VMX-C001 / VarmX - LARVOL DELTA

VMX-C001-03: Single Dose Trial of VMX-C001 in Healthy Subjects With and Without FXa Direct Oral Anticoagulant (clinicaltrials.gov) - P1 | N=40 | Completed | Sponsor: VarmX B.V. | Active, not recruiting ➔ Completed

Trial completion • Hematological Disorders

EQUILIBRIX-S: Phase 3 Trial of VMX-C001 vs Usual Pharmacological Care in Patients Taking a FXa Direct Oral Anticoagulant Who Require Urgent Surgery With or Without Heparin. (clinicaltrials.gov) - P3 | N=800 | Recruiting | Sponsor: VarmX B.V. | Initiation date: Mar 2026 ➔ Aug 2026 | Not yet recruiting ➔ Recruiting

Enrollment open • Trial initiation date • Hematological Disorders

VMX-C001-06: Phase 3 trial of VMX-C001 vs usual pharmacological care in patients taking a FXa direct oral anticoagulant who require urgent surgery with or without heparin (clinicaltrialsregister.eu) - P2/3 | N=124 | Not yet recruiting | Sponsor: VarmX B.V.

New P2/3 trial

Effects of VMX-C001 on the Anticoagulant Effect of Different Forms of Heparin (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: VarmX B.V. | Active, not recruiting ➔ Completed | Trial completion date: Oct 2026 ➔ Apr 2026

Trial completion • Trial completion date • Hematological Disorders

Coagulation assays for assessing the bypassing of factor Xa direct oral anticoagulants using VMX-C001. (PubMed, Res Pract Thromb Haemost) - "Additionally, dPT/dRVVT were measured in plasma spiked in vitro with apixaban, edoxaban, or rivaroxaban (0-1600 ng/mL) in the absence and presence of VMX-C001 (15-60 μg/mL), andexanet (50-200 μg/mL), or 4-factor prothrombin complex concentrates (0.25-0.50 IU/mL). Using both assays, clotting time from healthy subjects and nursing home residents receiving FXa DOACs correlated strongly with plasma drug concentrations. dPT and dRVVT assays can serve as surrogate end points in studies of VMX-C001 and can also be used to monitor FXa DOAC anticoagulation."

Journal

EQUILIBRIX-S: Phase 3 Trial of VMX-C001 vs Usual Pharmacological Care in Patients Taking a FXa Direct Oral Anticoagulant Who Require Urgent Surgery With or Without Heparin. (clinicaltrials.gov) - P3 | N=800 | Not yet recruiting | Sponsor: VarmX B.V.

New P3 trial • Hematological Disorders

Vmx-C001 has no effect on the anticoagulant function of heparin in healthy subjects (ASH 2025) - "This study tested the anticoagulant effects of UFH and LMWH administered shortlyafter VMX-C001 in healthy subjects in situations simulating (a) patients taking FXa DOACs who requirerestoration 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. This Phase I, single site, open-label study in healthy subjects (aged ≥18–49 years) investigatedthe effects of VMX-C001, in combination with the FXa DOAC rivaroxaban and alone, on the anticoagulanteffect of UFH (UFH cohort) and LMWH (enoxaparin; LMWH cohort), respectively. 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 ACTincreased, 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:..."

Clinical • TINCR

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 (ASH 2024) - P1 | "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."

Clinical • P1 data • PK/PD data • Cardiovascular • Hematological Disorders • Thrombosis

Vmx-C001 Prevents Rivaroxaban-Induced Bleeding in a Liver Injury Model in Cynomolgus Monkeys (ASH 2024) - "VMX-C001 has previously been shown to be safe and well tolerated in a FIH study in subjects treated with apixaban and rivaroxaban. Changes in PT/aPTT appear not to predict the effect of VMX-C001 on bleeding. Results on coagulation assays TG, dRVVT and dPT are pending and will be communicated at the congress."

Anesthesia • Hepatology • Liver Failure

Paradigm Shifts in Hemostasis: From Mechanisms to Therapies and Back (ASH 2024) - "VMX-C001 also prevented rivaroxaban induced bleeding in a primate liver injury model. Puy will elucidate factor XI pivotal role in modulating endothelial cell permeability and barrier function, shedding light on its implications in thrombotic and inflammatory conditions. This presentation will deepen our understanding of factor XI multifaceted involvement in health and disease."

Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Hepatology • Inflammation • Liver Failure • Rare Diseases • Rheumatology • Thrombosis

Effects of VMX-C001 on the Anticoagulant Effect of Different Forms of Heparin (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: VarmX B.V. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Disorders

VMX-C001 bypasses the effects of FXa-direct oral anticoagulants in healthy adults: ROTEM analysis (ISTH 2025) - "Additionally, older adults (50–79 years) received FXa-DOACs (rivaroxaban, apixaban, edoxaban) for 3.5 days, followed by a single VMX-C001 dose (89–226 mg) or placebo (days 1–4). Results were consistent across groups and VMX-C001 doses. Table or Figure Upload"

Clinical

Effects of VMX-C001 on the Anticoagulant Effect of Different Forms of Heparin (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: VarmX B.V. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Hematological Disorders

Effects of VMX-C001 on the Anticoagulant Effect of Different Forms of Heparin (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: VarmX B.V.

Combination therapy • New P1 trial • Hematological Disorders

VMX-C001-03: Single Dose Trial of VMX-C001 in Healthy Subjects With and Without FXa Direct Oral Anticoagulant (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: VarmX B.V. | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2024 ➔ Aug 2026

Combination therapy • Enrollment closed • Trial completion date • Hematological Disorders

A novel bleeding model in monkeys to assess efficacy of VMX-C001 for bypassing of FXa-DOAC anticoagulation (ISTH 2024) - "In monkeys administered VMX-C001 alone, PT and, particularly, aPTT increased versus baseline. These increases were not associated with altered bleeding outcome post-injury (Fig 1). In animals pre-treated with rivaroxaban, PT and aPTT were prolonged (PT from 9.8±0.5 to 20.9±5.7 seconds; aPTT from 23.0±1.25 to 36.7±4.9 seconds); VMX-C001 administration shortened PT to 14.2±1.2 seconds and further prolonged aPTT to 52.0±6.6 seconds; however, VMX-C001 reversed the rivaroxaban-induced increases in bleeding time and blood loss post-injury to baseline levels (Fig 2)."

Clinical • Anesthesia

Single Dose Trial of VMX-C001 in Healthy Subjects With and Without FXa Direct Oral Anticoagulant (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: VarmX B.V.

Combination therapy • New P1 trial • Hematological Disorders

Phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of VMX-C001 in healthy subjects (ISTH 2023) - P1 | "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. 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."

Clinical • P1 data • PK/PD data

Coagulation assays for assessing direct Factor Xa inhibitor oral anticoagulant reversal effects (ISTH 2023) - "Plasma samples from healthy volunteers were then spiked ex vivo with apixaban (n=22), edoxaban (n=3), or rivaroxaban (n=3) at 0‒400 ng/mL with and without VMX-C001 (0.3 U/mL) and dRVVT and dPT were measured. Both assays were validated and sensitive to FXa-DOACs, resulting in dose-dependent prolongation of dRVVT and dPT, which was reversed when VMX-C001 was present in plasma, resulting in normal dRVVT and dPT (Figure 1). Assay validity was also confirmed with the plasma samples taken from subjects treated with FXa-DOACs in vivo (Figure 2).Conclusion(s): dRVVT and dPT assays can be used to monitor FXa-DOAC anticoagulation with a high degree of sensitivity and can serve as surrogate endpoints in studies of the FXa-DOAC reversal agent VMX-C001."

Study of Intravenous VMX-C001 in Healthy Subjects and in Combination With Selected Direct Oral Anticoagulants in Healthy Older Subjects (clinicaltrials.gov) - P1 | N=105 | Completed | Sponsor: VarmX B.V. | Recruiting ➔ Completed

Combination therapy • Trial completion • Hematological Disorders

When and How to Use Reversal Agents for Direct Oral Anticoagulants? (PubMed, Curr Cardiol Rep) - "Specific (idarucizumab for dabigatran and andexanet alfa for direct factor Xa inhibitors) and non-specific (prothrombin complex concentrates) reversal agents are effective in neutralizing the anticoagulant effect of DOACs. New investigational antidotes such as ciraparantag and VMX-C001 offer an alternative to andexanet alfa in reversing the anticoagulant activity of direct oral factor Xa inhibitors, but more clinical data are needed before they could be licensed for use. Specific reversal agents are recommended for use in clinical situations within their licensed indications (i.e.: reversal of DOACs in patients with severe uncontrolled or life-threatening bleeding or in need of emergency surgery or other invasive procedures), while non-specific reversal agents may be used when specific antidotes are not available or indicated."

Journal • Review

Study of Intravenous VMX-C001 in Healthy Subjects and in Combination With Selected Direct Oral Anticoagulants in Healthy Older Subjects (clinicaltrials.gov) - P1 | N=128 | Recruiting | Sponsor: VarmX B.V. | N=88 ➔ 128

Combination therapy • Enrollment change • Hematological Disorders

Study of Intravenous VMX-C001 in Healthy Subjects and in Combination With Selected Direct Oral Anticoagulants in Healthy Older Subjects (clinicaltrials.gov) - P1 | N=88 | Recruiting | Sponsor: VarmX B.V. | Trial completion date: Jul 2022 ➔ Mar 2023 | Trial primary completion date: Jul 2022 ➔ Mar 2023

Combination therapy • Trial completion date • Trial primary completion date • Hematological Disorders

Preclinical safety and toxicokinetics of VMX-C001 - an intravenous bypassing agent for factor Xa inhibitors (ISTH 2022) - "In either species there were no unscheduled deaths, no clinical signs, no effects on body weight or food consumption nor on ECGs. There were also no hematology, coagulation (including TAT and d-dimer), clinical chemistry and urinalysis changes during the dosing and recovery periods. In rats, no positive ADAs were observed at the end of dosing."

Preclinical • Hematological Disorders

VMX-C001 is an effective factor Xa inhibitor reversal agent and displays a favorable pharmacodynamic profile in animal models (ISTH 2022) - "Five minutes after intravenous administration, VMX-C001 corrected the effect of edoxaban on ETP and lag time and restored peak height to near normal levels (Figure 1). In another setup, five male monkeys received rivaroxaban by oral gavage (10 mg/kg) and VMX-C001 was administered once 3 hours after the factor Xa inhibitor... In rats, regardless of sex, there were no VMX-C001 related changes compared to pre-dose and placebo in endogenous thrombin potential (ETP), thrombin peak height and time to initiation of thrombin generation (ie. lag time). Similarly, administration of VMX-C001 to monkeys was not associated with significant changes in TG parameters."

PK/PD data • Preclinical