This prospective, randomized, multi-center phase 2 study found that the 0.4% dose of K-115, a rho kinase inhibitor, is the most optimal for controlling IOP over an eight-week period in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).
Rho kinase inhibitors have been shown to reduce IOP in rabbits and monkeys by increasing aqueous humor drainage through the primary outflow pathway in the eye, the trabecular meshwork.
Preclinical studies have demonstrated that K-115 increases outflow. Phase 1 clinical trials for concentrations of up to 0.8 % administered twice-daily showed significant IOP-lowering effects. Also, the subsequent phase 2a clinical trial showed IOP-lowering effects of K-115 over 24 hours in concentrations of 0.2 % and 0.4 % administered twice-daily for one day in patients with POAG or OHT; the main adverse event was mild conjunctival hyperemia. Based on these findings, the current phase 2 clinical trial was conducted to identify the optimal dose of K-115.
Subjects were 210 patients with POAG or OHT randomized to K-115 in concentrations of 0.1 %, 0.2 %, or 0.4 % or placebo twice-daily – one drop in each eye at 9 a.m. and 9 p.m. ‑ for eight weeks. IOP was measured with Goldmann tonometry every two weeks at 9 a.m. and 11 a.m. and every four weeks at 5 p.m.
Compared to placebo, the dose-dependent IOP-lowering effect of K-115 was statistically significant at all time points for the 0.1 % and 0.4 % groups, and at two hours after instillation (11 a.m.) for the 0.2 % group (P < 0.05). However, the 0.4% concentration resulted in the most significant and steady IOP reduction compared to placebo.
All adverse events after topical administration of K-115 were mild, with the exception of one case with moderate conjunctival hyperemia, and all concentrations (0.1 % to 0.4 %) exhibited an acceptable tolerability profile. The occurrence of ocular hyperemia is consistent with previous findings in animal experiments and clinical studies in which similar conjunctival hyperemia was identified after instillation of higher doses of Rho kinase inhibitor eye drops.
The authors note that there was an increasing and dose-dependent amount of conjunctival hyperemia in all groups, including more than 65 percent of patients in the 0.4 % treated group by eight weeks, compared to 13 percent in the placebo group, 43.4 percent in the 0.1 % group and 57.4 percent in the 0.2 % group. In contrast, although conjunctival hemorrhage was found in four patients, there was no apparent dose dependency in this occurrence: three eyes in the 0.1 % group, one eye in the 0.2 % group and no eyes in 0.4 % group.
They conclude that these results indicate that K-115 in concentrations of 0.1% to 0.4% is a safe topical agent for IOP reduction in patients with POAG or OHT for eight weeks of treatment. However, further studies will be required to assess the safety profile of prolonged use or in combination with other IOP-lowering eye drops.