Factor XI/XIa Inhibition in Cardio- and Cerebrovascular Disease

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Mohammad Urooj Zafar	--	3392	2022-12-16 17:44:42	\|
2	Reference format revised.	Lindsay Dong	+ 12 word(s)	3404	2022-12-19 05:31:20	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcdd9120437

Factor XI (FXI) is one promising target. Existing direct oral anticoagulants (DOACs) have improved treatment options compared to the classic heparins and vitamin K antagonists (VKA), but the bleeding risks associated with their use are substantial enough to expand the focus onto the development of their antidotes. Early indications are that FXI-directed strategies could offer similar protection against thrombotic events as DOACs, but with the added benefit of lower bleeding risk. Furthermore, the spectrum of modalities for FXI inhibition presents a range of options in both types of administration and duration of effect. With the possibility of once- or twice-monthly injections, some FXI-directed agents could also improve treatment compliance compared to current therapies. Altogether, FXIa inhibitors could be a therapeutic option in a broad spectrum of clinical scenarios.

factor XI factor XI inhibitor thrombosis

1. Introduction

Thromboembolism and its associated complications remain a huge healthcare burden worldwide. The central role of thrombosis is observable in a variety of cardiovascular disorders, most notably in coronary artery disease (CAD), atrial fibrillation and stroke, peripheral arterial disease (PAD), and venous thromboembolism (VTE). Ischemic heart disease and stroke collectively are responsible for nearly 25% of all deaths worldwide ^[1], whereas estimates for the incidence rate for VTE, comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), range from 115 to 269 per 100,000 people worldwide ^[2]. The impact of thrombosis extends beyond the cardiovascular arena and is increasingly being encountered in pathologies as diverse as cancer, immunological diseases, and even psychiatric disorders. Even among patients with human immunodeficiency virus (HIV) infection, who are living longer thanks to improvements in antiretroviral treatment, there is evidence of increased thrombosis ^[3], which contributes to their increasing morbidity and mortality from cardiovascular causes (6–15% of total mortality) ^[4]^[5].

The high human and financial cost of thromboembolic events underscore the need for newer and better therapeutic options for the management of thrombotic disorders. The challenge is in developing an agent that has potent antithrombotic effects but minimal bleeding risk, as it requires a very fine balancing act in modulating the hemostatic processes. Current anticoagulant options for clinical treatment of thrombotic disorders include antithrombin activators (unfractionated heparin), low molecular weight heparins (LMWHs and fondaparinux), vitamin K antagonists (VKA—warfarin), direct inhibitors of activated factor X (rivaroxaban, apixaban, edoxaban, betrixaban), and direct inhibitors of thrombin (hirudins, argatroban, and dabigatran). Although heparins and warfarin are low-cost options with a high degree of efficacy, both are associated with drawbacks that limit their clinical use. Heparin-induced thrombocytopenia, although infrequent, can be potentially lethal, and the development of osteoporosis and risk of contamination are additional factors to consider when using unfractionated heparin ^[6]. Some of these shortcomings have been reduced by LMWH and fondaparinux ^[6]. Warfarin presents the limitation of a narrow therapeutic window and major food- and drug-interactions ^[7]. The significant intra- and inter-patient variability of response of VKA makes frequent blood testing for dose-adjustment a cumbersome necessity. The last few years have provided a much-improved treatment option in direct oral anticoagulants (DOACs) that are convenient in administration while being potent and equally effective to VKA, often with a lower risk of bleeding ^[8]^[9]^[10]^[11]. Even so, the annual rate of major bleeding in patients on DOAC treatment remains significant ^[12], approximately 5% in elderly patients with atrial fibrillation (AF) ^[13]. This is partly why an unacceptably high proportion of AF patients—nearly one-third—do not receive the prophylactic anticoagulation they require. Even among those that do receive anticoagulation therapy, nearly half do not receive the proper doses ^[14].

2. Distinguishing Physiological Hemostasis from Pathological Thrombosis

Hemostasis is the normal, physiological process by which the clotting cascade seals up vascular damage to limit blood loss following injury. Thrombosis, on the other hand, encompasses various pathological conditions where the normally physiological clotting processes end up generating blood clot(s) inside the vascular lumen that are disruptive to the normal flow of blood. Thrombin generation and fibrin formation are the culminating steps in both hemostasis and thrombosis, but with important differences in the pathways involved.

Hemostasis is commonly triggered when tissue factor (TF) within the adventitial layer of blood vessels gets exposed to blood. Injury to vasculature that can lead to bleeding activates a series of soluble plasma proteins that act together in a cascade of enzyme activation events and culminate in the formation of platelet-fibrin clot(s). Because of the relatively high concentration of TF in such scenarios, the generation of thrombin is rapid and intense, quickly forming a hemostatic plug that seals the inciting TF away from blood. This disrupts the amplification of the coagulation processes through feedback mechanisms to the point of becoming pathological.

The concentration of TF in thrombosis is lower relative to hemostasis, but its duration of contact with blood components often lasts longer. Whether triggered by TF from disruption of an atherosclerotic plaque or activated monocytes/macrophages recruited to the site of injury or inflammation, or by implanted medical devices or neutrophil extracellular traps (NETs), these scenarios depend on the feedback mechanisms of the coagulation cascade for the growth and stabilization of the thrombus. This clot or thrombus can impede the flow of blood to the distal tissues and organs, leading to ischemia and necrosis, manifesting as clinical events including acute coronary syndrome, stroke, or deep vein thrombosis.

3. Classic Coagulation Cascade

The two major pathways for triggering blood clotting cascade are well known; (1) the tissue factor pathway and (2) the contact pathway. Both pathways trigger a series of cascading events that generate a blood clot (Figure 1) with the purpose to separate and seal the triggering agent from blood, thereby preventing its further contact with plasma components and arresting the thrombotic process.

/media/item_content/202212/639fe81415d52jcdd-09-00437-g001.png

Figure 1. The classic model of the coagulation cascade with the Tissue Factor/extrinsic, the Contact/intrinsic and the common pathways. Triggering factors for both pathways are shown in square boxes. NETs: neutrophil extracellular traps, ECMO: extracorporeal membrane oxygenation.

3.1. Tissue Factor Pathway

This pathway is also known as the ‘Extrinsic’ pathway, as it is triggered by plasma components coming into contact with an agent that is extrinsic to blood (i.e., TF). The contact may happen when TF, normally embedded in the vascular wall, is exposed to blood due to rupture of a plaque, or when TF is expressed on the surface of cells active in inflammatory and immunological processes (e.g., monocytes and macrophages).

Tissue Factor is an integral cell-membrane protein that forms a complex with the coagulation factor VIIa (FVIIa), normally present in plasma in the inactive zymogen form FVII. The TF:FVIIa complex is a potent activator of coagulation and converts factors IX (FIX) and X (FX) to the active forms FIXa and FXa, respectively (Figure 1). Each of these active enzymes assembles with its protein cofactor (FVIIIa and FVa, respectively) on suitable membrane surfaces to further propagate the coagulation cascade. The end result is a large burst of thrombin, the last serine protease in the clotting cascade. Thrombin not only converts fibrinogen into fibrin via limited proteolysis—which in turn assembles into a fibrin clot—but is also one of the most potent activators of platelets. The activation and aggregation of platelets contributes to the formation of a hemostatic plug. Additionally, thrombin also activates FV, FVIII, and FXI, the latter two of which are part of the contact pathway. Thus, the initial thrombin generated by the TF pathway can lead to activation of the contact pathway.

3.2. Contact Pathway

Also known as the ‘Intrinsic’ pathway, this pathway is triggered when blood comes into contact with anionic surfaces, such as extracellular DNA, RNA from activated or dying cells including neutrophil extracellular traps (NETs) released by activated neutrophils ^[15], or polyphosphates from the dense granules of activated platelets or microorganisms ^[16], or those on artificial surfaces ^[17]. This leads to a change in the conformation of plasma factor XII (FXII) into the active factor XII (FXIIa) ^[18]^[19]. FXIIa activates Prekallikrein to Kallikrein, which in turn reciprocally activates FXII to FXIIa in a positive feedback loop ^[20]. Downstream, FXIIa activates FXI to FXIa, which in turn leads to proteolysis of factor IX (FIX) to the active form (FIXa). The complex of FIXa and FVIIIa then activates FX to FXa at the point where the TF and contact pathways converge to form the final common pathway (Figure 1). The end result of all these interactions again is thrombin generation and formation of a blood clot.

4. Factor XI as a Therapeutic Target

Factor XI is a blood coagulation zymogen produced by the liver that is part of the early phase of the contact pathway ^[21]. It is converted to the active serine protease FXIa by thrombin, FXIIa, and by FXIa itself and in turn activates FIX to further advance the coagulation process ^[21]. FXI plays an important part in blood coagulation because its feedback activation amplifies in vivo thrombin generation and fibrin formation ^[22]. The additional thrombin formed via the FXI feedback loop also promotes the activation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI), which increases the clot’s resistance to fibrinolysis, thereby helping to stabilize the formed clot.

The greater role of FXIa in thrombosis compared to hemostasis is evident from several epidemiological and genetic studies. Higher levels of circulating FXI levels are associated with increased risk for venous and arterial thrombosis, including stroke ^[23]^[24]. Deficiency of FXI (Hemophilia C, Plasma Thromboplastin Antecedent Deficiency, Rosenthal Syndrome) is rare and characterized by little to no bleeding tendency. Bleeding risk with factor XI deficiency selectively increases in tissues with high fibrinolytic activity (e.g., following dental surgery, tonsillectomy, and prostate surgery) ^[25]. Most frequent presentations involve nosebleeds or bleeding after tooth extractions. In fact, patients suffering from congenital FXI deficiency appear to have some degree of protection from thrombotic events, with lower rates of ischemic stroke and venous thromboembolism ^[26]^[27].

5. Pharmacologic Strategies for Factor XI Inhibition

Given the larger role FXI is thought to play in thrombosis than in hemostasis, novel approaches to inhibit its generation and activity are being explored as new therapeutic strategies (Figure 2). These include: (a) Antisense Oligonucleotides (ASOs) that act on the liver to knockdown hepatic synthesis of FXI, (b) small molecules that target the FXI active site or the heparin allosteric site on FXIa, (c) monoclonal antibodies that act by blocking the activation or inhibiting the activity, and (d) Aptamers.

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Figure 2. Sites of action (represented by the yellow circles) of the factor XI/XIa inhibitory drugs currently at different stages of clinical development. The anti-FXI ASOs (Antisense Oligonucleotides) block mRNA transcription of FXI in the hepatocytes, thus inhibiting its synthesis. Some monoclonal antibodies attach to the catalytic domain of FXI and block its FXIIa-mediated conversion to the active FXIa form, thus locking it in the inactive zymogen state. Most of the currently in development anti-FXIa antibodies act similar to the small molecule FXIa inhibitors and bind to the active site(s) on FXIa, thereby blocking its activity.

In addition to their varying mechanisms of action, these strategies also differ in their routes of administration (oral vs. parenteral), the onset of action, and the duration of effect. Parenteral administration is a requirement for ASOs, aptamers and monoclonal antibodies, whereas small molecule agents offer the option of either parenteral or oral administration. The varied onset and duration of action may present a broad set of treatment options depending on the pathology at hand; acute thrombotic events requiring quick-acting agents whereas longer-acting options, such as antibodies, would be more suitable for chronic prophylactic and preventative measures.

5.1. Antisense Oligonucleotides (ASOs)

Antisense Oligonucleotides are short, single-stranded nucleic acid sequences that pair with specific regions of mRNA and regulate its gene expression ^[28]^[29], thereby downgrading the hepatic synthesis of FXI. Their benefits include high specificity, predictable pharmacokinetics (PK), and long half-life. Furthermore, ASOs lack the drug–drug interactions commonly seen with conventional therapeutic agents.

IONIS-FXIRx.

This agent (formerly known as ISIS 416858) is the ASO furthest in clinical development. Administered subcutaneously, IONIS-FXIRx has been shown to produce a concentration-dependent reduction in FXI antigen and activity levels ^[30]. In a phase II study of 315 patients undergoing total knee replacement, IONIS-FXIRx reduced the risk of postoperative VTE more than enoxaparin, without increasing the risk of bleeding. Rates of VTE were 27% and 4% among patients treated with 200 and 300 mg doses of IONIS-FXIRx, respectively, versus 30% in patients who received enoxaparin 40 mg once-daily ^[31].

IONIS-FXI-LRx.

A second-generation, ligand-conjugated antisense (LICA) agent named IONIS-FXI-LRx is also under clinical development. Its increased potency allows for once-monthly administration at lower doses, which helps to reduce the potential for injection-site reactions seen with IONIS-FXIRx.

5.2. Small Molecules

5.2.1. Small Molecules Targeting the Active Site on FXIa

Asundexian (BAY 2433334).

This small molecule is in the most advance stages of development among FXIa inhibitors, with results from three phase 2 studies published recently. The first to be published was a dose-finding trial that compared asundexian with placebo for the prevention of major adverse cardiac events in patients with recent acute MI on dual-antiplatelet therapy ^[32]. Patients (n = 1601) were randomized within 5 days of an MI to oral asundexian 10, 20, or 50 mg or placebo, given once-daily for 6–12 months in addition to aspirin plus a P2Y₁₂ inhibitor. Over a year of follow-up, asundexian produced dose-dependent inhibition of FXIa activity without significant increase in bleeding (Bleeding Academic Research Consortium (BARC) bleeding type 2, 3, or 5: 7.6%, 8.1%, and 10.5%, respectively, with asundexian doses, vs. 9.0% with placebo) and had low rates of ischemic events (composite of cardiovascular death, MI, stroke, or stent thrombosis: 6.8%, 6.0%, and 5.5%, respectively, vs. 5.5% with placebo).

Milvexian (JNJ-70033093/BMS-986177).

This orally active agent is also in the advance stage of clinical development among FXIa inhibitors. In a phase II dose-finding trial in patients undergoing elective knee arthroplasty (AXIOMATIC-TKR; n = 1242), postoperative FXIa inhibition with milvexian was effective for the prevention of venous thromboembolism, with a dose-related response in both once-daily and twice-daily administrations ^[33]. With twice-daily administration of milvexian 25, 50, 100, and 200 mg, the dose-response relationship was statistically significant and the incidence of VTE significantly lower than the prespecified benchmark of 30% (21%, 11%, 9%, and 8%, respectively).

Other Small-Molecules in Early Development

A number of other oral and parenteral inhibitors of FXIa are in earlier phases of development. These include ONO-7684, an orally active agent that was well-tolerated in a phase I study with healthy volunteers. This study reported low overall incidence of adverse events with no evidence to suggest bleeding risk ^[34].

The parenteral small molecules under development include EP-7041. A placebo-controlled study to evaluate its safety, PK, and PD was conducted in healthy volunteers ^[35]. The drug was well-tolerated except for some cases of mild headache (23%) and infusion site bruising (7%). EP-7041 exhibited rapid onset–offset and dose-related increases of aPTT without affecting PT. Despite these positive results, there was no further development with this agent until 2021, when an IND application for its use as an investigational treatment for COVID-19 patients in ICU was accepted by the FDA (NCT05040776).

BMS-962212 is another parenterally administered, FXIa-inhibiting small molecule investigated in healthy participants. In testing of multiple doses, the drug was well-tolerated, with no bleeding events and mild adverse events in 17.6% participants ^[36]. Dose-dependent changes in aPTT and FXI were observed with maximal effects by approximately 2 h, and no changes in PT or INR.

5.2.2. Small Molecules Targeting Heparin Allosteric Site on FXIa

This group of FXIa-directed agents exert their inhibitory effects by attaching to the heparin-binding site on the catalytic domain of FXIa. Given the structural similarities between the active sites of various serine proteases, it is believed that allosteric inhibition would have the advantage of being more specific. Some of the sulfated glycosaminoglycan (SPGG) mimetic compounds under development in this group not only exhibit a highly selective inhibition of FXIa than any other target in the coagulation cascade, but also display a reversal of their anticoagulant effects with FXI and serum albumin ^[37].

5.3. Monoclonal Antibodies

Abelacimab (MAA868).

A monoclonal antibody that binds the procoagulant enzymatic site of both FXI (zymogen) and the active form FXIa ^[38]. By binding to the catalytic domain, abelacimab locks both the FXI and activated FXIa in an inactive, zymogen-like conformation, thereby taking them out of the coagulation system. In a phase I testing, the pharmacodynamic effects of a single subcutaneous administration lasted up to 4 weeks or longer, suggesting the possibility of a once-monthly dosing ^[38].

Osocimab (BAY 1213790).

This is a fully human IgG1 antibody. Its crystal structure analysis has shown a novel allosteric mechanism of action, with the antibody binding to a region adjacent to the FXIa active site, leading to structural rearrangements and blocking of activity.

Osocimab has been compared with enoxaparin and apixaban for thromboprophylaxis in patients undergoing elective knee arthroplasty in the phase II FOXTROT trial (n = 813). A single intravenous administration of osocimab (given postoperatively at 0.3, 0.6, 1.2, or 1.8 mg/kg, or preoperatively at 0.3 or 1.8 mg/kg) was tested vs. once-daily enoxaparin (40 mg subcutaneous) and twice-daily apixaban (2.5 mg oral) ^[39] to prevent the incidence of VTE (assessed between 10 and 13 days postoperatively with bilateral venography or confirmed symptomatic deep vein thrombosis or pulmonary embolism). Postoperatively osocimab administration was noninferior at all, but the lowest dose vs. enoxaparin (VTE rates of 18%, 8%, 13%, and 14% vs. 20%, respectively).

Xisomab 3G3 (AB023).

This is a human IgG2b monoclonal antibody that binds to the apple 2 domain of FXI and FXIa and inhibits the activation of FXI by FXIIa. Despite suppressing the FXIIa-mediated activation of FXI, it leaves intact the ability of thrombin to reciprocally activate FXI, as well as the enzymatic active site of the formed FXIa itself. In a small (n = 24) study with ESRD patients on chronic hemodialysis, there were fewer occlusive events requiring hemodialysis circuit exchange and lower levels of thrombin-antithrombin complexes and C-reactive protein after xisomab administration compared with data collected prior to dosing ^[40].

Other Antibodies in Clinical Testing.

Other agents from different manufacturers are also in early stages of clinical development. These include MK-2060, which has a placebo-controlled phase II study actively recruiting to evaluate the efficacy and safety in 489 patients with ESRD on hemodialysis (NCT05027074), and REGN9933, with a phase I, placebo-controlled PK and PD study recruiting healthy participants (NCT05102136).

5.4. Aptamers

Aptamers are single-stranded oligonucleotides that act as potent antagonists by binding to their target protein. A number of specific aptamers have been developed that serve as strong anticoagulants by disrupting complex interactions on their target proteins ^[41].

To date, aptamers targeting FXI directly or indirectly are in very early stages, with none reaching clinical development. In laboratory testing, an agent designated Factor ELeven Inhibitory APtamer (FELIAP) was shown to competitively inhibit FXIa-catalyzed FIX activation and complex formation with antithrombin, without affecting FXI activation itself. Plasma clotting and thrombin generation assays were also inhibited by this aptamer ^[42].

6. Therapeutic Investigation

6.1. Active Areas of Investigations

6.1.1. Atrial Fibrillation

It is the most common clinically significant arrhythmia ^[43], with an age-related risk of occurrence, and cardiac thrombus formation and systemic embolization are its most significant clinical complications, raising the risk of stroke by 4–5 fold ^[44]^[45]. The DOACs have shown better results than warfarin in preventing stroke in non-valvular AF patients, with lower or equivalent rates of bleeding complications ^[46]. However, the need for safer agents still persists and is even more pressing in AF patients requiring hemodialysis. There is uncertainty as to whether the benefits of VKA actually outweigh their harm in AF patients requiring hemodialysis, and trials investigating the role of DOACs in this population are mostly in the early stages. Even in the absence of AF, hemodialysis on its own is a major problem, with cardiovascular events accounting for nearly half of the mortality in these patients. The availability of a newer antithrombotic agent with a better safety profile than existing strategies could significantly improve clinical outcomes in AF patients with or without the need for hemodialysis and in those who require dialysis, with or without AF. An FXI-inhibiting strategy could be an improved therapeutic option in these patients and warrants investigation in clinical trials.

6.1.2. Venous Thromboembolism

Anticoagulant therapy is the mainstay for the prevention and treatment of VTE diseases. The development of DOACs has improved the management of VTE compared to where it was with LHMH/VKA ^[47]. As a result, rates of idiopathic VTE appear to be on the decline, but the incidence of non-idiopathic DVT and PE seem to be steady or increasing ^[48], highlighting the need for newer treatment options. Even when used at reduced doses, there is a risk of bleeding with DOAC therapy in these patients ^[49].

6.2. Potential Areas for Therapeutic Investigations

Inhibitors of FXI/FXIa are currently in the early stages of clinical development, and over time the spectrum of their clinical application will evolve into specific, focused indications. The areas for the investigation of their therapeutic applications potentially include any pathology where thromboembolism plays an important role. Given the wide-ranging times of their onset and duration of action, FXIa inhibitors have the potential to develop into therapeutic strategies for the treatment and prevention of both acute and chronic, venous, and arterial thromboembolic disorders.

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Juan J. Badimon

Gines Escolar

M. Urooj Zafar

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