UNI-494 Phase 1 Safety, Tolerability, and Pharmacokinetics

Background: Currently, there are no effective treatments approved for acute kidney injury (AKI). Inflammation and reactive oxygen species driven mitochondrial permeability transition pore (mPTP) opening causes mitochondrial dysfunction/swelling and cell death. This is implicated in acute diseases originating from ischemia reperfusion injury or delayed graft function (DGF). Furthermore, unresolved inflammation exacerbates sustained mPTP opening, evident in chronic kidney diseases. UNI-494 is a selective mitochondrial ATP-sensitive potassium channel activator that binds to ATP-sensitive potassium channels which reverses mitochondrial dysfunction by closing mPTP. We present results from a study evaluating safety, tolerability, and pharmacokinetics (PK) of UNI-494 capsules administered to healthy subjects. Methods: This was a single-center, double-blind, placebo-controlled, randomized single ascending dose (SAD) (Part 1) and multiple ascending dose (MAD) (Part 2) study in healthy males and females of non-childbearing potential. Part 1 enrolled up to 40 subjects in 5 cohorts of 8 subjects each (6 active/2 placebo per cohort). There was an interim decision meeting after each dose cohort, to review the safety, tolerability, and PK data up to 48 h post-dose to decide the dose level for the subsequent cohort. Part 2 enrolled up to 20 subjects in 2 cohorts of 10 subjects each (8 active/2 placebo per cohort) dosed for 5 days. The dose level for the Part 2 Cohort 1 was selected based on the safety, tolerability, and PK data from Part 1. Results: Following single and multiple oral administration of 10, 20, 40, 80, and 160 mg UNI-494 capsules there were no serious or severe adverse events, and no subjects were withdrawn for adverse events. In the SAD cohorts, mean UNI-494 Cmax was 14.9, 52.8, and 80.3 ng/mL and mean AUC(0-last) was 44.6, 154, and 308 hour*ng/mL for the 40, 80, and 160 mg UNI-494 dose groups, respectively. Conclusion: Single and multiple doses of UNI-494 capsules were safe and well-tolerated in healthy volunteers. Exposure to UNI-494 increased in a dose-proportional manner. Therapeutic levels of nicorandil in SAD dosing were achieved at 160 mg UNI-494. UNI-494 is a potential candidate for the prevention of DGF and other AKI clinical conditions. Future studies should evaluate this promising treatment in the target population of patients with AKI. Funding: Commercial Support - Unicycive Therapeutics, Inc.