Abstract
Introduction: VMX-C001 is in clinical development to restore coagulation in patients taking factor Xa direct oral anticoagulants (FXa DOACs), who need urgent surgery or have severe bleeding. It is important to ensure patients who require intra-procedural anticoagulation with unfractionated heparin (UFH) and/or post-procedural thromboprophylaxis with low molecular weight heparin (LMWH) can do so after receiving VMX-C001. This study tested the anticoagulant effects of UFH and LMWH administered shortly after VMX-C001 in healthy subjects in situations simulating (a) patients taking FXa DOACs who require restoration of coagulation with VMX-C001 and then require UFH, e.g., for cardiopulmonary bypass; and (b) patients receiving VMX-C001 who then require LMWH for thromboprophylaxis.
Methods: This Phase I, single site, open-label study in healthy subjects (aged ≥18–49 years) investigated the effects of VMX-C001, in combination with the FXa DOAC rivaroxaban and alone, on the anticoagulant effect of UFH (UFH cohort) and LMWH (enoxaparin; LMWH cohort), respectively. The UFH cohort received: on day 1, 5000 IU IV UFH; on days 2 to 5, 20 mg oral rivaroxaban once daily; and on day 5, 4 hours (hrs) after rivaroxaban, 170 mg IV VMX-C001 over 10 sec then, after 20 min, 5000 IU IV UFH. The LMWH cohort received: on day 1, 40 mg SC enoxaparin; and on day 4, 170 mg IV VMX-C001 over 10 sec then, after 20 min, 40 mg SC enoxaparin. Descriptive statistics were used.
Pharmacodynamic endpoints: Both cohorts: prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and thrombin generation (TG); UFH cohort: activated clotting time (ACT), thrombin time, dilute prothrombin time (dPT), and dilute Russell's viper venom time (dRVVT); LMWH cohort: anti-FXa activity. TG results shown are endogenous thrombin potential with 20 pmol tissue factor; however, full TG results are available.
Other endpoints: Included safety (adverse events; AEs) and immunogenicity.
Results: In the UFH cohort (N=7), mean age was 28±8 years, 5 (71.4%) were female and all were non-Hispanic white. Following UFH alone on day 1, changes from baseline at 1 hr post-UFH: PT, aPTT and ACT increased, dPT +16.41 sec and dRVVT -2.85 sec; TG decreased to undetectable levels (-100% vs. baseline). Four hrs after rivaroxaban administration on day 4: PT increased, dPT +152.63 sec and dRVVT +89.83 sec; aPTT and ACT showed only small changes and TG -28.55% vs. baseline. On day 5, rivaroxaban had similar effects to day 4. VMX-C001 was administered post-rivaroxaban and, by 15 mins post VMX-C001, restored dPT (-8.67 sec vs. baseline), dRVVT (-3.11 sec vs. baseline) and TG (-6.74% vs. baseline). UFH given after VMX-C001 reduced TG to undetectable levels at 1 hr (-100% vs baseline), as on day 1.
In the LMWH cohort (N=8), mean age was 29±6 years, 6 (75.0%) were female and 6 (75.0%) were non-Hispanic white. On day 1, 4 hrs post-LMWH alone, anti-FXa activity greatly increased and TG decreased markedly (-37.94% vs baseline). On day 4, 4 hrs after VMX-C001 followed by LMWH administration, anti-FXa activity greatly increased and TG decreased markedly (-34.17% vs. baseline) and similarly to day 1.
PT and aPTT were slightly increased post-VMX-C001 in both cohorts but generally returned to the normal range by 24 hrs post-UFH/LMWH.
Treatment-emergent AEs (TEAEs) were reported in 4 (57.1%) and 8 (100%) subjects in the UFH and LMWH cohorts, respectively, were mostly mild and resolved by end of study. The most common TEAE was LMWH injection site pain. There were no reports of severe AEs, serious AEs or TEAEs leading to study drug interruption, withdrawal or premature study discontinuation.
A total of 4 of 15 subjects developed anti-VMX-C001 antibodies (titer ≤1:9); however, no abnormalities in PT or aPTT were observed in these subjects at the last follow-up visit (day 31). Anti-FX antibodies were detected in one subject in the UFH cohort at the first follow-up visit, but this was considered a false positive (titer <1:1, no positive anti-VMX-C001 antibody results and no effect on dPT or dRVVT).Conclusion(s): VMX-C001 with or without a FXa DOAC did not impact the anticoagulant activity of UFH or LMWH. This shows VMX-C001 can restore coagulation in people taking FXa DOACs and UFH can be administered immediately after VMX-C001 for anticoagulation during vascular surgery or for cardiopulmonary bypass and LMWH can be used as thromboprophylaxis or anticoagulation in individuals administered VMX-C001.
