A specific FX activator for bleeding treatment in hemophilia with inhibitors: multicenter, open-label, phase I/II trials

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 two consecutives multicenter, open-label clinical trials. The phase Ib/IIa study assessed the safety, hemostatic efficacy, and pharmacokinetics/pharmacodynamics characteristics of bemiltenase alfa at a dose of 0.1U/kg. The phase IIb study further evaluated the safety and efficacy at a dose of 0.1U/kg. Primary efficacy endpoints encompassed the effective hemostasis rate, safety assessment and anti-drug antibodies (ADAs) development. There were six participants enrolled in phase Ib study, 20 in phase IIa and 25 in phase IIb study. Patients received bemiltenase alfa for bleeding episodes in phase IIa and IIb studies. In phase IIa, the effective hemostasis rates were 94.1% (95% CI: 88.7-97.4). Phase IIb showed an 81.9% rate (95% CI: 71.0-92.9). Most adverse events were mild with grade one in severity, with no serious events. ADA was detected in five patients, but no impact on efficacy and safety was found. Pharmacokinetics findings showed repeated doses of bemiltenase alfa resulted in progressive drug concentration, as indicated by the accumulation ratio index. Pharmacodynamics results indicated a reduction in activated partial thromboplastin time and an increase in thrombin generation peak. Additionally, a mild decline in FX activity was observed post-administration. 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 HAwI and HBwI patients. (clinicaltrials.gov: NCT05027230, NCT06289166).