Inhibiting Factor XIa has the potential to treat both arterial and venous thromboembolism as it might cause less bleeding than existing anticoagulants; although Factor XIa is believed to increase thrombin generation, its role in haemostasis is limited.
Milvexian’s safety, tolerability, PK and PD were assessed in a two part, double-blind, placebo-controlled sequential single and multiple ascending dose trial.2
In all, 48 healthy adults were given doses ranging from 4 to 500 mg of milvexian or a placebo. All dosing regimens were safe and well tolerated, with no clinically significant bleeding events and only mild treatment-emergent adverse events.
The effect of a high-fat meal was also assessed and this increased bioavailability in a dose-dependent manner. In the multiple dose groups, steady state plasma concentration was reached within 3 days with once-daily doses and 6 days with twice-daily doses.
In a parallel group Phase II trial, 1242 patients undergoing knee arthroplasty were randomised to receive 25, 50, 100 or 200 mg of milvexian twice daily, 25, 50 or 200 mg once daily or once-daily 40 mg doses of enoxaparin.3
In the twice-daily groups, 21% of those given 25 mg doses developed a venous thromboembolism, as did 11% of the 50 mg group, 9% with 100 mg and 8% with 200 mg.
For the once-daily groups, the incidence was 25%, 24% and 7%, respectively. It was 21% for the enoxaparin group. Bleeding was experienced by 4% of all patients, but major or clinically relevant non-major bleeding was more common in those given enoxaparin (2% versus 1%).
A second Phase II clinical trial has also been done to evaluate its efficacy and safety in terms of preventing ischaemic stroke or covert brain infarction in patients also receiving aspirin and clopidogrel after acute ischaemic stroke or transient ischaemic attack. The results of this study have yet to be published.
However, Phase III trials are now under way. These studies will assess its potential in nearly 50,000 patients across three indications: stroke prevention after an acute ischaemic stroke or high-risk transient ischaemic attack; stroke prevention in patients with atrial fibrillation; and acute coronary syndromes.
References
- A.K. Dilger, et al., J. Med. Chem. 65, 1770 (2022).
- V. Perera, et al., Clin. Transl. Sci. 15, 330 (2022).
- J.I. Weitz, et al., N. Engl. J. Med. 385, 2161 (2021).