A clinical research team based at the Yale University School of Medicine have reported that best-corrected visual acuity (BVCA) in eyes with choroideremia (CHM) appears to follow a 2-phase linear decline, with a transition age of approximately 39 years. The study looked at 1,004 eyes indicating a clear demarcation of the rate of BCVA decline, suggesting that young patients “may not be able to use BCVA as a primary or sole endpoint, but rather, may need to employ additional disease biomarkers that change before age 39”. The report, published in the British Journal of Ophthalmology (epub May 29th, 2020), considers how to apply primary endpoints for BCVA in clinical trials in the context other clinical endpoints.
Choroideremia (CHM) is an X-linked retinal degeneration that impacts an estimate of 1/50,000 males worldwide, exhibiting retinal thickening, photoreceptor degeneration, RPE depigmentation, and retinal remodelling. Males develop nyctalopia in their teens progressing to a loss of peripheral visual field leading to profound blindness in the fifth and sixth decades. CHM encodes Rab Escort Protein 1 (REP-1) which is a ubiquitously protein required for geranylgeranylation of ras-related GTPases, or Rab proteins, trafficking of vesicles in endocytic and exocytic pathways. Currently, there are several gene therapy studies focused on CHM treatment using both primary and secondary outcomes. In the natural history study in CHM performed at Yale, the research showed that BCVA was a function of age followed a 2-phase decline, slow followed by rapid decline, with an estimated transition age of 39.1 years (95% CI 33.5 to 44.7). BCVA followed a 2-phase decline until it reached 0 letters (r2=0.90) thereafter. The BCVA decline rate was 0.33 letters/year (95% CI −0.38 to 1.05) before 39 years, and 1.23 letters/year (95% CI 0.55 to 1.92) after 39 years (p=0.004).
Commenting on the research, that authors stated that, “for future trials that will continue to use BCVA as a primary endpoint, investigators need to identify patients who have a measurable BCVA decline in the relatively short time frame. We suggest that the age may serve as a biomarker for trials to recruit patients with measurable BCVA decline using 39 years as a potential cut-off. Furthermore, our study showed a moderate correlation between the BCVA of right and left eyes (r=0.60), and the BCVA decline rate was independent of the laterality. These findings indicate that CHM is a bilateral disease, but there are concerns about using the fellow eyes as controls in treatment trials. Some patients had extremely different BCVA between the right and left eyes and the BCVA decline rate between the worse-seeing and better-seeing eyes may not always be the same”.