients who are compound heterozygotes for CEP290 mutations.