First FXIa Approval in Stroke Prevention Shifts Dual-Pathway Standard Despite AF Failure

Bayer's Asundexian Receives First-Ever FDA Approval for Secondary Stroke Prevention

Bayer announced that the U.S. Food and Drug Administration (FDA) has granted marketing authorization for asundexian, branded as Sunharbo®, 50 mg tablets. This oral, once-daily Factor XIa inhibitor is approved for use in combination with antiplatelet therapy to reduce the risk of secondary stroke in adults who have recently experienced a non-cardioembolic ischemic stroke or high-risk transient ischemic attack (TIA). This approval marks asundexian as the first FXIa inhibitor to be approved worldwide, based on positive data from the pivotal Phase III OCEANIC-STROKE study, which demonstrated a significant 26% reduction in ischemic stroke with a similar rate of major bleeding.

• First-in-Class Global Approval: Asundexian (Sunharbo®) has achieved a landmark regulatory milestone by becoming the first Factor XIa inhibitor approved globally, specifically by the U.S. FDA. This approval introduces a novel therapeutic class for secondary stroke prevention, addressing a critical unmet need in patients at high risk of recurrent cerebrovascular events. The drug's unique mechanism of action offers a new approach to antithrombotic therapy.
• Compelling Clinical Efficacy and Safety Profile: The FDA's decision is underpinned by robust data from the Phase III OCEANIC-STROKE study, which enrolled 12,327 participants. The study demonstrated that asundexian 50 mg, when added to antiplatelet therapy, significantly reduced the risk of ischemic stroke by 26% compared to antiplatelet therapy alone. Importantly, this efficacy was achieved with a safety profile comparable to placebo regarding ISTH major bleeding, highlighting a favorable benefit-risk balance.
• Addressing High Unmet Need in Stroke Survivors: Secondary stroke prevention is a major priority, as approximately one in five non-cardioembolic ischemic stroke survivors experience another stroke within five years, often with more severe outcomes. Asundexian provides a crucial new option for this vulnerable patient population, with consistent treatment effects observed across diverse subgroups, reinforcing its potential for broad clinical applicability in post-stroke care.

Asundexian's Safety and Tolerability Profile Supporting Approval

In atrial fibrillation, asundexian showed lower bleeding than direct oral anticoagulants without an increase in overall adverse events. In PACIFIC-AF, ratios of incidence proportions for the primary endpoint of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events), with asundexian 20 mg resulting in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations and asundexian 50 mg resulting in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. In OCEANIC-AF, major bleeding occurred in 17 patients (0.2%) who received asundexian 50 mg once daily and in 53 (0.7%) who received apixaban (hazard ratio, 0.32; 95% CI, 0.18 to 0.55), and the incidence of any adverse event appeared to be similar in the two groups. A pooled analysis of phase II trials in atrial fibrillation (n = 755) reported major/CRNM events of 3 of 249; incidence rate [IR] per 100 patient-years 5.47 for asundexian 20 mg vs 1 of 254 [IR: not calculable] for asundexian 50 mg vs 6 of 250 [IR: 11.10] for apixaban, and all bleeding of 12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56].

In acute non-cardioembolic ischaemic stroke, asundexian added to antiplatelet therapy did not increase bleeding compared with placebo, including in patients with hemorrhage-prone small-vessel disease. In PACIFIC-Stroke, the primary safety outcome of major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91-2·71]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]), with most common sites of major/CRNM bleeding with asundexian reported as gastrointestinal, respiratory, urogenital, and skin, and no significant association between asundexian exposure and major/CRNM bleeding. In PACIFIC-STROKE participants with baseline MRIs, new microbleeds occurred in 10.2% of patients assigned to any asundexian dose and 10.5% of patients assigned to placebo (OR 0.96, 95%CI 0.66-1.41), with no interactions between microbleeds and treatment assignment for ischemic stroke/TIA, ICrH, all-cause mortality, hemorrhagic transformation, and new microbleeds (p for interaction>0.05).

In recent acute myocardial infarction on dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor, asundexian produced dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition, without a significant increase in bleeding. Over a median follow-up of 368 days, the main safety outcome of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71-1.35]). Across cardiovascular conditions, a meta-analysis of four RCTs reported ISTH major or clinically relevant non-major bleeding showed a non-significant trend toward lower risk with Asundexian (RR 0.63, 95% CI 0.21-1.91, P = .41; I² = 77%) and adverse events (RR 1.00, 95% CI 0.95-1.04, P = .85) were comparable between groups.

The Persistent Burden of Secondary Stroke and Unmet Needs

The risk of secondary events following noncardioembolic ischemic stroke or transient ischemic attack (TIA) is high and especially pronounced in the first days and weeks following the initial event. Monotherapy with antiplatelet agents is only modestly effective in secondary prevention of ischemic stroke (IS), particularly in patients with multiple risk factors such as cervicocephalic arterial stenosis, diabetes, and hypertension.

• Narrow efficacy window for dual antiplatelet therapy (DAPT): Compared with monotherapy, DAPT with clopidogrel and aspirin was associated with significantly lower rates of any stroke (risk ratio [RR] 0.80; 95% confidence interval [CI] 0.72-0.89) and ischemic stroke (RR 0.75; 95% CI 0.66-0.85). Short-duration DAPT (≤ 1 month) started during the early acute ischemic phase was associated with less bleeding than longer DAPT and greater reduction of recurrent strokes compared with monotherapy, whereas long DAPT and DAPT started later after the index event (≥ 1 month) were associated with similar rates of any stroke compared with monotherapy.

• Increased bleeding with intensified or prolonged DAPT: Although significant increases in intracranial bleeding (RR 1.55; 95% CI 1.20-2.01) and major bleeding (RR 1.90; 95% CI 1.33-2.72) were associated with DAPT, especially with long-term follow-up, the number needed to harm was 258 and 113, respectively. In the POINT trial, major hemorrhage occurred in 21 patients (0.9%) receiving clopidogrel plus aspirin and 6 (0.2%) in the aspirin alone group (hazard ratio, 3.57; 95% CI, 1.44-8.85; P = .003; number needed to harm, 159). Dual therapy is associated with an increased risk of major bleeding, particularly when the treatment is extended for greater than 30 days.

• Higher hemorrhagic burden with alternative DAPT regimens and genetic variability: Aspirin plus ticagrelor is superior to aspirin monotherapy for the prevention of recurrent ischemic stroke, although this combination is associated with a higher risk of hemorrhagic complications when compared to other dual antiplatelet regimens. Among patients who carry CYP2C19 genetic polymorphisms associated with a slow bioactivation of clopidogrel, short-term treatment with aspirin plus ticagrelor is superior to aspirin plus clopidogrel for the reduction of recurrent stroke; however, the use of ticagrelor is associated with a higher risk of any bleeding. Resistance to ASA and clopidogrel poses an incremental risk of deleterious cardiovascular events and stroke.

• Antiplatelet failure and paucity of data to guide next steps: Patients who develop ischemic stroke despite taking antiplatelet drugs represent a considerable proportion of stroke hospital admissions, and there have been no clinical trials to test whether increasing the dose or switching antiplatelet agents reduces the risk for subsequent events. Therapeutic failure may be due to either poor adherence to treatment, associated co-morbid conditions and diminished antiplatelet effects (resistance to treatment).

• Tolerability, persistence and treatment gaps: Bleeding is potentially the most significant antiplatelet-associated side effect, and bleeding risk with aspirin monotherapy is dose dependent, while preventive efficacy appears similar at all doses above 50 mg/day. The addition of extended-release dipyridamole (ER-DP) to aspirin does not increase bleeding risk, although ER-DP is associated with risk of headache, which may be severe. In the United Kingdom, 13.9% (1292) might not receive antithrombotic therapy within 90 days of hospital discharge, and at 1-year post-hospitalization, 36.9, 43.3, and 35.1% of those receiving clopidogrel, aspirin, and clopidogrel + aspirin dual antiplatelet therapy discontinued them, respectively, and of the patients initiating DAPT, 62.3% switched to single antiplatelet therapy.

Decoding the Pivotal OCEANIC-STROKE Trial Design and Endpoints

Secondary prevention trials in recent ischemic stroke or high-risk TIA evaluate single and dual antiplatelet strategies across acute and extended windows. Key designs compare ticagrelor versus aspirin, genotype-guided ticagrelor or clopidogrel with aspirin, and cilostazol-based dual therapy versus monotherapy.

The Evolving FXIa Inhibitor Landscape Beyond Asundexian

Milvexian and abelacimab are Factor XI/XIa inhibitors under investigation for prevention of thrombo-embolic events in patients with atrial fibrillation. Milvexian is an oral, small-molecule inhibitor of factor (F) XIa evaluated in the Phase 3 LIBREXIA program, while abelacimab was compared with rivaroxaban in AZALEA-TIMI 71.