Anticoagulants are the mainstay for the prevention and treatment of thrombosis. However, bleeding complications remain a primary concern. Recent advances in understanding the contribution of activated factor XI (FXIa) in arterial thrombosis with a limited impact on hemostasis have led to the development of several FXIa-targeting modalities. Injectable agents including monoclonal antibodies and antisense oligonucleotides against FXIa have been primarily studied in venous thrombosis. The orally active small molecules that specifically inhibit the active site of FXIa are currently being investigated for their antithrombotic activity in both arteries and veins. This review focuses on a discussion of the potential clinical benefits of small molecule FXIa inhibitors, mainly asundexian and milvexian, in arterial thrombosis based on their pharmacological profiles and the compelling results of phase 2 clinical studies. The preclinical and epidemiological basis for the impact of FXIa in hemostasis and arterial thrombosis is also addressed. In recent clinical study results, asundexian appears to reduce ischemic events in patients with myocardial infarction and minor-to-moderate stroke, whereas milvexian possibly provides benefits in patients with minor stroke or high-risk transient ischemic attack (TIA). In addition, asundexian and milvexian had a minor impact on hemostasis even in combination with dual-antiplatelet therapy. Other orally active FXIa inhibitors also produce antithrombotic activity in vivo with low bleeding risk. Therefore, FXIa inhibitors might represent a new class of direct-acting oral anticoagulants (DOACs) for the treatment of thrombosis, although the explicit clinical positions of asundexian and milvexian in patients with ischemic stroke, high-risk TIA, and coronary artery disease require confirmation from the outcomes of ongoing phase 3 trials.

2022-03-10·Journal of medicinal chemistry1区 · 医学

Targeting the S2 Subsite Enables the Structure-Based Discovery of Novel Highly Selective Factor XIa Inhibitors

1区 · 医学

Article

作者: Liao, Chenzhong ; Tian, Yongbin ; Han, Jihong ; Kong, Yi ; Xie, Zhouling ; Jia, Zhiping ; Yao, Ningning ; Hou, Shuzeng ; Yang, Xiaoxiao ; Duan, Yajun

FXIa inhibition has been a promising strategy for treating thrombotic diseases. Up to date, many small-molecule FXIa inhibitors have been identified; however, most of them exhibit undesirable selectivity over the homologous plasma kallikrein (PKal). By employing structure-based drug design strategies, we identified many novel selective FXIa inhibitors that have extra interactions with the S2 subsite of FXIa. Among them, compound 35 displayed good inhibitory activity against FXIa and high selectivity over PKal and even several other serine proteases. Additionally, 35 showed significant anticoagulant activity toward the intrinsic pathway without affecting the extrinsic pathway. In vivo, 35 exhibited significant antithrombotic activity without increasing the bleeding risk and obvious toxicity in mice, demonstrating that it could be a promising candidate for further research. This study first demonstrates the importance of the S2 subsite of FXIa, paving the way to design highly selective FXIa inhibitors for clinical uses.

2022-02-10·Journal of medicinal chemistry1区 · 医学

Persistence Pays Off: Milvexian Emerges from the Industry’s Longstanding Search for Orally Bioavailable Factor XIa Inhibitors

1区 · 医学

Article

作者: Goodwin, Nicole C.

Over the past two decades, Factor XIa inhibitors have emerged as an exciting new class of antithrombic agents. Identification of orally bioavailable small molecule inhibitors has presented a formidable challenge for medicinal chemists. Herein, those challenges and the problem-solving that resulted in the discovery of milvexian will be presented.

项与 Factor XIa inhibitors(Novartis) 相关的新闻（医药）

2025-11-24

·BioPharmaDive

Bayer’s experimental blood-thinner notches trial win in stroke prevention

Dive Brief:Bayers experimental blood thinner asundexianmet its main goal in a closely watched Phase 3 stroke prevention trial, reducing the recurrence of a stroke in people who took the therapy along with standard treatments. The trial compared treatment with a combination of asundexian and an antiplatelet therapy against a placebo and the same antiplatelet treatment.The German-based company didnt release detailed data, stating that researchers will disclose them at an upcoming medical meeting while company executives discuss them with regulators ahead of possible approval applications.Results of the trial lifted optimism for asundexian'sdrug class, called Factor XIa inhibitors, following a series of clinical setbacks. Most recently, a rival drug missed its main goal in a trial of people whod had a recent heart attack.Dive Insight:The spotlight has been on Factor XIa inhibitors as the next big innovation in cardiovascular medicine, with drugmakers and researchers hoping they will prove safer and more effective than aging franchises like Bristol Myers Squibbs Eliquis. These drugs, which include asundexian,Bristol Myers and Johnson & Johnsons milvexian and Novartis abelacimab, block a protein involved in forming blood clots but is believed to be less essential in stopping bleeding.The balancing act in preventing stroke or any acute cardiovascular episode due to blood vessel blockages is in suppressing clotting without raising the risk that people will have uncontrolled bleeding incidents. In people who have irregular heartbeats, Eliquis is able to do just that better than an older drug called warfarin or aspirin.In treating people whove already had one stroke that wasnt caused by an irregular heartbeat, in a setting called secondary prevention, doctors use one or two drugs to thin the blood, known as antiplatelet medications. The drugs used include aspirin, clopidogrel, AstraZenecas Brilinta and Eli Lillys Effient.In the trial called Oceanic Stroke, Bayer aimed to measure whether adding asundexianto the mix would help, testing it against a placebo in over 12,000 people. The company said the experimental drug reduced the risk of ischemic stroke compared to placebo and added that its addition didnt increase the risk of major bleeding episodes.Bayers German-listed shares rose more than 12% following the news, changing hands at about 31 euros apiece. Two years ago, Bayer terminated a head-to-head trial of asundexianagainst Eliquis in people with irregular heartbeats, an early Phase 3 readout that cast some doubt over the promise of Factor XIa inhibitors.Milvexiansfailure in acute coronary syndrome earlier this month didnt boost optimism, but the asundexianresults may reverse some of the doubt.After a string of class setbacks, this is a needed win, wrote Cantor Fitzgerald analyst Carter Gould, who covers Bristol Myers, in a note to clients.Bristol Myers and J&J are expecting milvexiansPhase 3 trials in people with irregular heartbeats, as well as secondary stroke prevention, in the fourth quarter of 2026. Bristol Myers shares rose 5% in morning trading. '

临床3期

100 项与 Factor XIa inhibitors(Novartis) 相关的药物交易

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