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Addressing the Need for an Effective Anticoagulant

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The process of forming a blood clot is called coagulation. Coagulation is a key player in the repair and maintenance of the circulatory system. However, in some cases, such as major surgery, there is a significant risk of clotting – which must be managed using anticoagulants. Whilst several anticoagulants currently exist, they have limited discrimination between the intrinsic pathway (responsible for thrombosis) and extrinsic pathway (responsible for hemostasis), both involved in coagulation, meaning there is the chance of increased bleeding which can be dangerous. 

Technology Networks recently spoke with Dr Neil Hayward Ph.D., CEO at eXIthera Pharmaceuticals to learn more about the role of the intrinsic and extrinsic pathways, and how they are exploiting coagulation mechanisms to develop antithrombotic therapeutics.

Laura Lansdowne (LL): For some of our readers less familiar with eXIthera could you tell us a little about the company mission and history?

Neil Hayward (NH):
eXIthera is a clinical stage biotechnology company developing potent and selective Factor XIa small molecules that stop clot formation but importantly without the detrimental major bleeding issues that are observed with all current anticoagulants. The company’s mission is to precisely manage the risk of clotting during major surgeries, without increasing bleeding and thus save lives. By properly managing this, we can reduce the cost for payers, health systems and pharmaceutical companies.

I am the founder and CEO of eXIthera. Previously, I worked on Factor XI for Daiichi (and Sankyo via merger in 2005). To streamline the two companies, my department, along with the rest of our site in Cambridge, Massachusetts, was laid off. At that time, and with the help of my former boss from Daiichi, I secured the rights and patents related to my work on a promising, yet under-researched, anticoagulant target, Factor XIa, and founded eXIthera in 2012.

LL: Could you delve into the “science of coagulation” and explain how you are exploiting coagulation pathways to develop therapeutics?

Coagulation, or blood clotting, is the body’s mechanism for repairing and maintaining the circulatory system—blood clotting allows for vessel repair. This complex process has two parallel but distinct pathways. One is hemostasis, initiated in response to trauma to the vascular system and is often called the extrinsic pathway. Another is thrombosis, which is initiated by intravascular injury and is described as the intrinsic or contact pathway. These pathways merge to a common pathway leading to activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin, to form a clot.

All currently available anticoagulants/blood thinners have limited discrimination between the intrinsic and extrinsic pathways, resulting in undesired impairment of normal hemostasis. As a result, there is an increased risk of bleeding and delayed vessel repair.

We circumvent this problem by specifically targeting, and blocking, one critical enzyme, Factor XIa, in the contact pathway, to reduce unwanted bleeding, whilst preserving its beneficial antithrombotic effects. Because our lead compound, EP-7041, targets a different protein than other anticoagulants, we have observed protection against unwanted blood clots without the concern of uncontrollable bleeding. Additionally, it acts rapidly with a desirable safety therapeutic window, meaning the drug works as soon as it is administered and if accidentally administered at higher dose levels should still not cause an increase in bleeding.

LL: Could you touch on some of the concerns/risks related to currently available treatments in this area?

In the ICU, patients are often put on extra corporeal membrane oxygenation (ECMO) machines and, during major heart surgery, all patients are put on a heart-lung machine. These patients—along with their life-saving machines—need to be anticoagulated to prevent clotting. Because current standard-of-care anticoagulants are nonselective or target a specific protein that can cause severe, uncontrollable bleeding, cardiac surgeons must reverse the effects of the anticoagulant with a drug called protamine, which has additional unwanted side effects, before closing the patient’s chest. This is concerning for the surgeon, as his/her patient, who has now successfully completed open-heart surgery, needs to remain on the operating table as the surgeon ensures that the blood is clotting correctly, thereby exposing the patient to infection and other complications. EP-7041 ensures the inhibition of clot formation with decreased bleeding liabilities, and is promptly cleared from the patients system (due to the drug’s short half-life), thus removing the need for an additional drug/reversal agent to be used. Surgeons will now be able to perform in a clearer “dry” operating field (they won’t have as much blood in the patient’s cavity) and will be able to complete surgery and close the patient faster.

LL: Could you tell us more about the two candidates currently featured in your development pipeline?

Our lead drug candidate, EP-7041, is our injectable, potent and selective small molecule Factor XIa inhibitor and has successfully completed a Phase I clinical trial in healthy human subjects. We are currently identifying the therapeutic dose to proceed with in our opening Phase II clinical studies in patients on ECMO or undergoing cardiac surgery.

We also have a subcutaneous formulation of EP-7041, which we plan to develop in the future, along with our second candidate, an oral/tablet Factor XIa inhibitor for chronic indications.

LL: You plan to initiate a Phase II study at the end of 2020 for your small molecule, EP-7041, in acute hospital settings. Could you tell us more about this study?

We are currently conducting preclinical studies to determine the therapeutic dose of EP-7041 that we plan to use in the Phase II study. We have been in close contact with the regulatory agencies as well as our target clinical sites. When our preclinical studies are complete, we will file an investigational new drug (IND) with the FDA to open a Phase II study of EP-7041 in ICU patients that are on an ECMO machine. Upon acceptance of our IND, we plan to initiate this clinical study later this year.

Neil Hayward Ph.D, was speaking to Laura Elizabeth Lansdowne,
Senior Science Writer, Technology Networks.