DOAC reversal agents have been on the market since 2015, and while effective, clinicians are calling for further improvements that could help advance treatment outcomes for patients.

In a presentation at ISTH 2022, clinical investigator Dr Jack Ansell, a former Chairman of the Department of Medicine at Lenox Hill Hospital in New York, outlined three promising future prospects that could help to fulfil unmet need in the area.

Describing the current gaps in care, he said key desired attributes of the next generation of reversal agents include being “readily available at the point of care and [quick] to prepare,” having rapid action, and being able to induce sustained normalisation of coagulation without the need for repetitive dosing or continuous infusion.

Point of care testing to assess DOAC drug levels is particularly important as currently “up to 25% of patients do not have clinically relevant DOAC drug levels,” and any reversal agent must not induce a prothrombotic state “because these patients are already prothrombotic due to their underlying condition”.

Also, “[clinicians] would like a drug that would allow for re-coagulation 24 or more hours later if the need should arise that does not induce tolerance, that does not induce an immune response and, perhaps most difficult of all, is inexpensive or at least cost-effective,” he said.

Dr Ansell highlighted three DOAC reversal methodologies currently in various stages of development with the potential to address some of these issues and improve overall outcomes: “VMX-C001 – an engineered factor Xa resistant to Xa inhibitors yet active in thrombin generation, thus bypassing the Xa inhibitor and restoring coagulation; CytoSorb – an extracorpeal blood purification system capable of removing rivaroxaban during open heart surgery and restoring coagulation; and ciraparantag, a small molecule that binds to the Xa inhibitors and prevents them from binding to their target, thus restoring coagulation”.

Brown snake venom

VMX-C001 is a modified recombinant human blood factor X zymogen based on the venom of the Australian brown snake Pseudonaja textiles and synthesised from Chinese hamsters ovary (CHO) cells.

It is currently in development as a reversal agent for the treatment of severe spontaneous bleeding and the prevention of bleeding during surgery.

“The drug has been modified so that it doesn’t interact with Xa inhibitors but does act on the coagulation cascade, so in a sense, [it’s] a replacement therapy or a bypassing therapy for factor X, to allow coagulation to proceed even in the presence of the Xa inhibitors,” he said.

There have been a number of preclinical animal studies with VMX-C001, which have shown a half-life of around 7-9 hours, no serious side effects or pro-coagulant activity. The drug has also shown an in vivo and ex vivo reversal of the effect of apixaban or rivaroxaban, and a dose-dependent reversal of anticoagulation in Factor Xa DOAC spiked plasma from health donors.

A major first in human trial was started seven months ago involving 88 healthy individuals, which is expected to complete this Summer.

CytoSorb has already been on the market for a number of years, where it is predominantly used to reduce bleeding during heart surgery, as well as to remove inflammatory cytokines amid COVID-19.

The system is essentially comprised of a cartridge containing biocompatible absorbent polymer microbes which can remove a variety of low molecular weight hydrophobic substances from the blood.

“There have already been a number of preclinical studies showing that CytoSorb can remove up to 90% of rivaroxaban bringing levels back to baseline, or sub-therapy levels, and other trials showing its ability to remove apixaban in spiked blood,” he said.

Also, “a retrospective analysis of real world data, which analysed surgical outcomes of haemadsorption in a small number of patients treated with rivaroxaban or ticagrelor who underwent emergency cardiac operations for acute aortic dissection, showed that the system reduced surgical time, reduced bleeding and reduced the need for platelets”, Dr Ansell noted.

Currently a trial in the US designed to support approval for rivaroxaban removal in patients undergoing urgent on-pump cardiothoracic surgery is ongoing, he said.

Broad spectrum

Ciraparantag is a small synthetic molecule with a broad spectrum of activity against the DOACs as well as various heparin preparations, being developed by Covis Pharma and Norgine, with Dr Ansell a trial investigator on several studies linked to the drug.

“One of the challenges linked with the drug is that its effect cannot be measured by routine anticoagulation assays,” as it binds strongly to anionic substances, such as agents in a test-tube used to generate plasma, he told delegates.

However, a coagulometer was developed “which gives precise and reproducible results in a short time period” and is already approved for use in Europe, he said.

Animal trials of the drug have shown a significant reduction in bleeding, while a Phase II dose ranging study in humans, recently published in the European Heart Journal and led by Dr Ansell, showed that clotting time returned to normal in 80% within 15 minutes.

According to Dr Ansell, ciraparantag was also well tolerated, with adverse events generally related to hot flushes or feeling cold, and quickly resolved.

A Phase IIb trial of the drug is about start, with a view to initiating Phase III development in 2023 testing its safety and efficacy for patients taking DOACs with major or life-threatening bleeding as well as those requiring emergency surgery or urgent procedures, he said.

This presentation at ISTH was sponsored by Norgine.