Antisense oligonucleotide treatment in CEP290‐related leber congenital amaurosis

Abstract Purpose To assess safety and efficacy of the antisense oligonucleotide (QR‐110) in LCA10 patients carrying the c.2991+1655A>G allele in the ciliopathy gene CEP290. Methods In a three‐center open‐label clinical trial (NCT03140969), subjects received intravitreal injections of QR‐110 in the worse seeing eye every three months. There were two combinations of loading/maintenance doses: 160/80 μg or 320/160 μg. Systemic and ocular safety was evaluated with standard methods. Efficacy was evaluated with visual acuity (VA), oculomotor control and instability (OCI), two‐colour full‐field stimulus test (FST), and mobility course testing among others. In a patient with an exceptional response, additional specialized tests of visual function were performed. Study was planned for 4 injections over one year but based on exceptional results in one patient an interim analysis was performed with the data cutoff date of Aug 2018. Results Ten patients received at least 1 and up to 4 injections, and were followed for at least 1 and up to 9 months. At 3 months after the first (loading) injection, treated eyes were significantly improved compared to baseline by an average of 0.67 log (7 lines) in VA (P=0.022), 0.62 log in red FST (P=1E‐6) and 0.81 log in blue FST (P<2E‐16). At 3 months after the second (maintenance) injection, VA and FST results remained improved, and OCI results also demonstrated greater stability. Exceptional responder showed a VA improvement from light perception to 20/400, and large improvements in FST. Removing the exceptional responder from the analyses did not change the main statistical conclusion supporting significant improvements of vision at 3 months. Adverse events included cystoid macular oedema and cataract. Conclusions Preliminary results with QR‐110 support an acceptable safety profile and potential for improvement of visual acuity and light sensitivity. Safety of the drug, and the efficacy and durability of the effect continue to be evaluated.