A Dutch biotechnology company, ProQR Therapeutcis N.V., (NASDAQ:PRQR), Leiden, has announced the results of a Phase 2/3 study for the treatment of Leber Congenital Amaurosis 10 (LCA10), due to the p.Cys998X mutation in the CEP290 gene. The randomized study comprised 36 patients, aged eight years or older, receiving either “sepofarsen” at the target registration dose, a low dose, or sham treatment. The study was registered at ClinicalTrials.gov (NCT03913143) and its primary endpoint was the mean change from baseline in BCVA at month 12. According to the company, sepofarsen is an investigational RNA therapy designed to restore vision in LCA10. The mutation leads to aberrant splicing of the mRNA and non-functional CEP290 protein. Sepofarsen is designed to enable normal splicing, resulting in restoration of normal (wild type) CEP290 mRNA and subsequent production of functional CEP290 protein.
As well characterised, LCA10 is the most common form of LCA in Europe and North America, arising from mutations in the CEP290 gene. While most CEP290 patients have profound vision loss, fundus examination and OCT analysis show a relatively well-preserved central macular anatomy well into the third decade of life. Despite such, LCA10 is one of the most severe forms of juvenile retinopathies and the most common mutation found in such LCA patients (the p.Cys998X error in CEP290), a nonsense mutation understood to account for up to 20% of all LCA patients in north western Europe. While there are no approved treatments yet available for the disease, several academic and commercial teams are actively engaged in a number of gene therapy related development programmes.
ProQR Therapeutics was aimed to present a “first-in-class” investigational treatment however, unfortunately, the top-line results have been disappointed to date. The study, termed, “Illuminate”, used a randomized, sham-controlled trial at 14 study sites in 9 countries. Participants were randomized to three equal groups (1:1:1) of the target registration dose sepofarsen (160 μg/80 μg loading dose/maintenance doses), a low dose of sepofarsen for masking (80 μg/40 μg loading dose/maintenance doses), or sham procedure, with sepofarsen administered via intravitreal injection and the sham procedure mimicking an injection with no drug or injection given. The key findings from the results at month 12, indicated the mean change from baseline in BCVA in the 160/80 μg dose group was -0.11 logMAR (p=0.96), in the 80/40 μg group -0.13 logMAR (p=0.97), and in the sham group -0.12 logMAR. P values are treatment group vs. sham, ANCOVA. In addition, for secondary endpoints full-field stimulus test (FST) and mobility, there was also no difference between the treated and sham groups in the analysis. Commenting on the outcome, Benjamin R. Yerxa, Chief Executive Officer at the Foundation Fighting Blindness stated that, “[t]his was not the outcome we had hoped for and we share in the disappointment many are feeling in the community. We will continue to work alongside ProQR to learn more from the ongoing analyses and as they work to advance RNA therapies to potentially help children, adults, and families who are affected by rare genetic eye diseases.”