Oral FXIa inhibitor reduces stroke recurrence without increasing major bleeding events

The oral factor XIa (FXIa) inhibitor asundexian scores high for secondary prevention in patients with non-cardioembolic stroke or high-risk transient ischaemic attack (TIA) who are receiving standard antiplatelet therapy, having met its primary efficacy and safety endpoints in the phase III OCEANIC-STROKE trial.

Compared with placebo, asundexian was associated with a 26-percent reduction in the incidence of ischaemic stroke over 780 days of follow-up (6.2 percent vs 8.4 percent; cause-specific hazard ratio [csHR], 0.74, 95 percent confidence interval [CI], 0.65–0.84; p<0.001), reported principal investigator Prof Mike Sharma from McMaster University and the Population Health Research Institute in Hamilton, Ontario, Canada. [ISC 2026, abstract LB9]

“The difference between the treatment arms began early and continued throughout the treatment,” Sharma said. He added that the beneficial effect of asundexian on ischaemic stroke was consistent across subgroups, including those defined by age, sex, geographic regions, race, risk factors of stroke (eg, hypertension and diabetes), and history of stroke/TIA prior to index event.

With regard to the primary safety event, the incidence of major bleeding (defined according to the International Society on Thrombosis and Haemostasis [ISTH] criteria) did not significantly differ between the asundexian and placebo arms (1.9 percent vs 1.7 percent; csHR, 1.10, 95 percent CI, 0.85–1.44; p=0.46).  

A big win

Asundexian is a small-molecule direct oral inhibitor of FXIa. What makes FXIa an attractive drug target, according to Sharma, is its “ability to uncouple haemostasis from thrombosis.”

Commenting on the trial, American Heart Association Member Dr Braydon Dymm from Charleston Area Medical Center, Charleston, West Virginia, US, expressed his enthusiasm for asundexian and the impact it could have on reducing stroke risk for his patients.

“The biggest takeaway for me is that we have another option to prevent strokes, and this is a big win… [The drug] gives patients the opportunity to have less risk of a stroke going forward, without another risk of haemorrhage, which is really important,” said Dymm, who was not involved in the trial.

“We have not had a big win in a while, so everyone’s really excited about this,” he added.

OCEANIC-STROKE

Conducted at 702 sites across 37 countries and regions, OCEANIC-STROKE included 12,327 patients (mean age 68 years, 34 percent women) who had a history of atherosclerosis or evidence of plaque or nonlacunar stroke on imaging and were on antiplatelet therapy (63 percent were on dual antiplatelet therapy). Of these patients, 95 percent had an acute non-cardioembolic stroke (NIHSS score of ≤15) and 5 percent had a high-risk TIA (ABCD² score of 6 or 7).

A total of 27.4 percent of patients underwent IV thrombolysis and/or endovascular thrombectomy for acute treatment. The most common TOAST stroke subtype was large-artery atherosclerosis (41 percent), followed by stroke of undetermined aetiology (29 percent) and small-vessel occlusion (22 percent). About one in five patients (22 percent) had a prior stroke/TIA. Median NIHSS score at baseline was 2, with around 30 percent having a score of >3.

Within 72 h of the index event, the patients were randomly assigned to receive asundexian 50 mg once daily (n=6,162) or matching placebo (n=6,165). Treatment period lasted between 3 and 31 months, after which there was a common end-of-treatment safety follow-up period of 2 weeks.

The asundexian arm showed a significant reduction in the incidence of secondary efficacy events, including all strokes (6.6 percent vs 8.8 percent; csHR, 0.74, 95 percent CI, 0.65–0.84; p<0.001), cardiovascular death, myocardial infarction (MI), or stroke (9.2 percent vs 11.1 percent; csHR, 0.83, 95 percent CI, 0.74–0.92; p<0.001), and all-cause mortality, MI, or stroke (10.5 percent vs 12.3 percent; csHR, 0.85, 95 percent CI, 0.77–0.95; p=0.003) relative to the placebo arm.

Disabling/fatal stroke was also less common in the asundexian than the placebo arm (2.1 percent vs 3 percent; csHR, 0.69, 95 percent CI, 0.55–0.87), as was ischaemic stroke in the first 90 days, although this difference did not reach statistical significance (3 percent vs 3.5 percent; csHR, 0.84, 95 percent CI, 0.69–1.02).

Results for the secondary safety events were also similar between the asundexian and placebo arms. These included ISTH major or clinically relevant nonmajor (CRNM) bleeding (5.5 percent vs 5 percent), CRNM bleeding (3.8 percent vs 3.4 percent), symptomatic intracranial haemorrhage (0.7 percent vs 0.6 percent), haemorrhagic stroke (0.2 percent vs 0.3 percent), fatal bleeding (0.2 percent vs 0.1 percent), and minor bleeding (7.8 percent vs 8.4 percent).

“Asundexian holds the potential to reduce the risk of a recurrent stroke over the long term without an increased safety risk. This is a major advance in our ability to prevent strokes in people at risk of stroke recurrence,” Sharma said.