Factor XI inhibitors: The ongoing search for anticoagulation strategies in the prevention of arterial thromboembolism in cardiac and cerebrovascular disease

Over the last decade, direct oral anticoagulants (DOACs) have rapidly replaced vitamin K antagonists (VKAs) for several clinical indications in neurology and cardiology like cardioembolic stroke prevention in non-valvular atrial fibrillation (NVAF), prevention of recurrence in cerebral venous sinus thrombosis (CVST) and probably in cervicocerebral arterial dissection, post-acute coronary syndromes (ACS) and peripheral arterial disease (PAD) with claudication [1]. Despite the considerable convenience, versatility, and safety advantages of DOACs, the incidence of bleeding is not negligible, having an unmet need regarding safety outcomes. In terms of efficacy, there are special subpopulations in which current DOACs have demonstrated to be challenging, problematic and non-effective. These include patients with mechanical heart valves, thrombotic antiphospholipid syndrome (APS), advanced renal and liver disease, and extremes of body weight, to mention a few. In all these conditions, and in attempt of reducing bleeding risk of DOACs, research has turned to factor XI/XIa inhibitors.

The coagulation cascade (hemostasis) is mainly divided into 3 major pathways: intrinsic (the contact pathway), extrinsic (the tissue factor pathway) and common. Factor XI plays an important role in the contact pathway by mediating and modulating the amplification phase for the burst/growth/propagation of thrombi within the blood vessel. Selective modulation of the contact pathway theoretically should lower the risk of thrombosis without increasing bleeding, that is, sparing hemostatic mechanisms [2], [3].

In recent years, researchers have performed a tireless effort to find an “ideal” anticoagulant, one equally effective but safer. These endeavor targets factor XI, a serine protease that is mainly biosynthesized in the liver, and to a lesser extent in the pancreas and renal tubules. Drugs that inhibit factor XI activation (inhibitors of FXI/XIa) have the ability to prevent venous and arterial thromboembolism (ATE), while, at the same time, having a very modest role in achieving hemostasis, and therefore, could entail a low risk of bleeding [2].

Currently, quite a few new FXI/XIa inhibitor molecules have been developed and are currently being tested in phase 2 and 3 clinical trials. They are classified into the following classes (Table 1): (A) Antisense oligonucleotides (ASOs: ISIS, fesomersen, IONIS/LICA), (B) monoclonal antibodies (e.g., abelacimab, xisomab and osocimab), (C) small molecules (e.g., asundexian, milvexian, etc.), (D) aptamers (short, single-stranded DNA or RNA molecules that can selectively bind to Factor XIa; e.g., FELIAP [Factor ELeven Inhibitory APtamer]), and (E) natural inhibitors (e.g., fasxiator [a factor XIa inhibitor from snake venom]). ASOs reduce hepatic biosynthesis of factor XI by binding to its messenger RNA, inducing its degradation. Monoclonal antibodies block factor XI activity while small molecules block the active site. ASOs and monoclonal antibodies are administered parenterally with longer half-lives (weeks to month). Small molecules are taken orally and given daily.

Table 1.

Pharmacological properties of novel anticoagulants targeting factor XI and XIa.

	Monoclonal antibodies	Small Molecules	ASOs	Aptamers
Mechanism	Bind target protein	Bind target protein	Blocks protein biosynthesis in liver	Bind target protein
Administration route	IV or SC	IV or Oral	SC	IV or SC
Frequency of administration	Monthly	Once or Twice Daily	Weekly to Monthly	Daily
Onset of action	Rapid (hrs. – days)	Rapid (min. – hrs.)	Slow (weeks)	Rapid (min. – hrs.)
Offset of action	Slow (weeks)	Rapid (min. – hrs.)	Slow (weeks)	Rapid (min. – hrs.)
Renal excretion	No	Minimal	No	No
CYP metabolism	No	Yes	No	No
Potential for drug-to-drug interactions	No	Yes	No	No
Drugs	Abelacimab MK-2060 Osocimab Xisomab 3G3 REGN9933 REGN7508	Asundexian Milvexian ONO-7684 EP-7041 BMS-962212	Fesomersen IONIS-FXIRX	Not tested in humans

Abbreviations: ASOs, Antisense oligonucleotides; CYP, Cytochrome P450; FXI, Factor XI; FXIa, FXIa inhibitors; IV, Intravenous; SC, Subcutaneous; min, minutes; hrs, hours. Reproduced with permission from Ref. [2].

The phase 2b clinical trial AZALEA-TIMI 71, evaluating the safety and tolerability of abelacimab (MAA868) versus rivaroxaban in 1287 patients with NVAF at moderate to high risk for cardioembolic strokes (CHA₂DS₂-VASc score of ≥4) for secondary prevention of cardioembolic stroke, was planned to compare two doses of abelacimab (90 mg and 150 mg SQ monthly) with rivaroxaban 20 mg PO daily. Both doses were superior to rivaroxaban in reducing bleeding events. The primary endpoint, major or clinically relevant non-major bleeding (CRNMB) events, was 2.7 % for abelacimab 150 mg vs. 1.9 % for abelacimab 90 mg vs. 8.1 % for rivaroxaban, (P < 0.001 for both doses of abelacimab vs. rivaroxaban). These results lead to an early termination of such trial due to a greater than expected benefit with abelacimab [4]; although the AZALEA TIMI-71 trial was not powered to assess clinical efficacy, the absolute risk of ischemic strokes across all arms of the study was about 1 %; it is also worthwhile noting that the “net clinical outcome”, a composite of ischemic stroke, systemic ATE, overall bleeding, and all-cause death was approximately 50 % less in the arm of abelacimab 150 mg vs rivaroxaban (p < 0.001) [4]. Full scientific details are yet to be published but were presented at the American Heart Association (AHA) scientific congress in November 2023. Abelacimb is currently being studied in a large phase 3 randomized trial (LILAC-TIMI 76), comparing with placebo in patients with high-bleeding profile (e.g., elderly, frail, taking antiplatelet agents concomitantly, and those with multiple comorbidities) [5].

The PACIFIC-AF was a randomized, double-blind, phase 2 trial studied the small molecule asundexian in patients with NVAF. Investigators compared asundexian 20 mg or 50 mg once daily versus apixaban 5 mg twice daily in patients aged 45 years or older with atrial NVAF with a CHA₂DS₂-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The primary safety endpoint was the composite of major or CRNMB according to International Society on Thrombosis and Hemostasis (ISTH) criteria. Investigators concluded that both doses resulted in lower rates of bleeding compared with standard dosing of apixaban [6].

The PACIFIC-AMI and PACIFIC-Stroke studies provided reassuring data in patients post-ACS and post-ischemic stroke. The OCEANIC-AF was a multicenter, international, randomized, active comparator-controlled, double-blind, double-dummy, parallel-group, 2-arm, phase 3 trial that studied asundexian 50 mg once daily ((NCT05643573) compared to apixaban. Eligible patients had CHA₂DS₂-VASc score ≥3 if male or ≥4 if female patients. The independent data monitoring committee (IDMC) decided to prematurely stop such trial in November 2023 due to lack of efficacy and inferiority of asundexian compared to apixaban for the prevention of cardioembolic stroke and systemic embolism in patient with NVAF [7]. Despite this premature termination of the OCEANIC-AF trial, interestingly, investigators and the same IDMC that stopped the OCEANIC-AF trial, decided to continue active enrollment of patients intended for the OCEANIC-Stroke trial [7] (NCT05686070), an ongoing multicenter, international, randomized, placebo controlled, double-blind, parallel Group, phase 3 trial of asundexian (BAY 2433334) for the secondary prevention of ischemic stroke after an acute non-cardioembolic ischemic stroke or high-risk TIA within 7 days post index event. Their main rationale for continuation with enrollment was due to exploring a different clinical setting: secondary prevention, with a different comparator (placebo), as an add-on antithrombotic therapy, and since all the patients will be receiving DAPT [7].

The AXIOMATIC-SSP trial was a phase 2, randomized, double-blind, placebo-controlled, dose-finding to received one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo for 90 days. All participants received dual antiplatelet therapies (DAPT) for 21 days, and then aspirin 100 mg daily for 90 days. The primary efficacy endpoint was the composite of ischemic stroke or incident brain infarct. The primary safety endpoint was major bleeding events. Patients (n = 2366) were randomized to placebo (n = 691), milvexian 25 mg once daily (n = 328), or twice-daily doses of milvexian 25 mg (n = 318), 50 mg (n = 328), 100 mg (n = 310), or 200 mg (n = 351). Although milvexian, added to DAPT, did not meaningfully increase the risk of major bleeding, at 90 days, the estimates of the percentage of participants with either symptomatic ischemic stroke or covert brain infarcts were 16.8 (90.2 % CI 14.5–19.1) for placebo, 16.7 (14.8–18.6) for 25 mg milvexian once daily, 16.6 (14.8–18.3) for 25 mg twice daily, 15.6 (13.9–17.5) for 50 mg twice daily, 15.4 (13.4–17.6) for 100 mg twice daily, and 15.3 (12.8–19.7) for 200 mg twice daily. No significant dose–response was observed among the five milvexian doses for the primary composite efficacy outcome [8].

Simultaneously, the LIBREXIA program is currently studying milvexian in 3 mega clinical trials across the main major clinical cardiovascular populations. LIBREXIA-AF is going to explore the safety and efficacy of milvexian versus apixaban; the LIBREXIA-STROKE the safety and efficacy for stroke prevention after an acute ischemic non-cardioembolic stroke or high-risk transient ischemic attack (TIA); and the LIBREXIA-ACS will aim to demonstrate if milvexian can reduce the risk of major adverse cardiovascular events (MACE) added to standard therapies post ACS [5].

Even if factor XI/XIa inhibitors are determined in initial phase 2 clinical trials to be “safer” from the safety point of view, than DOACs, some patients on these medications may experience major bleeding, CRNM events or require emergent surgical interventions; thus, this represents an important question to address and to analyze while performing large-scale phase 3 randomized trials, with adequate reversal strategies for dealing with such situations are required [9], [10]. The activity of factor XI inhibitors may be assessed utilizing aPTT; however, the extent of aPTT prolongation may vary amongst different classes of factor XI inhibitors. Because factor XI/XIa inhibition could potentially impair thrombin activatable fibrinolysis inhibitor (TAFI), antifibrinolytic agents like tranexamic acid represents the cornerstone for bleeding in patient taking factor XI inhibitors. Low doses of recombinant factor VIIa effectively prevent abnormal bleeding in FXI-deficient patients with alloantibody inhibitors to FXI who undergo surgery, representing another potential reversal strategy [9], [10]. Nevertheless, upcoming results of phase 3 randomized clinical trials will inform us in regards the frequency of the need for such reversal strategies.

Clinicians and researchers are eagerly awaiting large scale, phase 3 clinical trials powered for efficacy and safety endpoints to further define the precise role of factor XI/XIa inhibitors, potentially impacting our clinical practice in years to come. Moreover, further research should be needed in the following cardiovascular areas: artificial contact surfaces-associated thrombosis like mechanical valves, extracorporeal membrane oxygenation (ECMO), left ventricular assisted-devices (LVADs) and central-venous catheter associated thrombosis, thrombotic APS, and PAD with claudication, to mention a few [2].

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.