Abstract
Purpose :
The objective of this study is to determine safety, tolerability and pharmacokinetic (PK) profile of different doses of SYL1801 ophthalmic solution in healthy volunteers. SYL1801 is a small interfering ribonucleic acid (siRNA) inhibitor of NRARP (Notch-Regulated Ankyrin Repeat Protein) synthesis, a key regulator of choroidal neovascularization.
Methods :
This is an observer-masked, parallel groups, time-lagged study comprised of two treatment intervals: single ascending dose (SAD) and multiple ascending dose (MAD). Four different dose levels of SYL1801 were evaluated: 10 mg/mL q.d. (once daily), 25mg/mL q.d., 50 mg/mL q.d. and b.i.d. (twice daily). SAD intervals included three subjects per cohort and consisted of one treatment day, while MAD intervals had six subjects per cohort treated for 7 consecutive days. Administration in eye drops at Day 1 (through Day 7 for MAD interval) was conducted in one randomly chosen eye. Follow up visits were performed 24 and 72 hours after last administration.
Primary outcomes were ocular tolerability at the site of administration (cornea and conjunctiva) 72 hours after last instillation of SYL1801 and primary PK parameters determination. Secondary outcomes included ocular tolerability at 1 and 24 hours, electrocardiography, laboratory parameters, secondary PK parameters and adverse event (AE) occurrence. PK samples were collected 2, 15, 30 minutes, 1, 4 and 24 hours after last administration (LLOQ: 1 ng/mL).
Results :
A total of 36 healthy volunteers were allocated into one of the different administration schedules and completed the study. Preliminary reports after study close-out showed that 4 possibly related AEs (blepharitis in 2 subjects; queratitis, hyperemia and ocular irritation, in 1 subject each) were reported; all of them were mild and resolved in less than 72 hours. PK parameters could not be determined given SYL1801 was only detected in one study sample. No cumulative effect was observed
Conclusions :
This study provides evidence that SYL1801, a new siRNA administered in eye drops for retinal diseases, is safe and well tolerated. Few related AEs occurrence together with limited systemic bioavailability supports good safety profile. This, together with in vitro and in vivo efficacy data, further supports clinical development of SYL1801.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.