Efficacy and safety of SNJ ‐1656 in primary open‐angle glaucoma or ocular hypertension

The results of phase 1 trial of SNJ-1656, an ophthalmic solution of a Rho-associated kinase (ROCK) inhibitor, were reported previously (Tanihara et al. 2008). Here, we report the results of a randomized, double-masked, multicentre, phase 2 clinical study of SNJ-1656. Subjects with primary open-angle glaucoma (POAG) or ocular hypertension (OHT), aged 20–74 years, with intraocular pressure (IOP) 22–31 mm Hg and corrected visual acuity ≥20/40 were included. After screening examination, IOP-lowering drugs were washed out, and subjects received either 0.03%, 0.05% or 0.1% of SNJ-1656 or placebo twice daily (between 8:30 and 10:30 AM, and between 8:00 and 10:00 PM) in both eyes for 7 days. The eye with the higher IOP at the initial visit (right eye if the IOPs were the same) was chosen as the study eye for efficacy. Safety was evaluated in both eyes. Ophthalmologic findings and physiologic conditions were examined at the visit for starting administration of SNJ-1656 and the final visit during the trials, and the conjunctiva and cornea were examined with slit-lamp microscopy before and 2 hr after administration at each visit. By calculation, at 2.5% of significance level and 90% of statistical power, 13 subjects per group were required to achieve the probability of the estimates of treatment differences between the groups. Unless otherwise indicated, data are expressed as mean ± SD. P value of less than 0.05 was considered statistically significant, which were analysed by SAS for Windows Release 9.13 (SAS Inc, Cary, NC, USA). In total, 66 subjects were enrolled, of which 63 subjects completed the study. Non-completing subjects were discontinued due to hyperaemia in 2 subjects, and headache and foreign body sensation in 1 subject treated with 0.05% SNJ-1656. There were no differences in the characteristics of the population among the groups (Fig. 1A). After 7-day instillation of placebo or 0.03%, 0.05% or 0.1% SNJ-1656, changes in IOP from the baseline just before instillation of the morning eyedrops were −2.2 ± 1.9, −3.8 ± 2.7, −4.3 ± 2.3 and −4.0 ± 2.5 mm Hg, respectively (Fig. 1B). The corresponding values 2 hr after instillation of the morning eyedrops were −1.5 ± 2.2, −5.0 ± 2.4, −4.4 ± 2.7 and −4.5 ± 1.9 mm Hg, respectively (Fig. 1C; p = 0.0002, 0.0025 and 0.0010 for the 0.03%, 0.05% and 0.1% solution, respectively). Seventy-five treatment-related adverse events in 41 subjects were reported in a total of 66 patients: 15 treated with 0.03% SNJ-1656, 31 with 0.05% SNJ-1656, 28 with 0.1% SNJ-1656, and 1 in the placebo group, which were different among groups (p < 0.0001). Conjunctival hyperaemia was the most frequently reported adverse event: 9, 15 and 15 subjects, that were moderate in 1, 3 and 3 subjects, treated with 0.03%, 0.05% and 0.1% SNJ-1656, respectively. Punctate keratitis was observed in 1 subject treated with 0.03% SNJ-1656 and in 1 subject with 0.1% SNJ-1656. One subject had mild hepatic dysfunction after 0.05% SNJ-1656 instillation. All adverse events were mild to moderate except in 1 case: hyperaemia in 1 subject treated with 0.03% SNJ-1656. Adverse events requiring treatment were headache and abdominal pain, conjunctival hyperaemia and nasopharyngitis in 1 subject each, all of which recovered. There was no abnormal value in haematologic and urine examinations, except in 1 subject for 0.05% SNJ-1656 with mild hepatic dysfunction, recovered after the cessation of SNJ-1656 without treatment. Systolic blood pressure was not different between day 0 and 7 in any of the groups before and after instillation except the placebo group before instillation, which were 131.6 ± 20.2 and 126.3 ± 18.7 mm Hg on day 0 and 7, respectively (p = 0.007).