Abstract A004: HRS-7450 for Acute Ischemic Stroke at 4.5 to 24 Hours: A Phase 1b Dose-Escalation Study of a Novel Plasminogen Activator with Neuroprotective Properties

Background: The current thrombolytics, including alteplase and tenecteplase, are underused due to high risk of symptomatic intracranial hemorrhage (sICH) and narrow time window. HRS-7450 is a novel thrombolytic that reduces the risk of sICH and provides neuroprotection via anti-inflammatory and antioxidant effects in vivo . This study assessed the safety and efficacy of HRS-7450 in stroke patients with onset time between 4.5 to 24 hours. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial (NCT06447415), patients who had a National Institutes of Health Stroke Scale (NIHSS) score of 3 to 25, anterior circulation artery occlusion, and a favorable penumbral profile (ischemic core 1.2, volume difference >10 mL) were eligible. Patients were randomized (2:1 for 1 mg/kg and 3 mg/kg; 1:1 for 6 mg/kg) to receive a single intravenous infusion of HRS-7450 or placebo. The primary endpoint was sICH incidence within 36 hours after treatment. Results: Among 63 treated patients (35 with HRS-7450; 28 with placebo), baseline characteristics were balanced (Table 1). No sICH events occurred within 36 hours in either group after treatment. No extracranial major bleeding events occurred in either group up to day 7. Two patients died (7.1%) in the placebo group by 90 days. No treatment-related adverse events led to death. Recanalization (arterial occlusive lesion score at 24 hours after treatment ≥2) rate was higher in the 1 mg/kg (16.7% 1/6) and 3 mg/kg (16.7% 1/6) HRS-7450 groups than that in the placebo group (11.1% 3/27). Major reperfusion (≥ 90% reduction in the penumbra) was rate also higher in the 1 mg/kg (33.3% 2/6) and 3 mg/kg (16.7% 1/6) HRS-7450 groups, compared with the placebo group (11.1% 3/27). Major neurologic improvement (NIHSS score 0–1 or an improvement of ≥8 points from baseline) occurred more frequently with 3 mg/kg HRS-7450 than with placebo (Table 2). Compared with placebo, 6 mg/kg HRS-7450 had higher rates of excellent functional outcome (mRS ≤1) at day 90 (40.9% 9/22 vs. 37.0% 10/27; difference: 3.9% 95% CI: –23.6, 31.3) and functional independence (mRS ≤2) at day 90 54.5%12/22 vs. 51.9%14/27; difference: 2.7% 95% CI: -25.4, 30.8) (Table 2). Conclusion: This study indicates HRS-7450, as a new dual-action thrombolytic, has a favorable safety profile—particularly in reducing ICH rate compared with other thrombolytics—and potential efficacy at doses of 1-6 mg/kg.