OC 31.3 - Phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of VMX-C001 in healthy subjects

Monday, June 26, 2023

11:15 – 11:30 ET

Room: 516

Session Available As: Live-Stream and On-Demand

Presenting Author(s)

Gerard Short, MRCP FFPM MBA

Chief Medical Officer
VarmX, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands

Co-Author(s)

DV

Daniël Verhoef

Director of Research
VarmX, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
TG

Tainá Gomes

R&D Scientist
VarmX, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
HS

Henri Spronk

Chief Executive Officer
Coagulation Profile, Maastricht, The Netherlands
Maastricht, Limburg, Netherlands
JO

Jan Ohrstrom

Chief Executive Officer
VarmX, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
BP

Bo Persson

Senior Vice President, CMC Development & Project Management
VarmX, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
JW

Jeffrey I. Weitz

Professor of Medicine and Biochemistry and Biomedical Sciences at McMaster University
McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
Hamilton, Ontario, Canada
PR

Pieter Reitsma

Chief Scientific officer
VarmX, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands

Background: VMX-C001 is a recombinant variant of human coagulation factor X (FX) insensitive to inhibition by FXa direct oral anticoagulants (FXa-DOACs) under development for reversal of FXa-DOACs in patients with serious bleeding or requiring urgent surgery.

Aims: To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VMX-C001 in healthy subjects.

Methods: In Part 1 of this phase 1, single-center, double-blind, randomized, placebo-controlled, first-in-human study (NCT05152420), single ascending intravenous doses of VMX-C001 (100‒3000 IU; n=6) or placebo (n=2) were administered to 6 cohorts of 8 healthy subjects (age 18–49 years). In Part 2, 7 cohorts of 8 healthy older subjects (age 50‒79 years) who had received a 3.5-day course of treatment with apixaban (5 mg twice-daily) or rivaroxaban (20 mg once-daily) were given, 5 min after their last FXa-DOAC dose, a single intravenous dose of VMX-C001 or placebo administered over 5 min. The local ethics committee approved the study; all volunteers provided written informed consent. Blood samples were collected before and after study drug administration for determination of PK parameters, thrombin generation, diluted prothrombin time (dPT), and diluted Russell viper venom time (dRVVT). Safety assessments included adverse events, immunogenicity (antibodies against VMX-C001 or FX), and the levels of D-dimer, thrombin-antithrombin complexes, and prothrombin F1.2.

Results: Subject dosing is completed but the data are still blinded. Overall, 78 subjects received VMX-C001 either alone (n=36) or in combination with FXa-DOACs (n=42). There were no safety or tolerability concerns. Blinded PK data (Figure 1) revealed dose-proportional linear kinetics with a half-life (t½) of approximately 30 h and a volume of distribution of approximately 9 L. Preliminary PD data (Figure 2) suggest that VMX-C001 reverses the anticoagulant effects of apixaban and rivaroxaban. The complete results will be presented.

Conclusion(s): Preliminary data warrant further clinical development of VMX-C001 for the reversal of FXa-DOACs.

Learning Objectives:

Appreciate the need to restore coagulation in people taking DOAC anticoagulants in cases of severe bleeding and prior to emergency surgery
Understand that VMX-C001 is a novel FXa DOAC bypassing agent that, following a single 5 min infusion, has been shown to be safe and well tolerated with a long half life and clear evidence of restoration of coagulation in the presence of FXa DOACs
Appreciate that the effects seen in phase 1 support further development of VMX-C001 to reduce or prevent bleeding in patients taking FXa DOACs who experience severe bleeding or require emergency surgery.