A novel inhibitor of Factor XIa as potential haemostasis-sparing anticoagulant for patients with atrial fibrillation

Comment on ‘Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study’ which was presented at the American College of Cardiology (ACC) 2022 Scientific Sessions and simultaneously published online in Lancet.https://doi.org/10.1016/S0140-6736(22)00456-1. PACIFIC-AF1 is an industry-promoted, multicentre, randomized, double-blind, Phase 2 dose-finding study aimed at determining the optimal dose of asundexian, an orally active small molecule that selectively inhibits the activated form of Factor XI (FXIa), and to compare the incidence of bleeding with that of the FXa inhibitor, apixaban, in patients with atrial fibrillation (AF). Patients enrolled in the study had CHA2DS2-VASc scores ≥2 if male or ≥3 if female, and increased bleeding risk. A total of 753 patients were randomly assigned in 1:1:1 ratio to receive asundexian 20 mg (n = 249) once daily, asundexian 50 mg (n = 254) once daily, or standard dose of apixaban twice daily (n = 250) for a period of 12 weeks with a 2-week post-treatment observation period. Randomization was stratified based on whether participants were receiving a direct-acting oral anticoagulant (DOAC) before the study started or were treatment-naïve. In the first case, had to have at least one bleeding risk feature (history of previous bleeding requiring medical attention within 12 months, estimated glomerular filtration rate of 30–50 mL/min, or current indication for aspirin). The primary safety endpoint was a composite of major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) criteria, assessed in all patients who took at least one dose of study medication. Secondary safety endpoints were all bleeding, ISTH major bleeding, ISTH clinically relevant non-major bleeding, and ISTH minor bleeding. There were no primary efficacy objectives for this trial. The thrombotic endpoints (the composite of cardiovascular death, myocardial infarction, ischaemic stroke, or systemic embolism, as well as the individual components, and all-cause mortality) were exploratory and underpowered. The mean age of patients enrolled was 73.7 ± 8.3 years, 41% were women, 45% were previously on DOACs, 29% had chronic kidney disease, and the mean CHA2DS2-VASc score was 3.9 ± 1.3. There was high-grade inhibition of Factor XIa activity with asundexian 20 and 50 mg at trough and peak concentrations (81 and 92% inhibition at trough concentrations, respectively). At 12 weeks, there were no episodes of major bleeding, 10 patients experienced a non-major clinically relevant bleeding event and 48 had any bleeding event (mostly minor bleeding). Ratios of incidence proportions for the primary endpoint were 0.50 [90% confidence interval (CI), 0.14–1.68] for 20 mg asundexian, 0.16 (0.01–0.99) for 50 mg asundexian, and 0.33 (0.09–0.97) for the pooled asundexian doses, compared with apixaban. Results for all bleeding events showed similar reductions in favour of asundexian: 0.46 (0.23–0.83) for asundexian 20 mg, 0.38 (0.16–0.68) for asundexian 50 mg, and 0.42 (0.26–0.67) for pooled asundexian vs. apixaban. Asundexian was well tolerated. Rates of non-bleeding adverse events and adverse events leading to discontinuation of the study drug were similar in the treatment groups. Although DOACs, which selectively and reversibly inhibit FXa or thrombin in the common pathway of the coagulation cascade, provide safer and more reliable prevention of thrombotic events compared with vitamin K antagonism, bleeding remains an important limitation of oral anticoagulation, particularly in vulnerable or older patients with renal dysfunction.2 Around 40% of AF patients are either under-treated, receiving a lower dose than is recommended, or not treated at all. This can leave patients vulnerable to potentially life-threatening thrombo-embolic events. Enthusiasm for drugs targeting FXI or FXIa is based on the promise that such agents will uncouple desired antithrombotic effects from deleterious anti-haemostatic effects.3 Indeed, epidemiological and preclinical studies suggest that FXIa, a component of the intrinsic coagulation pathway upstream of FXa and thrombin, is essential for thrombus growth in pathological thrombosis by propagating a formed thrombus and downregulating fibrinolysis, while being dispensable in physiological haemostasis, through a marginal role in consolidating clots.3–5 In Phase 2 studies, FXIa inhibition with subcutaneous antisense oligonucleotides, human monoclonal antibodies, or orally administered inhibitors has been shown to prevent venous thromboembolism with a low risk of bleeding in patients undergoing knee replacement when compared with standard treatment.6–10 PACIFIC-AF1 is the first trial to compare oral anticoagulation with an FXIa inhibitor vs. FXa inhibition in patients with AF at risk for stroke. In this clinical setting, often requiring lifelong anticoagulant therapy, the advantages of reducing thrombosis without impairing haemostasis might be even more relevant. The results of the study might contribute to the growing body of evidence that justifies pursuing antithrombotic strategies that target FXI or FXIa. Asundexian displays attractive pharmacokinetic characteristics. Being a small molecule, the rapid onset of action extends its utility for acute therapy; its half-life, between 14 and 17 h, improves its manageability in the case of bleeding; the 15% renal elimination makes the molecule suitable for older patients with renal dysfunction. Finally, its oral absorption facilitates its usefulness in the chronic setting. However, PACIFIC-AF has limitations. It was designed as a Phase 2 dose-finding study. The primary objective of Phase 2 studies is to find the appropriate dose(s) to be used in Phase 3 trials. PACIFIC-AF explored a relatively narrow dose range, with both doses being at or near the top of the dose–response relationship for Factor XIa inhibition and similar safety profile, leaving us without a clear answer. Furthermore, the study was marginally powered to assess the risk of bleeding with asundexian compared with apixaban; however, the number of bleeding events was only half of the anticipated number (10 vs. 20 events), and no major bleeding events were observed, resulting in extremely wide 90% CI ranging from a trivial 1% to an unrealistic 99% reduction associated with asundexian 50 mg. Therefore, although it is possible that asundexian may have caused less bleeding than apixaban, the results did not allow the magnitude of the effect to be reliably determined. Long-lasting observation of patients lacking FXI indicates that they are more prone to bleeding in the nasopharyngeal and reproductive tracts than in other sites, suggesting that tissues with high fibrinolytic activity may be more dependent on FXI than others.2,5 Those patients do not present more intracranial or gastrointestinal haemorrhage than the general population.5 Given this observation, compared with FXa inhibitors, FXIa inhibitors might not only be associated with fewer bleeding episodes, but also with types of bleeding events that are less life-threatening. Larger studies designed to investigate this possibility are required. Finally, PACIFIC-AF was not powered to test differences in rates of thrombosis between groups. Although FXI represents an attractive target for novel anticoagulant strategies, and additional Phase 2 studies are currently ongoing in different clinical settings (i.e. AF, recent ischaemic stroke, recent myocardial infarction), only large-scale Phase 3 trials will establish the safety and clinical efficacy of FXIa vs. FXa inhibition in preventing venous and arterial thrombosis. FXI-directed strategies may provide a more effective and safer approach to reducing thrombotic events in selected clinical settings, such as stroke prevention in haemodialysis patients with AF, clotting prevention in the haemodialysis circuits, extracorporeal membrane oxygenation circuits, and/or mechanical devices, where anti-FXa strategies have not been tested or have failed. However, at this stage, the jury is still out concerning the relative haemostatic safety of the two anticoagulant strategies. Conflict of interest: G.L. received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service, and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis. C.P. received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline, Tremeau, Zambon, and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation.