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Factor XI(a): a potential new option in anti-thrombotic therapy?

People at risk of developing a blood clot (thrombosis) are often treated with an anticoagulant. However, since anticoagulation therapies may be associated with an increased risk of bleeding, the benefits versus risks need to be carefully assessed before they are prescribed, especially in specific groups of patients. 

A new class of drugs called Factor XIa (FXIa) inhibitors are currently being investigated and could represent a new approach in thrombosis management. By selectively modulating coagulation, Factor XI(a) inhibitors have the potential to prevent thromboembolic events without increasing the risk of bleeding compared to standard of care (SoC) aiming to become a treatment option also for patients who up to now did not have an option to be treated with an anticoagulant.

Cardiovascular diseases (CVDs) are the leading cause of death globally, taking an estimated 17.9 million lives each year. i,ii 85% of these deaths are due to heart attack and strokeii, in fact, stroke alone is one of the leading causes of death and disabilityiii, with 1 in 4 people over the age of 25 projected to suffer a stroke in their lifetime.iv Often, heart attacks and strokes are caused by blood clots that block blood vessels in the heart or brain, respectively. 

Since the early 20th century, anticoagulants have been a mainstay in treating and preventing thrombosis. However, their use can be associated with an increased risk of bleeding. Advancements over the last 15 years, such as the development of Direct Oral Anticoagulants (DOACs), have reduced the risk of severe bleeding in patients significantly, but concerns about bleeding risks remain a limiting factor especially in some specific patient groups. Some patients are treated sub-optimally or do not get therapy at all, demonstrating the need for alternative treatment options in thrombosis prevention.

Our clear goal is to develop a new treatment option to efficaciously prevent thrombotic events, expanding treatment possibilities to an even wider group of cardiovascular patients
Dr. Hardi Mundl
Group Head Thrombosis, Clinical Development and Operations, Bayer

About FXI

Factor XI is a protein in the blood which is transformed into its active enzyme form (Factor XIa) as part of the blood coagulation cascade. The potential role of FXI in thrombosis was discovered by serendipity. In 2008v, it was demonstrated that people with low levels of FXI (FXI-deficiency) have a significantly lower risk of suffering from strokes than the general population. Together with the knowledge that FXI affects only one part of the coagulation cascade (the intrinsic pathway), researchers developed a hypothesis that inhibiting either FXI or its activated form (FXIa) might be a promising way to prevent harmful clots (those causing stroke or heart attack) while maintaining proper clotting function (for example, following an injury) and hence, not increase the bleeding risk. 

“We seem to have found a suitable target with Factor XIa inhibition”, says Dr. Mundl, who works in the development of antithrombotic therapies at Bayer. “Clinical and pre-clinical data on asundexian, a small molecule FXIa inhibitor, strongly confirm that it may provide a new promising therapeutic option to further advance innovative medicines in the treatment of cardiovascular diseases, building on Bayer’s strong heritage and decades of expertise in this field.”

In order to create a new class of anti-thrombotics that could be offered to more patients than ever before, we have set up an extensive clinical development program focusing on Factor XI(a) inhibition with asundexian in clinical development.

Asundexian was studied in the PACIFIC clinical trial program, consisting of three Phase IIb studies, each one focusing on one of the following medical conditions: atrial fibrillation (irregular heartbeat), a recent non-cardioembolic ischemic stroke or a recent acute myocardial infarction (heart attack)vi,vii,vii In April 2022, Bayer presented data from the Phase IIb PACIFIC-AF trial at the American Congress of Cardiology (ACC) Annual Scientific Session and data from the Phase IIb PACIFIC-AMI and PACIFIC-STROKE trials at the European Society of Cardiology (ESC) Congress 2022. Following the PACIFIC clinical trial program we will initiate the OCEANIC Phase III clinical trial program in late 2022, starting with the Phase III studies, OCEANIC-AF and OCEANIC-STROKE. OCEANIC will be one of the largest Phase III endeavours Bayer has undertaken so far. The program is designed to assess the potential of asundexian to protect patients from pathological thrombus formation without a corresponding increase in bleeding risk aiming to improve the benefit-risk profile compared to current treatment options.

i World Health Organization. Cardiovascular Diseases. August 2022. Available at: Cardiovascular diseases (who.int)
ii World Heart Federation. Cardiovascular Diseases – Global Facts and Figures. August 2022. Available at: https://world-heart-federation.org/resource/cardiovascular-diseases-cvds-global-facts-figures
iii GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:439–458. 
iv World-stroke.org. Learn about stroke. August 2022. Available at: https://www.world-stroke.org/%20world-stroke-day-campaign/why-stroke-matters/learn-about-stroke#:~:text=Globally%201%20in%204%20adults,the%20world%20have%20experienced%20stroke.
v Salomon et al (2008) https://doi.org/10.1182/blood-2007-10-120139
vi Clinicaltrials.gov. Study to Gather Information About Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following a Recent Non Cardioembolic Ischemic Stroke Which Occurs When a Blood Clot Has Formed Somewhere in the Human Body (But Not in the Heart) Travelled to the Brain. (PACIFIC-STROKE). Available here: https://clinicaltrials.gov/ct2/show/NCT04304534?term=pacific+bayer&draw=2&rank=5. Last accessed: August 2022.
vii Clinicaltrials.gov. Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack (PACIFIC-AMI). Available here: https://clinicaltrials.gov/ct2/show/NCT04304508?term=pacific+bayer&draw=2&rank=6. Last accessed: August 2022.
viii Clinicaltrials.gov. Study to Gather Information About the Proper Dosing of the Oral FXIa Inhibitor BAY 2433334 and to Compare the Safety of the Study Drug to Apixaban, a Non-vitamin K Oral Anticoagulant (NOAC) in Patients With Irregular Heartbeat (Atrial Fibrillation) That Can Lead to Heart-related Complications. (PACIFIC-AF). Available here: https://clinicaltrials.gov/ct2/show/NCT04218266?term=pacific+bayer&draw=2&rank=4. Last accessed: August 2022.

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