A specific FX activator for bleeding treatment in hemophilia with inhibitors: multicenter, open-label, phase 1/2...

Bemiltenase alfa, a factor X (FX) activator derived from Daboia russelii siamensis venom, was developed as a hemostatic agent for hemophilia A and B with inhibitors (HAwI and HBwI). We conducted 2 consecutives multicenter, open-label clinical trials. The phase 1b/2a study assessed the safety, hemostatic efficacy, and pharmacokinetic/pharmacodynamic characteristics of bemiltenase alfa at a dose of 0.1 U/kg. The phase 2b study further evaluated the safety and efficacy at a dose of 0.1 U/kg. Primary efficacy end points encompassed the effective hemostasis rate, safety assessment, and antidrug antibody (ADA) development. There were 6 participants enrolled in the phase 1b study, 20 in phase 2a, and 25 in phase 2b. Patients received bemiltenase alfa for bleeding episodes in the phase 2a and 2b studies. In phase 2a, the effective hemostasis rate was 94.1% (95% confidence interval [CI], 88.7-97.4). Phase 2b showed a rate of 81.9% (95% CI, 71.0-92.9). Most adverse events were mild with grade 1 severity, with no serious events. ADA was detected in 5 patients, but no impact on efficacy and safety was found. Pharmacokinetic findings showed repeated doses of bemiltenase alfa resulted in progressive drug concentration, as indicated by the accumulation ratio index. Pharmacodynamic results indicated a reduction in activated partial thromboplastin time and an increase in thrombin generation peak. Furthermore, a mild decline in FX activity was observed postadministration. The study demonstrates FX activation as a novel hemostatic strategy, with snake venom-derived bemiltenase alfa showing promising safety and efficacy for treating bleeding episodes in patients with HAwI and HBwI. These trials were registered at www.clinicaltrials.gov as #NCT05027230 and #NCT06289166.