Key Points
- Selective XIa inhibitor Asundexian may innovate the field of oral anticoagulation by uncoupling hemostasis from thrombosis and potentially providing protection from thromboembolic events without increasing bleeding risk among patients with acute non-cardioembolic stroke.
- The Phase 2 PACIFIC-STROKE trial (n=1,808) compared Asundexian 10 mg, 20 mg and 50 mg versus placebo (on top of antiplatelet therapy) among patients suffering from acute non-cardioembolic stroke. Overall, all doses of Asundexian appeared safe as with non-statistically different rates of major and clinically-meaningful non-major ISTH bleeding compared to placebo. At the same time, however, even the highest dose of Asundexian did not achieve a statistically significant reduction in the primary ischemic outcome, namely reducing the incidence of symptomatic ischemic stroke or covert brain infarct (detected by MRI) at 6 months from the index event. Nonetheless, secondary exploratory analyses of Asundexian 50 mg suggested a dose-dependent reduction in the risk of recurrent symptomatic ischemic strokes and TIAs. Adequately powered Phase 3 data are needed to understand whether Asundexian may provide additional protection from recurrent ischemic events among patients who have acute non-cardioembolic strokes.
During the American College of Cardiology (ACC) Conference in April 2022, the first in-human data from the novel anticoagulant Asundexian were presented to the scientific community. Asundexian is a Factor XIa inhibitor, which acts in a more targeted fashion compared to the other DOACs that are already available on the market. Specifically, DOAC-mediated Factor Xa inhibition prevents the formation of pathological thrombi, but also blocks the tissue factor pathway, which in turns may prevent the formation of thrombin-mediated “beneficial clots” that are needed in routine homeostasis of blood vessels around the body. This status quo, however, could be revolutionized with selective Factor XIa inhibition, which would be capable of preventing the formation of pathological thrombi while still allowing activation of the tissue factor pathway and thus the formation of “beneficial clots”.
In the ACC 2022 conference, the randomized phase 2 dose-finding PACIFIC-AF trial (n=755) compared Asundexian 20 mg, Asundexian 50 mg and apixaban among patients with atrial fibrillation. In this study, Asundexian 50 mg showed a significant reduction in the primary outcome of major and non-major clinically relevant bleeding; the overall low bleeding rate resulted in wide confidence intervals, and the even fewer ischemic events did not allow the pre-specified exploratory analyses to identify any major differences between the arms. These data, however, paved the way for larger Phase 3 randomized trials that will be forthcoming in the AF arena.
Importantly, Phase 1 trials of Asundexian generated sufficient evidence that this agent does not have a significant interaction with antiplatelet agents like clopidogrel or impact on CYP3A4. As such, a dedicated trial was conceptualized to study the use of Asundexian on top of antiplatelet therapy among patients with acute non-cardioembolic stroke, in an attempt to address an important unmet need. As a matter of fact, non-cardioembolic strokes represent over 75% of all ischemic strokes, and they have a recurrence rate of >5% per year with current guideline-recommended antiplatelet therapy. It would be important, therefore, to identify a targeted way to provide additional ischemic protection to these patients.
During the 2022 European Society of Cardiology Conference in Barcelona, Dr. Ashkan Shoamanesh presented the results of the PACIFIC-STROKE trial (NCT04304508). This multicenter, prospective, randomized, placebo-controlled, double-blind, dose-ranging study enrolled 1,808 patients within 48 hours from acute non-cardioembolic stroke and randomized them to Asundexian 50 mg (n=447), Asundexian 20 mg (n=450), Asundexian 10 mg (n=455), or placebo (n=456) on top of antiplatelet therapy. Patients were older (mean age 67 years), ~35% female, with about ~15% patients with prior strokes. Notably, the mean NIHSS score at randomization was 3±2, about 10% of patients also received thrombolysis at the time of their index stroke, and about 45% were treated with dual antiplatelet therapy.
With regard to safety outcomes, a pooled analysis of all three Asundexian doses to placebo found similar rates of major and clinically-relevant non-major ISTH bleeding, compared to placebo (3.9% vs 2.4%, HR 1.57, 90% CI 0.91-2.71), and similar rates of hemorrhagic transformation/infarct of the index stroke (30.3% with Asundexian 50 mg vs 32.8% with placebo). With regard to efficacy outcomes, the primary outcome was incidence of symptomatic ischemic stroke or covert brain infarct (detected by MRI) at 6 months from the index event. None of the three doses of Asundexian were found to significantly reduce the rate of the primary outcome, which were around 20% in all arms – including placebo. In secondary exploratory analyses, however, a dose-dependent reduction in the risk of recurrent symptomatic ischemic strokes and TIAs was highlighted particularly with the highest dose of Asundexian 50 mg, compared to placebo (5.4% vs 8.3%, HR 0.64, 90% CI 0.41-0.98), especially with patients with any extra-or intra-cranial atherosclerosis (HR 0.39, 90% CI 0.18-0.85).
In conclusion, selective XIa inhibitor Asundexian may innovate the field of oral anticoagulation by finally uncoupling hemostasis from thrombosis and potentially allowing similar protection from recurrent ischemic events without increasing bleeding risk among patients with non-cardioembolic strokes. Larger Phase 3 trial data, however, continue to be needed in order to have a more definitive understanding of the efficacy and safety of this novel agent, and whether it may confer additional protection from recurrent ischemic events among patients at high stroke risk.