A first-in-human study evaluating safety, PK, and PD of a novel universal anticoagulant reversal agent, OKL-1111

OKL-1111 is a small-molecule γ-cyclodextrin universal reversal agent for anticoagulants and platelet inhibitors that was being developed to significantly shorten time to treatment for intracerebral hemorrhage. Part A of this single-center, randomized, placebo-controlled, double-blind, single-ascending-dose, alternating-group, partial crossover trial evaluated the safety, tolerability, and pharmacokinetics (PK) of single IV doses of OKL-1111 in healthy adult male volunteers (N = 24). In addition, the pharmacodynamic (PD) response to OKL-1111 in the absence and presence of dabigatran or apixaban was assessed ex vivo. Part B evaluated the safety, PK, and PD of OKL-1111 after a single 220 mg dose of dabigatran. Single IV doses of OKL-1111 up to 1000 mg were safe and well tolerated. No discernible differences from placebo or dose relationship in the number or severity of reported adverse events were observed, and no treatment-related adverse effects were identified in any of the safety assessments. No serious adverse events were reported, and there was no indication of thrombosis. PK showed dose proportionality, as expected for a mainly renally cleared compound, and was not affected when combined with dabigatran. OKL-1111 showed a dose-dependent reduction in the ex vivo apixaban-induced increase in lag time in the calibrated automated thrombogram assay. OKL-1111 could be safely administered to healthy volunteers up to 1000 mg, with evidence of a dose-related effect. However, development of OKL-1111 was discontinued after completion of this first-in-human study because of safety findings in subsequent repeat-dose animal toxicology studies. This trial was registered at www.clinicaltrialsregister.eu as EudraCT2022-003463-19.