Blood clots are commonly missed. According to the National Blood Clot Alliance (NBCA), “fewer than 1 in 4 people have any recognition of blood clots or their signs and symptoms.” So what exactly happens during the clotting process? And when does clotting go from a necessary bodily function to the danger zone?
First, let’s discuss what happens during clotting. Protein in the blood, fibrinogen, is converted into fibrin with the help of clotting factors. When tissue injury occurs, clotting factors become activated in an intricate pathway known as the coagulation cascade.
When a blood vessel is injured, the coagulation cascade is triggered, and several proteins, or clotting factors, come into play. The cascade results in fibrin strands weaving and sticking together over a clump of platelets on the injured site to stop the bleeding. The formation of this clot is often a necessary function of the body.
Clotting, however, is not always a welcome event. We spoke with Bayer, a member of the Biotechnology Innovation Organization (BIO), about clotting and their work to develop a new class of medications that give hope to patients who face a high risk of bleeding and dangerous clotting.
The dangers of clots
A clot, or thrombus, that breaks off the site of injury can pass in the blood to a smaller artery or vein and become lodged there. When this happens and the blood supply is cut off, the tissue or organ depending on that blood flow will become deprived of oxygen and die.
Venous thromboembolism (VTE) is the third most common cardiovascular disease worldwide and the most common avoidable cause of hospital death. VTE includes two serious medical conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE).
DVT is a clot that may develop in the extremities or pelvis. If this clot breaks apart and moves to the small vessels in the lungs, it now becomes a pulmonary embolism. Approximately 900,000 people are affected by DVT or PE each year, with those who have recently had surgery or a long hospitalization facing the highest risk due to long periods of immobilization.
According to a scientific statement from the American Heart Association (AHA) and the International Society on Thrombosis and Hemostasis (ISTH), up to 50% of patients develop long-term exercise limitations after DVT or PE. And nearly 100,000 cases will result in death.
The economic burden of medical costs associated with the treatment of VTE and complications is around $10 billion per year.
Advances in anticoagulation are promising, though a lot of patients remain untreated given their higher bleeding risk. In fact, approximately 40% of patients in need of anticoagulation are either not treated with direct oral anticoagulation or are left untreated.
What’s next for thrombus prevention?
Research in thrombus prevention has reached a pivotal period. Sameer Bansilal, M.D., Vice President of U.S. Medical Affairs, Cardiovascular Division, at Bayer, spoke with Bio.News about the latest updates on an entirely new class of antithrombotic treatment options and how it will play a role in the future of cardiovascular disease.
In May 2023, Bayer received U.S. Food and Drug Administration (FDA) Fast Track Designation for its investigational drug asundexian for the potential treatment of stroke and systemic embolism in patients with atrial fibrillation (AF).
AF is one of the most common heart rhythm abnormalities and affects more than 2 million adults in the United States. AF is the result of disorganized electrical signals in the atria of the heart and results in an irregular and often fast heart rhythm. With this blood flow irregularity within the heart, patients are at risk for clot formation and subsequent embolism to the brain, or stroke.
The oral Factor XIa (FXIa) inhibitor, administered as a single dose, is at the center of a wider platform under clinical development by Bayer. The key action for this novel class anti-thrombotic is its ability to reduce clot formation while leaving the body’s response to bleeding intact. The primary benefits include a 17-hour half-life, less than 15% renal elimination, no interaction with clopidogrel, CYP inhibitors, or food, and high bioavailability.
How does Factor XIa work?
As a protein in the blood, Factor XI is converted into its active form, Factor XIa, while participating in the previously mentioned coagulation cascade. The FXIa inhibitor selectively blocks the FXIa protein, which involves the formation of a thrombus. At this point in the process, the potential exists to prevent a stroke. At the same time, the pathway involved in hemostasis is left unaffected. So, while the patient is being treated for a stroke, they do not have the added risk of bleeding.
This is exciting news for Bayer, as this is one of the largest Phase III trials they have undertaken.
The OCEANIC (Oral FaCtor Eleven A iNhibitor asundexIan as novel anti-thrombotic) program is intended to provide relevant data for the safety and efficacy of asundexian compared with apixaban in patients with AF at risk for stroke and in patients with acute non-cardioembolic ischemic stroke or high-risk transient ischemic attack (TIA).
The goals of the study were to compare and evaluate the risk-benefit profiles of the FX1A against current treatment alternatives on the market. The trials, OCEANIC-AF and OCEANIC-STROKE, began in December 2022 and January 2023, respectively, and are expected to enroll more than 27,000 patients in over 40 countries until 2025.
According to Dr. Bansilal, the PACIFIC Phase II clinical trial program set the stage for asundexian’s success by “analyzing dose and safety” of the FXIa inhibitor. “PACIFIC consisted of three separate studies, involving nearly 4,000 patients, with one of three medical conditions: AF, a recent non-cardioembolic ischemic stroke, or a recent myocardial infarction (MI or heart attack).”
Per Dr. Bansilal, a key endpoint for the FXIa inhibitor AF studies will be to “show the benefit of its efficacy and safety.” For the stroke study, they will be able to “gather meaningful information pertaining to severity of the stroke, level of disability, and impact on quality of life.”
The future of the FXIa inhibitor
In the end, according to Dr. Bansilal, “if the promise of the theoretical mechanism of the FXIa inhibitor is fully delivered, they may also be able to reduce the risk of ischemic strokes in addition to providing the safety benefit. This increases the value of the FXIa inhibitor over existing medications on the market used to treat these same medical conditions.”
“Bayer is committed to the treatment of cardiovascular disease. Specifically, with MI and stroke, in which they have made significant progress beyond aspirin and Xarelto and are currently expanding their reach within the thrombosis pipeline,” concludes Dr. Bansilal.
We’ll be keeping an eye out as they plan to present data on asundexian in the next few years.
