Factor XI Inhibitors: The Dawn of a New Age of Oral Anticoagulants?

Study #1 Title: A Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of BMS-986177, an Oral Factor XIa Inhibitor, for the Prevention of New Ischemic Stroke or New Covert Brain Infarction in Patients Receiving Aspirin and Clopidogrel Following Acute Ischemic Stroke or Transient Ischemic Attack (TIA)

ClinicalTrials.gov Identifier: NCT03766581

Participating Centers: Multicenter

Accrual Goal: 2,350 participants

Study Design: Phase II randomized clinical trial

Study #2 Title: A Randomized, Open-Label, Study Drug-Dose Blind, Multicenter Study to Evaluate the Efficacy and Safety of JNJ-70033093 (BMS-986177), an Oral Factor XIa Inhibitor, Versus Subcutaneous Enoxaparin in Subjects Undergoing Elective Total Knee Replacement Surgery

ClinicalTrials.gov Identifier: NCT03891524

Participating Centers: Multicenter

Accrual Goal: 1,200 participants

Study Design: Phase II randomized clinical trial

Summary: Factor XI is an intriguing target for the next generation of anticoagulants. It is involved in the intrinsic pathway of the classic coagulation cascade, is activated by factor XIIa, and in turn activates factor IX. Additionally, factor XI participates in the feedback amplification of thrombin generation as it is also activated by factor IIa (thrombin) and can activate thrombin activatable fibrinolysis inhibitor (TAFI), leading to decreased fibrin degradation. Two prior phase II clinical studies have demonstrated initial safety and efficacy of either reducing factor XI levels or inhibiting its activity. The first study, published in 2014, examined the use of a factor XI antisense ogligonucleotide (FXI-ASO) administered preoperatively by intravenous infusion for the prevention of venous thromboembolism (VTE) in the setting of total knee replacement surgery.¹  The second study, published in early 2020, examined the use of a parenterally administered monoclonal antibody (osocimab) against factor XIa, also in patients undergoing total knee replacement surgery.²  Each trial demonstrated a potential for similar or greater VTE prevention and a similar or lower bleeding rate compared to enoxaparin.

Promising results from these clinical studies has fueled ongoing interest in factor XI as a target, and now two additional phase II trials of orally administered factor XI inhibitors are ongoing, anticipated to complete in 2021. The oral factor XI inhibitors (JNJ-70033093 or BMS-986177) are in fact the same drug being developed collaboratively by Bristol-Myers Squibb and Janssen Research & Development. The first and largest of the two studies (AXIOMATIC-SSP) plans to randomize 2,350 participants with acute ischemic stroke or transient ischemic attack who are older than 40 years and have evidence of extracranial or intracranial atherosclerotic plaques. Participants will be randomized to seven different doses of study drug or a placebo in addition to dual antiplatelet therapy (aspirin and clopidogrel). The primary efficacy outcome is a composite of new ischemic stroke or new covert brain infarction detected by magnetic resonance imaging at 90 days. Secondary clinical outcomes will include bleeding events as determined by the Bleeding Academic Research Consortium and International Society of Thrombosis and Hemostasis criteria. The second study (AXIOMATIC-TKR) will randomize 1,200 participants undergoing elective total knee replacement to seven dosing regimens (total daily dosing of 25-200 mg) of drug, or enoxaparin 40 mg, for 10 to 14 days postoperatively. The primary efficacy outcome is total VTE at 14 days defined by deep vein thrombosis (DVT) by venography assessment of the operated leg, objectively confirmed or symptomatic DVT, nonfactor pulmonary embolism, or any death. The primary safey outcome is a composite of major, clinically relevant nonmajor, and/or minimal bleeding.

Comments: The encouraging results of early phase II studies examining FXI-ASO and osocimab demonstrate the potential for factor XI as a therapeutic target, but are not without several drawbacks, largely related to the need for infusions of the drugs. Additionally, FXI-ASO does not have immediate effects on factor XI and needs to be administered well before the period of thrombotic risk. Indeed a search of ClinicalTrials.gov shows that phase III clinical trials are not being pursued with either of these two drugs (JNJ-70033093/BMS-986177). Instead, it is the phase II studies of oral agents discussed here that will be pivotal trials in determining if oral factor XI inhibitors will progress to phase III studies and potential drug approval. Whether or not this novel drug will translate into reduced thrombotic outcomes at a lower bleeding risk compared to the currently available anticoagulants, will be eagerly awaited. If successful, oral factor XI inhibitors could replace direct oral anticoagulants as the prefered agent for many conditions, and potentially even broaden the indications for anticoagulants into areas currently managed only with antiplatelet agents.