Phase 1, 3-Sequence Interaction Study of Intravenous Vlx-1005 and Argatroban Shows a Favorable Safety, Pharmacokinetic and Pharmacodynamic Profile in Healthy Volunteers

Introduction

VLX-1005 is a novel small molecule inhibitor of platelet-type 12-lipoxygenase (12-LOX) intended for the prevention or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). Argatroban, a direct thrombin inhibitor, is currently the only agent approved in the U.S. for use in HIT. Its use is associated with a substantial risk of major bleeding in HIT patients, and a stubbornly high rate of thrombosis. As VLX-1005 and argatroban are co-administered in the ongoing VLX-1005-003 ALATHEA (A study of VLX-1005 to evaLuAte Thrombocyte change in HEpArin Induced Thrombocytopenia) clinical trial in HIT patients, the present study was designed to characterize the safety and tolerability of these agents alone and in combination, and the pharmacokinetics and pharmacodynamics and potential interaction of both agents in a population of healthy subjects.

Methods

This was a 3-period, open-label, Phase I, drug-drug interaction (DDI) study of VLX-1005 and argatroban, each administered intravenously via PICC line to healthy volunteers. Treatment A was argatroban (5 mcg/kg/min constant IV infusion for 6 hours without a loading dose). Treatment B was VLX-1005 (400 mg IV over 1 hour). Treatment C was argatroban at 5 mcg/kg/min constant IV infusion for 6 hours, VLX-1005 dosed at 400 mg IV over 60 minutes from 180 minutes to 240 minutes from the start of the argatroban infusion. Twelve (12) healthy male or female (non-lactating and not of childbearing potential) subjects aged 19 to 55 inclusive, were randomized to 1 of 3 treatment sequences: A-B-C or B-C-A, or C-A-B with a 1-week washout period between each period to avoid carryover effects. During each treatment period, monitoring of vital signs, laboratory tests (hematology, clinical biochemistry, and coagulation studies with monitoring of aPTT), and 12-lead ECG was conducted by appropriately trained personnel. Telemetry was performed for 24-hour time periods postdose in each treatment. PK samples were obtained in each treatment period, analyzed and PK parameters calculated.

Results

A total of 12 participants received study treatments, and 11 participants completed the full dosing period. One participant (Treatment Sequence A-B-C) was discontinued by the investigator on Day 3 of Period 2 due to behavioral issues and noncompliance with clinic rules. There were no discontinuations or study disruptions because of treatment. There were 12 participants included in the safety analyses and 11 participants included in the PK analyses. There were no deaths, SAEs, or participant discontinuations due to AEs in this study. The incidence of AE reporting was minimal and was observed to be similar across the 3 treatments. The most common event reported overall was vessel puncture site pain, reported by 3 [25%] participants, followed by vessel puncture site bruise and rhinorrhea (2 [17%] participants each). The investigator considered 18 of the 28 TEAEs to be mild (grade 1) and 10 to be moderate (grade 2); all events resolved. Coadministration of argatroban and VLX-1005 had no effect on the PK of either drug and no impact on the effect of argatroban on activated partial thromboplastin time (aPTT) in healthy human adult participants.

Conclusions

All treatment regimens appeared to be safe and well tolerated by the male and female healthy human subjects in this study; no evidence of increased bleeding was noted across treatment groups. Coadministration of argatroban and VLX-1005 had no effect on the PK of either drug. The administration of VLX-1005 had no effect on aPTT in healthy human adult subjects. The coadministration of VLX-1005 with argatroban had no impact on the effect of argatroban on aPTT in healthy human adult subjects. The Phase 2 ALATHEA (A study of VLX-1005 to evaLuAte Thrombocyte change in HEpArin Induced Thrombocytopenia) study of VLX-1005 in HIT is currently ongoing.