Preclinical Evaluation of Safety and Efficacy of QLS-111: A Novel Formulation of an Adenosine Triphosphate-Sensitive Potassium Channel Opener.

Purpose: To evaluate the safety, tolerability, and ocular hypotensive properties of QLS-111, a preservative-free, novel, proprietary formulation of an adenosine triphosphate (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%). Intraocular pressure 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 mmHg in normotensive mice. QLS-111 lowered episcleral venous pressure (EVP) 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 mmHg compared to effects observed with QLS-111, latanoprost, or timolol alone. In rabbits, QLS-111 was well tolerated with no compound-related adverse events. Peak plasma exposure was ≤4.942 ng/mL, with a half-life between 1.3 and 2.9 hours. QLS-111 was undetectable beyond 6 hours posttreatment. No observed adverse effect level 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 EVP, QLS-111 shows additive IOP reduction with first-line glaucoma medications. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.