Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial

Shoamanesh, Ashkan; Mundl, Hardi; Smith, Eric E.; Masjuán, Jaime; Milanov, Ivan; Hirano, Teruyuki; Agafina, Alina; Campbell, Bruce C.V.; Caso, Valeria; Mas, Jean‐Louis; Dong, Qiang; Turčãni, Peter; Christensen, Hanne; Ferro, José M.; Veltkamp, Roland; Mikulík, Robert; Marchis, Gian Marco De; Robinson, Thompson; Lemmens, Robin; Stępień, Adam; Greisenegger, Stefan; Roine, Risto O.; Csiba, László; Khatri, Pooja; Coutinho, Jonathan M.; Lindgren, Arne; Demchuk, Andrew M.; Colorado, Pablo; Kirsch, Bodo; Neumann, Christoph; Heenan, Laura; Xu, Lizhen; Connolly, Stuart J.; Hart, Robert G.

doi:10.1016/s0140-6736(22)01588-4

Cited by 122 publications

(115 citation statements)

References 31 publications

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“…Furthermore, the first clinical evidence was generated from 3 phase 2b studies with asundexian in a total of ≈4000 patients with atrial fibrillation (PACIFIC‐AF [NCT04218266] 14 ), acute myocardial infarction (PACIFIC‐AMI [NCT04304534] 15 ), and noncardioembolic ischemic stroke (PACIFIC‐STROKE [NCT04304508] 16 ). In patients at risk for cardiovascular events in PACIFIC‐STROKE and PACIFIC‐AMI receiving 10 mg, 20 mg, or 50 mg once daily, there was no observed increase in major or not clinically relevant non‐major bleeding compared with placebo on top of standard of care 15,16 . These results were reinforced in PACIFIC‐AF where it was demonstrated that patients who received 20 mg or 50 mg of asundexian once daily had lower rates of observed bleeding compared with apixaban 14 .…”

Section: Figurementioning

confidence: 99%

Effects of Tablet Formulation, Food, or Gastric pH on the Bioavailability of Asundexian

Kanefendt

Brase

Unger

et al. 2022

Clinical Pharm in Drug Dev

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Absolute bioavailability (F) and the impact of gastric pH, tablet formulation, and food on the pharmacokinetics and safety of asundexian, an oral factor XIa inhibitor, was assessed in healthy White men aged 18–45 years in 4 studies. For F, fasted participants received 50 μg of [13C7,15N]‐labeled asundexian intravenously 2 hours after 25 mg of asundexian orally. Tablet formulation (50‐mg immediate release [IR], and different amorphous solid dispersion [ASD] IR 25‐mg and 50‐mg ASD IR tablets) and food effects were explored in 2 studies. Formulation was compared using 50‐mg IR versus 25‐mg ASD IR and 25‐mg ASD IR versus 50‐mg ASD IR (fasted); food effect using 25‐mg ASD IR and 50‐mg ASD IR. Gastric pH modulation was assessed using omeprazole or antacid coadministration with asundexian in the fasted state. Pharmacokinetic parameters included area under the concentration‐time curve (AUC; and AUC/dose [D]) and maximum observed concentration (Cmax and Cmax/D) data were evaluable for 59 participants. F was 103.9%. Relative bioavailability with 25‐mg ASD IR and 50‐mg ASD IR tablets, respectively, was marginally affected by formulation (AUC/D ratios, 94.3% and 95.1%; Cmax/D ratios, 95.5% and 88.7%), food (AUC[/D] ratios, 91.1% and 96.9%; Cmax[/D] ratios: 78.3% and 95.1%), and gastric pH (omeprazole, no effect; antacid, AUC ratio, 89.9% and Cmax ratio, 83.7%). No serious adverse events or deaths occurred; most adverse events were mild or moderate. In summary, oral asundexian was well tolerated and demonstrated complete bioavailability irrespective of tablet formulation, food, or gastric pH.

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Section: Figurementioning

confidence: 99%

Effects of Tablet Formulation, Food, or Gastric pH on the Bioavailability of Asundexian

Kanefendt

Brase

Unger

et al. 2022

Clinical Pharm in Drug Dev

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“…New results have recently been reported with the small molecule inhibitors (Table ). [3][4][5] Asundexian was compared with apixaban in the PACIFIC-AF (Safety of the Oral Factor Xia Inhibitor Asundexian Compared With Apixaban in Patients With Atrial Fibrillation) trial. Although underpowered for efficacy, rates of bleeding severe enough to prompt medical care occurred onethird as often with asundexian than with apixaban.…”

Section: Clinical Trialsmentioning

confidence: 99%

What Is the Future of Factor XI Inhibitors?

Weitz

Eikelboom

2022

Circulation

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arenteral and oral factor XI (FXI) inhibitors, the next potential generation of anticoagulants, are undergoing phase-3 evaluation with the hope that they will be safer than currently available agents. 1 This article (1) addresses the unmet needs in anticoagulation therapy; (2) explains why FXI may be more important for thrombosis than for hemostasis; (3) identifies the FXI inhibitors in advanced stages of development;(4) describes the results of the phase 2 trials; and (5) provides perspective on the opportunities and challenges for this new class of anticoagulants.

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“…Several studies have reported the feasibility of achieving antithrombotic effects without interfering with the haemostasis physiology by inhibiting factor Xi or XIa. [1][2][3] Currently two orally bioavailable factor XIa inhibitors are being evaluated in various clinical trials for potential use in cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological targets of Asundexian relevant to its therapeutic efficacy in treating cardiovascular diseases.

Kumar

2022

Preprint

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Background Oral anticoagulant which don’t interfere with haemostasis physiology have potential application in management of acute cardiovascular events. Asundexian is once such oral anticoagulant, which is reported to be beneficial by minimising the rate of ischemic events. This study examined the pharmacological basis for cardiovascular benefits of asundexian. Materials and Methods All potential targets of asundexian in humans were identified by Insilco screening in the SwissTargetPrediction server and analysed. Results Unexpectedly factor XI or Xia was not observed to be targeted by asundexian in this study. However factor XII and thrombin were observed to be targeted by asundexian. In addition several GPCR’s, ion channels, enzymes and kinases relevant to positive modulation of cardiovascular physiology were observed to be targeted by asundexian. Conclusion The anticoagulant effects of asundexian is likely to be by indirect inhibition of factor XI or Xia by interfering with factor XII and/or thrombin. The cardiovascular benefits of asundexian is likely mediated by broader relevant off target effects.

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Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial

Cited by 122 publications

References 31 publications

Effects of Tablet Formulation, Food, or Gastric pH on the Bioavailability of Asundexian

Effects of Tablet Formulation, Food, or Gastric pH on the Bioavailability of Asundexian

What Is the Future of Factor XI Inhibitors?

Pharmacological targets of Asundexian relevant to its therapeutic efficacy in treating cardiovascular diseases.

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