Phase 1 Study of the Safety and Pharmacodynamics of a Single Dose of Vmx-C001 in Healthy Subjects with and without FXa Direct Oral Anticoagulants

Background: VMX-C001 is an engineered recombinant human coagulation factor X (FX) insensitive to inhibition by FXa direct oral anticoagulants (FXa-DOACs) which bypasses the effect of FXa DOACs and rapidly restores coagulation upon administration. It is under development for reversal of FXa DOACs in patients with serious bleeding or requiring urgent surgery. Because it acts as a bypassing agent the same dose is expected to be effective regardless of which FXa DOAC a patient has taken. VMX-C001 has previously been investigated in a First in Human study in subjects treated with apixaban and rivaroxaban. This study was performed to extend the range of doses tested with rivaroxaban, to test it in the presence of edoxaban and to test the tolerability of rapid administration.

Aims: To assess the safety, tolerability, PK and PD of VMX-C001 in healthy subjects in the absence and presence of FXa DOACs, rivaroxaban and edoxaban, and to test the safety and tolerability of the administration of VMX-C001 over 2 minutes and over 10 seconds.

Methods: This is a phase 1, single-center, double-blind, randomized, placebo-controlled study (NCT06372483). In Part 1 a single intravenous dose of VMX-C001 (170 mg; n=6) or placebo (n=2) was administered to a cohort of 8 male or female healthy subjects (age 18-49 years) over 2 minutes. In Part 2, 4 cohorts of 8 healthy older male and female subjects (age 50‒79 years) who had received a 3.5-day course of treatment with rivaroxaban (20 mg once-daily; one cohort) or edoxaban (60 mg once daily, 3 cohorts) were given, 5 min after their last FXa-DOAC dose, a single intravenous dose of VMX-C001 (doses of 113mg to 170mg) or placebo administered over 2 min (3 cohorts, 1 rivaroxaban, 2 edoxaban) or 10 seconds (1 cohort, edoxaban). 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), diluted Russell viper venom time (dRVVT), PT, aPTT and ACT. Safety assessments included adverse events, immunogenicity (antibodies against VMX-C001 or FX), and the levels of D-dimer, and prothrombin F1.2.

Results: Subject dosing is completed but the data are still blinded. Overall, 30 subjects received VMX-C001 either alone (n=6) or in combination with FXa-DOACs (n=24). There were no safety or tolerability concerns. Blinded PK data was consistent with previous results and showed dose-proportional linear kinetics with a half-life (t_½) of approximately 30 h and a volume of distribution of approximately 9 L. Administration over both 2 minutes and over 10 seconds was well tolerated with no infusion reactions or clinically significant changes in pulse or blood pressure regardless of administration time. Preliminary PD data suggest that VMX-C001 bypasses the anticoagulant effects of rivaroxaban and edoxaban. The complete results will be presented.

Conclusion: Previous data shows that VMX-C001 rapidly bypasses the effects of apixaban and rivaroxaban. Preliminary data from this study extends the data on doses of VMX-C001 bypassing rivaroxaban and provides data showing that VMX-C001 bypasses the effect of edoxaban. In this study VMX-C001 was well tolerated, can be administered via a 10 seconds iv push and has a half life of 30 hrs. These data indicate a suitable profile for emergency use and support further clinical development of VMX-C001 for the rapid restoration of coagulation in patients who have taken FXa-DOACs and are experiencing severe bleeding or require urgent surgery.

Short:Bloomsbury Gene Therapy: Consultancy; X Point Diagnostics: Current equity holder in private company; VarmX B.V.: Current Employment, Current holder of stock options in a privately-held company. Zoerer:VarmX B.V.: Current Employment, Current holder of stock options in a privately-held company. Hilton:VarmX BV: Current Employment, Current holder of stock options in a privately-held company. Gomes:VarmX B.V.: Current Employment. Ohrstrom:VarmX B.V.: Current Employment, Current holder of stock options in a privately-held company. Persson:VarmX BV: Current Employment, Current holder of stock options in a privately-held company. Verhoef:VarmX B.V.: Current Employment, Current holder of stock options in a privately-held company. Reitsma:VarmX B.V.: Current Employment, Current holder of stock options in a privately-held company.