Safety and Efficacy Clinical Trials for SYL1001, a Novel Short Interfering RNA for the Treatment of Dry Eye Disease.

Purpose: To evaluate the efficacy and safety of SYL1001, a short interfering (si) RNA targeting the transient receptor potential cation channel subfamily V member 1 (TRPV1), for the treatment of dry eye disease (DED). Methods: This study combines a phase I and two phase II clinical trials to test different doses of SYL1001 in a total of 156 healthy subjects and patients with DED. After 10 days of treatment, the primary efficacy endpoints were the effect on (1) the scoring in the Visual Analogue Scale (VAS) and Ocular Surface Disease Index (OSDI) questionnaires, and (2) ocular tolerance evaluated by corneal fluorescein staining and conjunctival hyperemia. Secondary endpoints included the assessment of systemic and local tolerance. Results: Topical administration of SYL1001 1.125% once daily produced a significant decrease in VAS scores compared with placebo from day 4 until the end of treatment (change from baseline at day 10: -1.73 ± 0.32 vs. -0.91 ± 0.34; P = 0.013). For all treatments, OSDI scores were significantly reduced compared to their respective baseline values (P < 0.01), although no significant changes were detected between groups. Conjunctival hyperemia (quantified as normal or abnormal) significantly improved after instillation of SYL1001 1.125% compared with placebo (50% vs. 20%; P < 0.05). Excellent tolerability was reported, with no differences in the rates of occurrence of adverse events between groups. Conclusion: These trials achieved their primary endpoints of identifying the most effective dose of SYL1001 (1.125%). SYL1001 showed a large safety margin and may provide novel therapeutic opportunity for the relief of dry eye. (ClinicalTrials.gov numbers, NCT01438281, NCT01776658, and NCT02455999.).

Phase I clinical trial of SYL040012, a small interfering RNA targeting ß-adrenergic receptor 2, for lowering intraocular pressure.

The objective of this study was to evaluate ocular tolerance, safety, and effect on intraocular pressure (IOP) of a topically administered small interfering RNA; SYL040012, on healthy volunteers. The study was an open-label, controlled, single-center study comprised of two intervals that enrolled 30 healthy subjects having IOP below 21 mmHg. SYL040012 was administered to one eye as a single dose to six subjects during interval 1. During interval 2 two different doses of SYL040012 were administered to one eye on a daily basis to two separate groups of 12 subjects each, over a period of 7 days. The contralateral eye was evaluated but not administered and served as control for the tolerance study. SYL040012 was well tolerated locally. No local or systemic adverse events related to the product developed in response to any of the doses studied. SYL040012 was not detected in plasma at any time point. Administration of SYL040012 over a period of 7 days reduced IOP values in 15 out of 24 healthy subjects regardless of the dose used. IOP decrease was statistically significant in response to one of the doses tested and responsiveness to SYL040012 seemed to be greater in individuals with higher baseline IOP.