The first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the factor XI monoclonal antibody SHR-2004 in healthy subjects.

BACKGROUND: Inhibiting the coagulation factor XI (FXI) is a novel strategy for prevention and treatment of thromboembolism without affecting extrinsic coagulation pathways. SHR-2004 is a humanized monoclonal antibody that selectively binds to FXI and factor XIa (FXIa). RESEARCH DESIGN & METHODS: This randomized, double-blind, dose-escalation, placebo-controlled study evaluated SHR-2004 administered either intravenously (i.v.; Part A) or subcutaneously (s.c.; Part B). In Part A, 24 subjects received a single i.v. dose of SHR-2004 (0.1, 0.3, or 1.0 mg/kg) or placebo. In Part B, 40 subjects received a single s.c. dose of SHR-2004 (0.5, 1.0, 3.0, or 4.5 mg/kg) or placebo. RESULTS: SHR-2004 was well tolerated. Plasma exposure to SHR-2004 increased in a dose-dependent manner. The geometric mean half-time ranged from 11.6 to 13.0 days. FXI activity decreased, and the activated partial thromboplastin time (APTT) was prolonged after i.v. and s.c. administration in a dose- and time-dependent manner. FXI activity was nearly completely abolished immediately after administering the highest i.v. dose, with the average APTT prolonged to nearly three times of baseline. CONCLUSION: SHR-2004 is a promising candidate for further development as an anticoagulant drug that exerts effective anticoagulation with minimal risk of bleeding. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05369767.

Factor XI inhibitors - Rising stars in anti-thrombotic therapy?

The "holy grail" of preventing and treating thrombosis and thromboembolism would be a drug that was highly effective (preventing clots) and at the same time had a low risk of bleeding. From a hemostasiological perspective, the inhibition of factor XI represents a promising target because a reduced level of factor XI protects against thrombosis without significantly increasing the risk of spontaneous bleeding. Currently, three different classes of drugs of factor XI-inhibition are tested. These are (1) monoclonal antibodies (mAbs), (2) so-called synthetic, small molecules and (3) antisense oligonucleotides (ASOs). This article provides a narrative overview of the current status of studies on all three classes of drugs. Tests with mAbs have been conducted primarily in DVT prevention after knee replacement surgery. One large phase 3 study is testing the mAbs Abelacimab in patients with atrial fibrillation. The synthetic, small molecules Asundexian and Milvexian are tested in several phase 3 trials, mainly in patients with non-cardioembolic ischemic stroke. Results can be expected in the coming years. Clinical testing of ASOs to inhibit factor XI are still in their infancies.

Therapeutic Potential of FXI Inhibitors: Hype or Hope?

Significant advancements have shaped the landscape of anticoagulant therapy in the past two decades, including the introduction of direct oral anticoagulants (DOACs), characterized by favorable safety and efficacy profiles and reduced drug-to-drug or food interaction resulting in excellent patient compliance. However, residual concerns still exist with standard-of-care anticoagulant therapy, including the inability to use DOACs in several clinical settings and the need to further reduce the risk of bleeding. Recent improvements in the understanding of the mechanisms behind thrombus formation have led to the awareness that the intrinsic pathway of the coagulation cascade may play an important role in pathological thrombosis, but not in hemostasis. This has represented the rationale for targeting this pathway with factor XI (FXI) inhibitors, with the aim of uncoupling hemostasis and thrombosis. Clinical evidence from patients with FXI deficiency further supports this concept. A number of compounds with different mechanisms of action have been developed to target FXI (i.e., asundexian, abelacimab, Ionis-FXIRx, milvexian, osocimab, and Xisomab 3G). To date, the majority of available trials have not gone beyond completion of phase 2 and results are conflictive making it difficult to appraise the clinical benefit of these compounds in the different clinical settings where they have been tested (i.e., atrial fibrillation, acute ischemic stroke, acute myocardial infarction, end-stage renal disease, total knee arthroplasty). Moreover, the largest phase 3 randomized trial designed to test the efficacy of asundexian over apixaban in patients with atrial fibrillation, the OCEANIC-AF, has been prematurely stopped as a result of the inferior efficacy of asundexian. In this review we discuss the pharmacological properties and available evidence generated thus far for factor XI inhibitors, providing a perspective on the current state of these drugs.

Will Factor XI Inhibitors Replace Current Anticoagulants for Stroke Prevention in Atrial Fibrillation?

PURPOSE OF REVIEW: This review provides an overview of the factor XI (FXI) inhibitor hypothesis for the development of novel anticoagulants which may be safer to those currently used in clinical practice and describes preliminary clinical data from phase 2 dose-ranging studies of patients with atrial fibrillation. RECENT FINDINGS: Recent data from phase 2 dose ranging studies demonstrate substantial reductions in bleeding with FXI pathway inhibition compared with currently approved anticoagulants. However, larger studies are necessary to demonstrate efficacy of FXI inhibition for stroke prevention in atrial fibrillation. FXI pathway inhibition holds great promise for revolutionizing the landscape of anticoagulation for atrial fibrillation, primarily by reducing bleeding risk; however, further data are necessary to demonstrate efficacy.

Factor XI inhibition in cardiovascular disease.

Cardiovascular disease remains the leading global cause of mortality, requiring effective antithrombotic strategies to prevent thromboembolic events. Currently available therapies are effective but have inherent bleeding risks which may limit or preclude their use, particularly in patients at the highest risk of bleeding. Factor XI (FXI) inhibitors are a promising new class of anticoagulants which may mitigate the risk of bleeding while maintaining efficacy. Further, they have the potential to provide effective anticoagulation in indications where direct oral anticoagulants (DOACs) are proven less effective than vitamin K antagonists (VKAs) or when DOACs are contraindicated. The development of FXI inhibitors was based on mechanistic considerations suggesting FXI's role in thrombus formation without significantly affecting hemostasis, supported by epidemiological data and animal experiments. FXI inhibitors, including antisense oligonucleotides, monoclonal antibodies, and small­molecule inhibitors, target different stages of FXI production or activation, offering a diversity of therapeutic options with differing onset and offset of action, drug interaction potential, and renal elimination. FXI inhibitors have shown potential benefits in phase II trials, demonstrating similar or reduced bleeding rates to existing agents, including DOACs. The early termination of AZALEA­TIMI 71 (Safety and Tolerability of Abelacimab [MAA868] vs Rivaroxaban in Patients With Atrial Fibrillation) and OCEANIC­AF (A Study to Learn How Well the Study Treatment Asundexian Works and How Safe it is Compared to Apixaban to Prevent Stroke or Systemic Embolism in People With Irregular and Often Rapid Heartbeat [Atrial Fibrillation], and at Risk for Stroke) trials underscores challenges in the selection of appropriate patient populations and anticoagulant class, agent, and dose. Ongoing phase III trials including OCEANIC­STROKE (A Study to Test Asundexian for  Preventing a Stroke Caused by a Clot in Participants After an Acute Ischemic Stroke or After a High­risk Transient Ischemic Attack, a So­called Mini Stroke) and LIBREXIA trials aim to further explore the efficacy of FXI inhibitors in stroke, acute coronary syndrome, and atrial fibrillation. In conclusion, FXI inhibitors hold promise as next­generation anticoagulants, potentially addressing limitations of current therapies. Ongoing research is required to establish their place in clinical practice and address unresolved questions.

Factor XI inhibition in hemodialysis patients: the safer anticoagulation?

Chronic hemodialysis patients exhibit an excessive cardiovascular risk and a marked increase in both thromboembolism and bleeding episodes. Factor XI inhibition may provide anticoagulation, with a low risk of bleeding, and several factor XI inhibitors, including fesomersen, an antisense oligonucleotide, are under development. Recently, a phase 2 study of fesomersen showed a good safety profile in chronic hemodialysis patients and suggested that clotting rates of the arteriovenous fistula and the dialysis circuit are lower.

Factor XI Inhibitors: perspectives in primary and secondary prevention of ischemic stroke.

Stroke is one of the most common causes of mortality and disability worldwide. Antithrombotic therapy represents the mainstay in primary and secondary prevention, both in cardioembolic and non-cardioembolic stroke. Particularly, direct oral anticoagulants play a crucial role in atrial fibrillation, the most common cause of cardioembolic stroke, whereas single or dual antiplatelet therapy is preferred in non-cardioembolic stroke. However, the limitations related to the residual risk of cardioembolic or cerebrovascular events, and the risk of major bleeding, still represent unmet medical needs. To overcome them, new drugs inhibiting Factor XI (FXI) and Factor XII have been proposed, with a selective inhibition of contact pathway of coagulation, delineating a new anticoagulant approach. This review provides a summary of the currently available evidence and future perspectives on FXI inhibitors, that can represent an additional therapeutic option in the primary and secondary prevention of cardioembolic and non-cardioembolic ischemic stroke, also in challenging therapeutic contexts.

Novel horizons in anticoagulation: the emerging role of factor XI inhibitors across different settings.

Anticoagulants have long been fundamental in preventing and treating thromboembolic disorders, with a recent shift of focus towards direct oral anticoagulants, thanks to their ease of use, efficacy, and safety. Despite these advancements, bleeding complications remain a major concern with any anticoagulant, highlighting the need for safer drugs. Factor XI (FXI) inhibitors have emerged as promising agents in this regard, offering a novel approach by targeting upstream factors in the coagulation system. Phase II trials have shown encouraging outcomes, indicating a reduced bleeding risk compared to that associated with traditional anticoagulants, particularly in the context of cardiovascular disease management when combined with antiplatelet therapy. However, the variability in findings and limited efficacy data call for a cautious interpretation pending insights from phase III trials. These trials are essential for validating the potential of FXI inhibitors to balance bleeding risk reduction and maintain anticoagulant efficacy. This review explores the pharmacology, potential indications, clinical data, and future directions of FXI inhibitors, providing a perspective on their evolving role in anticoagulant therapy. It also provides a detailed analysis of data from published clinical trials on FXI inhibitors in various indications. Preliminary data from ongoing trials are also outlined. As the field moves forward, a cautiously optimistic outlook can be expected, focusing on comprehensive data from phase III trials to define the role of FXI inhibitors in various clinical scenarios.

Emulation of randomized trials of direct oral anticoagulants with claims data and implications for new Factor XI inhibitors.

Direct oral anticoagulants (DOACs) revolutionized the management of thromboembolic disorders. Clinical care may be further improved as Factor XIs undergo large-scale outcome trials. What role can non-randomized database studies play in expediting understanding of these drugs in clinical practice? The RCT-DUPLICATIVE Initiative emulated the design of eight DOAC randomized clinical trials (RCT) using non-randomized claims database studies. RCT study design parameters and measurements were closely emulated by the database studies and produced highly concordant results. The results of the single database study that did not meet all agreement metrics with the specific RCT it was emulating were aligned with a meta-analysis of six trials studying similar questions, suggesting the trial result was an outlier. Well-designed database studies using fit-for-purpose data came to the same conclusions as DOAC trials, illustrating how database studies could complement RCTs for Factor XI inhibitors-by accelerating insights in underrepresented populations, demonstrating effectiveness and safety in clinical practice, and testing broader indications.

A Phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis.

Patients with kidney failure on hemodialysis (KF-HD) are at high risk for both atherothrombotic events and bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic Factor XI expression, versus placebo, for bleeding and atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding (MB/CRNMB). Exploratory endpoints included post-dialysis arterio-venous (AV)-access bleeding, major atherothrombotic events (composite of fatal or non-fatal myocardial infarction, ischemic stroke, acute limb ischemia/major amputation, systemic embolism, symptomatic venous thromboembolism), AV-access thrombosis, and clotting of the hemodialysis circuit. Of 308 participants randomized, 307 received study treatment and were analyzed. Fesomersen led to a dose-dependent and sustained reduction of steady-state median FXI levels by 53.6% (40 mg group), 71.3% (80 mg group), 86.0% (120 mg group), versus 1.9% in the placebo group. MB/CRNMB events occurred in 6.5% (40 mg group), 5.1% (80 mg group), 3.9% (120 mg group), and in 4.0% of those receiving placebo (pooled fesomersen versus placebo P = 0.78). Major atherothrombotic events occurred in 1 patient (1.3%) in each treatment arm. MB/CRNMB bleeding and post-dialysis AV-access bleeding were not related to predicted FXI levels. Lower predicted FXI levels were associated with reductions in hemodialysis circuit clotting (P = 0.002) and AV-access thrombosis (P = 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major bleeding compared with placebo. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04534114.

Systematic review of clinical trials on antithrombotic therapy with factor XI inhibitors.

INTRODUCTION AND OBJECTIVE: Data from phase 2 clinical trials suggest that factor XI inhibitors may exhibit a more favorable efficacy/safety profile compared to current antithrombotic therapies. The aim of this systematic review is to analyze the available evidence derived from these studies. METHODS: A literature search in the PubMed, Cochrane Library, Scopus, EMBASE databases, and clinical trial registration platforms Clinical Trials and Cochrane Central Register of Controlled was conducted. In accordance with the PRISMA statement, results were reported. RESULTS: A total of 18 completed or ongoing clinical trials addressing multiple scenarios, including atrial fibrillation, stroke, myocardial infarction, and venous thromboembolism, were identified. Evidence from 8 studies with available results was analyzed. Phase 2 studies with factor XI inhibitors, overall, demonstrated an acceptable efficacy and safety profile. The benefit-risk balance, in terms of reducing venous thromboembolism in patients undergoing total knee arthroplasty, was more favorable. For this scenario, factor XI inhibitors showed a 50% reduction in the overall rate of thrombotic complications and a 60% reduction in the rate of bleeding compared to enoxaparin. Modest results in studies involving patients with atrial fibrillation, stroke, and myocardial infarction were observed. CONCLUSIONS: Factor XI inhibitors offer new prospects in antithrombotic treatment and prophylaxis. Ongoing phase 3 studies will help define the most suitable drugs and indications.

Current Gaps in the Provision of Safe and Effective Anticoagulation in Atrial Fibrillation and the Potential for Factor XI-Directed Therapeutics.

The global prevalence of atrial fibrillation is rapidly increasing, in large part due to the aging of the population. Atrial fibrillation is known to increase the risk of thromboembolic stroke by 5 times, but it has been evident for decades that well-managed anticoagulation therapy can greatly attenuate this risk. Despite advances in pharmacology (such as the shift from vitamin K antagonists to direct oral anticoagulants) that have increased the safety and convenience of chronic oral anticoagulation in atrial fibrillation, a preponderance of recent observational data indicates that protection from stroke is poorly achieved on a population basis. This outcomes deficit is multifactorial in origin, stemming from a combination of underprescribing of anticoagulants (often as a result of bleeding concerns by prescribers), limitations of the drugs themselves (drug-drug interactions, bioaccumulation in renal insufficiency, short half-lives that result in lapses in therapeutic effect, etc), and suboptimal patient adherence that results from lack of understanding/education, polypharmacy, fear of bleeding, forgetfulness, and socioeconomic barriers, among other obstacles. Often this adherence is not reported to treating clinicians, further subverting efforts to optimize care. A multidisciplinary, interprofessional panel of clinicians met during the 2023 International Society of Thrombosis and Haemostasis Congress to discuss these gaps in therapy, how they can be more readily recognized, and the potential for factor XI-directed anticoagulants to improve the safety and efficacy of stroke prevention. A full appreciation of this potential requires a reevaluation of traditional teaching about the "coagulation cascade" and decoupling the processes that result in (physiologic) hemostasis and (pathologic) thrombosis. The panel discussion is summarized and presented here.

In vitro differential inhibition of the factor XI activity assay in the setting of a lupus anticoagulant.

Acquired factor XI deficiencies due to factor-specific inhibitors are rare and may be associated with lupus anticoagulant. We report a 63-year-old male with suspected postsurgical bleeding, prior surgical site infection, an isolated prolonged activated partial thromboplastin time, and a positive lupus anticoagulant. Although the factor II assay was normal, factor VIII and IX assays initially demonstrated nonparallelism with factor activity that consistently increased to normal reference ranges with serial dilutions. A discrepancy in factor XI activity results was discovered when the in-house method demonstrated undetectable activity (<3%); send-out testing using different instrument/reagent combinations revealed the presence of factor XI activity between 70% and 76%. The patient received surgical follow-up and was subsequently discharged home. Given the differential in vitro inhibition of factor XI activity on our initial in-house testing, this case highlights the importance of recognizing factor assay interference in the presence of a known lupus anticoagulant inhibitor, with strategies to mitigate potentially erroneous results.

Pharmacologic targeting of coagulation factors XII and XI by monoclonal antibodies reduces thrombosis in nitinol stents under flow.

BACKGROUND: Cardiovascular implantable devices, such as vascular stents, are critical for the treatment of cardiovascular diseases. However, their success is dependent on robust and often long-term antithrombotic therapies. Yet, the current standard-of-care therapies often pose significant bleeding risks to patients. Coagulation factor (F)XI and FXII have emerged as potentially safe and efficacious targets to safely reduce pathologic thrombin generation in medical devices. OBJECTIVES: To study the efficacy of monoclonal antibody-targeting FXII and FXI of the contact pathway in preventing vascular device-related thrombosis. METHODS: The effects of inhibition of FXII and FXI using function-blocking monoclonal antibodies were examined in a nonhuman primate model of nitinol stent-related thrombosis under arterial and venous flow conditions. RESULTS: We found that function-blocking antibodies of FXII and FXI reduced markers of stent-induced thrombosis in vitro and ex vivo. However, FXI inhibition resulted in more effective mitigation of thrombosis markers under varied flow conditions. CONCLUSION: This work provides further support for the translation of contact pathway of coagulation inhibitors for their adjunctive clinical use with cardiovascular devices.

Pharmacological and clinical appraisal of factor XI inhibitor drugs.

The evolution of anticoagulation therapy, from vitamin K antagonists to the advent of direct oral anticoagulants (DOACs) almost two decades ago, marks significant progress. Despite improved safety demonstrated in pivotal trials and post-marketing observations, persistent concerns exist, particularly regarding bleeding risk and the absence of therapeutic indications in specific subgroups or clinical contexts. Factor XI (FXI) has recently emerged as a pivotal contributor to intraluminal thrombus formation and growth, playing a limited role in sealing vessel wall injuries. Inhibiting FXI presents an opportunity to decouple thrombosis from haemostasis, addressing concerns related to bleeding events while safeguarding against thromboembolic events. Notably, FXI inhibition holds promise for patients with end-stage renal disease or cancer, where clear indications for DOACs are currently lacking. Various compounds have undergone design, testing, and progression to phase 2 clinical trials, demonstrating a generally favourable safety and tolerability profile. However, validation through large-scale phase 3 trials with sufficient power to assess both safety and efficacy outcomes is needed. This review comprehensively examines FXI inhibitors, delving into individual classes, exploring their pharmacological properties, evaluating the latest evidence from randomized trials, and offering insights into future perspectives.

Factor XI and coagulation. Factor XI inhibitors - antithrombotic perspectives.

Factor XI is a zymogen with an important role in the coagulation cascade. It is activated by FXII, thrombin and or it can be autoactivated. It has a prothrombotic effect after being activated by thrombin, but also through its antifibrinolytic action, stabilizing the formed clot. Hereditary deficiency of FXI causes haemophilia C - a disease manifested by an usually provoked, small to moderate mucosal bleeding. People with severe FXI deficiency have a low risk of thrombotic events. Conversely, increased FXI values have been found to be associated with increased risk of venous thromboembolism and ischemic stroke. Lowering serum FXI levels has become a treatment target for the prevention of thrombotic events. New pharmacological agents - FXI inhibitors - have been investigated in phase II clinical trials, with promising results in terms of efficacy and safety in the prevention of thrombotic events. FXI inhibitors are emerging as new anticoagulant agents with broad indication prospects beyond direct oral anticoagulants and vitamin K antagonists.

Pharmacological targeting of coagulation factor XI attenuates experimental autoimmune encephalomyelitis in mice.

Multiple sclerosis (MS) is the most common causes of non-traumatic disability in young adults worldwide. MS pathophysiologies include the formation of inflammatory lesions, axonal damage and demyelination, and blood brain barrier (BBB) disruption. Coagulation proteins, including factor (F)XII, can serve as important mediators of the adaptive immune response during neuroinflammation. Indeed, plasma FXII levels are increased during relapse in relapsing-remitting MS patients, and previous studies showed that reducing FXII levels was protective in a murine model of MS, experimental autoimmune encephalomyelitis (EAE). Our objective was to determine if pharmacological targeting of FXI, a major substrate of activated FXII (FXIIa), improves neurological function and attenuates CNS damage in the setting of EAE. EAE was induced in male mice using murine myelin oligodendrocyte glycoprotein peptides combined with heat-inactivated Mycobacterium tuberculosis and pertussis toxin. Upon onset of symptoms, mice were treated every other day intravenously with anti-FXI antibody, 14E11, or saline. Disease scores were recorded daily until euthanasia for ex vivo analyses of inflammation. Compared to the vehicle control, 14E11 treatment reduced the clinical severity of EAE and total mononuclear cells, including CD11b+CD45high macrophage/microglia and CD4+ T cell numbers in brain. Following pharmacological targeting of FXI, BBB disruption was reduced, as measured by decreased axonal damage and fibrin(ogen) accumulation in the spinal cord. These data demonstrate that pharmacological inhibition of FXI reduces disease severity, immune cell migration, axonal damage, and BBB disruption in mice with EAE. Thus, therapeutic agents targeting FXI and FXII may provide a useful approach for treating autoimmune and neurologic disorders.

Factor XI Inhibitors: Potential Role in End-Stage Kidney Disease.

Patients with end-stage kidney disease (ESKD) experience a high thrombotic risk but are also at increased risk of bleeding. There is an unmet need for safer antithrombotic therapy in patients with ESKD on hemodialysis. Factor XI (FXI) represents an attractive therapeutic target for anticoagulation because of the potential to mitigate the bleeding risks associated with currently approved anticoagulants, especially in patients at high risk of bleeding. FXI inhibition is also an attractive option in settings where coagulation is activated by exposure of the blood to artificial surfaces, including the extracorporeal circuit during hemodialysis. Therapies targeting FXI that are in the most advanced stages of clinical development include antisense oligonucleotides, monoclonal antibodies, and synthetic small molecules, which serve either to lower FXI levels or block its physiological effects. This review article presents the most recent pharmacological data with FXI inhibitors, briefly describes phase 2 and 3 clinical trials with these agents, and critically examines the potential future use of FXI inhibitors for extracorporeal circuit anticoagulation in patients with ESKD. In addition, laboratory monitoring and reversal of FXI inhibitors are briefly discussed.