Pipeline Insights

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

Persons at risk of developing a blood clot 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– the so-called “factor eleven a”, (FXI(a)) inhibitors- are being developed which may reduce the bleeding risk and, hence, become a treatment option also for patients who up to now did not have an option to be treated with an anticoagulant.

According to the latest update from the World Health Organization, an estimated 17.9 million people died from cardiovascular disease in 2019 1, making it the leading cause of death worldwide. An estimated 85% of these deaths are due to heart attack or stroke which are often 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. Since the development of Direct Oral Anticoagulants (DOACs)in 2008, the risk of severe bleeding in patients has been significantly reduced. Still, especially in some specific patient groups the concern about bleeding is to be taken into consideration when prescribing these drugs.

Dr. Hardi Mundl
In the evolution of anticoagulant development, we are now exploring a potential new option with FXIa inhibition”
Dr. Hardi Mundl
Group Head Thrombosis, Clinical Development and Operations, Bayer

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 2008 2, it was demonstrated that persons 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 XI(a) inhibition”, says Dr. Mundl, who works in the development of anticoagulant therapies at Bayer.

In order to create a new class of anti-thrombotics that can be offered to more patients than ever before, Bayer has set up an extensive clinical development program focusing on Factor XI(a) inhibition with three compounds in clinical development: 1) asundexian*, 2) osocimab**, and 3) fesomersen***. Asundexian is currently being studied in the PACIFIC clinical trial program that consists of three Phase IIb studies with more than 4,000 patients with one of the following three medical conditions: 1) atrial fibrillation (irregular heartbeat), 2) a recent ischemic stroke or 3) a recent myocardial infarction. The objective of the PACIFIC program is to test the safety and efficacy of asundexian in preventing future cardiovascular events, like another stroke or myocardial infarct, or even cardiovascular death.

In Bayer’s parallel FXI programs involving the two other drug candidates (osocimab and fesomersen), clinical trials are underway to develop new therapies to reduce cardiovascular events in patients with end-stage kidney disease - a group in whom currently the use of anticoagulation therapy is extremely limited. 

If shown to have an improved safety profile, Factor XI(a) inhibitors could represent a new development option in thromboembolic event prevention, expanding treatment possibilities to an even wider group of cardiovascular and renal patients in Dr. Mundl’s view. 

1  https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

2  Salomon et al (2008) https://doi.org/10.1182/blood-2007-10-120139

Compounds in clinical development:
* small molecule FXI(a) inhibitor
** anti-FXI(a) antibody 
*** FXI-ligand-conjugated antisense oligonucleotide (LICA) in-licensed from IONIS Pharmaceuticals