ABSTRACTPurpose To evaluate the safety, tolerability, and ocular hypotensive properties of QLS-111, a preservative-free, novel and proprietary formulation of an ATP-sensitive potassium channel opener, either alone or in combination with approved glaucoma drugs, in preclinical animal models. Design Preclinical study Subjects Wild-type C57BL/6J mice and Dutch-belted rabbits Methods Optimal effective dose of QLS-111 for intraocular pressure (IOP) lowering was determined in C57BL/6J mice (n=5) by topical ocular treatment with different concentrations (0.005 mM/0.00015% - 5 mM/0.15%). Efficacy of combination treatment was evaluated by treatment with various concentrations of QLS-111 along with timolol and a preservative free fixed dose combination (FDC) of QLS-111 (0.015%) with latanoprost (0.005%). IOP was measured with a handheld rebound tonometer. Aqueous humor dynamics were assessed for QLS-111 treatment using a constant flow infusion method. For evaluating pharmacokinetic, safety, and tolerability properties of QLS-111, both eyes of Dutch belted rabbits were topically treated, twice daily, with different concentrations of QLS-111 1 mM (0.03%), n=6; 2.5 mM (0.075%), n=6; 5 mM, n=10 (0.15%) or vehicle (n=10) for 28 consecutive days. Main outcome measures Safety and efficacy of QLS-111 Results QLS-111 at 0.5 mM (0.015%) showed the greatest IOP reduction of 4.9 ± 0.7 mm Hg in normotensive mice. QLS-111 lowered episcleral venous pressure but did not alter aqueous inflow, uveoscleral or trabecular meshwork outflow. QLS-111, administered in combination with timolol, or in preservative free FDC with latanoprost, lowered IOP by up to an additional 2.4 mm Hg compared to effects observed with QLS-111, latanoprost, or timolol alone. In rabbits, QLS-111 was well tolerated with no drug-related adverse events. Peak plasma exposure was ≤ 4.942 ng/mL, with a half-life between 1.3–2.9 h. QLS-111 was undetectable beyond 6 h post treatment. No-observed-adverse-effect level (NOAEL) was determined to be 0.06 mg/eye/dose (5 mM/0.15%). Conclusions QLS-111, a proprietary, preservative-free formulation of an ATP-sensitive potassium channel opener, is a well-tolerated and effective topical ocular hypotensive agent in preclinical animal models that is currently in human clinical trials. Due to its unique mode of action that reduces episcleral venous pressure, QLS-111 shows additive IOP reduction with first-line glaucoma medications.
Wirostko et al. (Sun,) studied this question.