Systemic and Ocular Toxicology and Pharmacokinetic Profiles of QLS-101, a Novel Topical IOP-Lowering Therapeutic

Abstract

Purpose : QLS-101, a water-soluble phosphate ester prodrug of an ATP-sensitive potassium channel opener, is being developed by Qlaris Bio as an ocular hypotensive agent with a novel mode of action that affects distal outflow resistance and episcleral venous pressure. This summarizes the potential toxicity and pharmacokinetic (PK) profiles of QLS-101 in beagle dogs.

Methods : To assess ocular toxicity and PK, beagle dogs (age 5-7 months) were dosed topically (OU) once daily for 28 days with 2.0%, 4.0%, or 8.0% QLS-101 (n=3 males and 3 females per group). To evaluate systemic maximum tolerated dose (MTD), single escalating doses of QLS-101 (0.05-5.0 mg/kg/day) were administered by i.v. bolus to one male and one female beagle dog, with a 48h minimum observation period between doses. Plasma samples were collected at various timepoints in both studies, concentrations of QLS-101 and its active moiety QLS-100 were determined by LC/MS-MS, and data used to generate PK parameters. Mortality, clinical observations, body and organ weights, and food consumption were assessed in each study. Necropsy examinations were performed and select tissues were isolated and prepared for histopathology.

Results : QLS-101 was well-tolerated at all dose levels except 5 mg/kg/day i.v. When dosed topically, the no-observed-adverse-effect level (NOAEL) was determined to be 8.0%. At this dose, the mean C_max and AUC T_last values on day 28 were 147 ng/mL and 1.26 ug*h/ml, respectively, for males, with similar results in females. QLS-100 C_max and AUC T_last levels at NOAEL were 31 ng/ml and 166 ng*h/ml in males, with similar results in females. Using dogs administered single escalating i.v. doses, the MTD was determined to be 3 mg/kg. Side effects were limited to non-adverse skin redness at all dose levels, consistent with vasodilation. Unexpectedly, the observed skin redness initially presented peripherally in the distal limbs (fore and hindpaws) and in the pinnae rather than the trunk, neck, or faceThe MTD corresponded to sex-combined C_max and AUC_Tlast values of 16.4 μg/mL and 106.55 μg*h/mL for QLS-101, and 35.5 ng/mL and 431 ng*h/mL, for QLS-100. No mortality, change in body weight or food consumption were noted. Histological examination showed no systemic toxicity as a result of QLS-101 treatment.

Conclusions : QLS-101 is well-tolerated in beagle dogs and suitable for clinical development as an IOP-lowering therapeutic.

This is a 2021 ARVO Annual Meeting abstract.