VMX-C001 / VarmX - LARVOL DELTA

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

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

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

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

VarmX to Present New Data at the 2022 ISTH Congress (Varmx Press Release) - "VarmX...today announced it will present new preclinical data on the pharmacodynamics, toxicokinetics, and safety of VMX-C001, its lead compound, at the 2022 ISTH (International Society on Thrombosis and Haemostasis) Congress in London. VarmX will deliver an oral presentation on Sunday, 10 July at 15.15-15.30 BST, and will showcase a poster on Tuesday 12 July at 18.30-19.30 BST."

Preclinical

First Subjects Dosed in First-in-Human Trial for VarmX’s Anticoagulant Reversal Agent, VMX-C001 (Businesswire) - "VarmX...today announced treatment of the first subjects in its first-in-human study for lead compound VMX-C001....It will assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenously administered VMX-C001, both alone and in combination with selected Direct Oral Anticoagulants (DOACs). It is anticipated that up to 88 participants will be enrolled."

Trial status • 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.

Clinical • Combination therapy • New P1 trial • Hematological Disorders

VarmX Awarded Funding From the EIC Accelerator to Support Scale up and Manufacturing of VMX-C001 (Businesswire) - "VarmX...has been awarded up to €17.5 million from the European Innovation Council (EIC) Accelerator, subject to negotiation, to upscale and accelerate cost effective manufacturing of its lead compound, VMX-C001....The funding will be used to support VarmX’s lead compound, VMX-C001, which is being developed for the treatment of severe spontaneous bleeding in patients taking Factor Xa Direct Oral Anticoagulants (FXa DOACs) and for the prevention of bleeding in patients taking FXa DOACs who require emergency surgery."

Financing • Hematological Disorders

VarmX to Present New Data on Lead Compound, VMX-C001, at the ISTH 2021 Virtual Congress - “VarmX…announces that new preclinical data on VMX-C001 has been selected to be presented during an oral presentation at the ISTH (International Society on Thrombosis and Haemostasis) Virtual Congress on Tuesday, 20 July, 2021 at 11.00-12.00 EDT….The abstract, which was selected by the conference organisers for oral presentation, is…VMX-C001 is an effective FXa-DOAC reversal agent and displays no thrombogenic potential in comparison to andexanet alfa and 4PCC”

Preclinical • Hematological Disorders

[VIRTUAL] VMX-C001 Is an Effective FXa-DOAC Reversal Agent and Displays No Thrombogenic Potential in Comparison to Andexanet Alfa and 4PCC (ISTH 2021) - "Methods : TG was performed in platelet poor plasma (PPP) from healthy donors spiked with VMX-C001, andexanet alfa (Andexxa®) or 4-factor PCC (Beriplex®) and FXa-DOAC...4PCC (0.25–1.0 U/mL) was not able to reverse the anticoagulant effect of apixaban and edoxaban and only partly reversed rivaroxaban inhibition...PCC does not restore thrombin generation and leads to overshooting of ETP in the absence of FXa-DOACs. Andexanet alfa restores thrombin generation, but ETP overshoots due to neutralization of TFPI."

"#VarmX to present new data on lead compound, VMX-C001, at the @ISTH 2021 Virtual Congress. https://t.co/BRBxQdkREM #ISTH2021" (@Instinctif_HLS)

How deadly snake venom can save lives - and a Leiden biotech company catches € 32 million for it [Google translation] (Business Insider) - "PseudoXa will hit the market in 2025 at the earliest, says CEO Alexander Vos. 'But it can also take longer, depending on how good the results are in the meantime.'...Investors are confident in the technology and have already pumped more than 45 million euros into PseudoXa...With 32 million euros in fresh capital, VarmX can scale up the production of the medicine and carry out the first tests on groups of healthy volunteers. This happens at research centers such as PRA Health Sciences, QPS and CHDR, which specialize in so-called phase 1 studies, which look at how people respond to a new drug."

Clinical • Financing • Launch

VarmX Raises €32 Million in Series B Financing to Develop Innovative Reversal Agent for the Treatment and Prevention of Severe Bleeding in Patients on Oral Anticoagulants (Businesswire) - "VarmX...today announces the completion of a €32 million Series B financing round....The proceeds from the Series B financing will enable the Company to obtain clinical proof of concept through a first in human (FIH) study of VMX-C001, and to further progress the program towards the start of registrational studies in both the severe bleeding and emergency surgery indications. The Company will also use the funds to accelerate the manufacturing trajectory for VMX-C001 towards commercial-scale, extend profiling studies for optimal clinical and commercial positioning, and advance its discovery platform program for next generation reversal agents."

Clinical • Financing