First in-Human Study with Okl-1111, a Novel Small Molecule Universal Anticoagulant and Platelet Inhibitor Reversal Agent

Background: Anticoagulant and platelet inhibitor use has been demonstrated clinically to increase both hematoma volumes and mortality risk in intracranial hemorrhage patients. Since current reversal agents require anticoagulant identification, reconstitution of powder and carry a significant thrombotic risk they are given rather late in the treatment of intracranial hemorrhage associated with anticoagulant and platelet inhibitor use. A safe, synthetic and ready to use universal agent has the potential to significantly shorten the treatment time of intracranial hemorrhage.OKL-1111 is a small molecule universal anticoagulant and platelet inhibitor reversal agent. It acts as a procoagulant in vitro and augments and restores coagulation potential in the presence of an anticoagulant or platelet inhibitor without initiating coagulation. OKL-1111 reversed the action of a wide variety of anticoagulants (dabigatran, apixaban, rivaroxaban, edoxaban, warfarin, enoxaparin and fondaparinux) as well as platelet inhibitors (ticagrelor and clopidogrel) in vivo without any sign of thrombotic overshoot. In addition, OKL-1111 substantially prevented hematoma expansion in a mouse intracranial hemorrhage model using a high dose of warfarin as anticoagulant. Objectives: The objective of this study was to evaluate the safety, tolerability and pharmacokinetics (PK) of OKL-1111 after single intravenous dosing in normal healthy male subjects. In addition, the pharmacodynamic (PD) response of OKL-1111 in the absence or presence of dabigatran was assessed ex vivo. Design: A single-center, randomized, placebo-controlled, double-blind, single-ascending dose, alternating-group, partial crossover trial in healthy adult men (n=24). Next to standard hematology and clinical chemistry assays, possible prothrombotic effects were measured by means of measuring d-dimer formation and thrombin-antithrombin (TAT) complexes. A potential PD response of OKL-1111 was measured ex vivo in thrombin generation analyses (TGA). Results: OKL-1111 was well tolerated up to a single intravenous administration of 1000 mg. There was no discernible difference from placebo or presence of dose-relationship in the number or severity of reported adverse events. No Serious Adverse Events were reported, and there were no indications of thrombosis (d-dimer, TAT). In addition, there were no treatment related effects of clinical significance on any safety and tolerability assessments. PK showed clear dose proportionality as expected for a mainly renally cleared compound and was not affected when individuals received dabigatran. OKL-1111 at a single dose of 1000mg reduced the dabigatran-induced lagtime increase in TGA. Discussion: OKL-1111, to our knowledge the first fully universal reversal agent and the only clopidogrel reversal agent, can be safely administered to volunteers up to 1000mg, without (serious) adverse events.