Results of clot waveform analysis and thrombin generation test for a plasma‐derived factor VIIa and X mixture (MC710) in haemophilia patients with inhibitors—phase I trial: 2nd report

We reported the results of a clinical pharmacological study of MC710 (a mixture of plasma‐derived FVIIa and FX) in haemophilia patients with inhibitors during a non‐haemorrhagic state. This report provides the results of a clot waveform analysis (CWA) and thrombin generation test (TGT) using blood samples obtained in this study. CWA and TGT were conducted using blood samples obtained from a pharmacokinetic and pharmacodynamic study in which MC710 (five dose rates: 20, 40, 80, 100 and 120 μg kg^?1) was compared with NovoSeven (120 μg kg^?1) and FEIBA (two dose rates: 50 and 75 U kg^?1) as control drugs in 11 haemophilia patients with inhibitors without haemorrhagic symptoms. CWA showed that MC710 provided significantly greater improvement than the control drugs in activated partial thromboplastin time (APTT) at 80 μg kg^?1; maximum clot velocity and maximum clot acceleration were more enhanced by MC710 than by control drugs. TGT revealed that MC710 significantly shortened the initiation time of thrombin generation in comparison to FEIBA and induced greater thrombin generation potency than NovoSeven. It was not clear whether or not MC710 caused significant dose‐dependent changes in the two measurements; however, differences between MC710 and the control drugs were clarified. MC710 was confirmed to have superior coagulation activity and thrombin productivity and is expected to have superior bypassing activity.     

Clinical pharmacological study of a plasma‐derived factor VIIa and factor X mixture (MC710) in haemophilia patients with inhibitors – Phase I trial

Summary. MC710, a combined product of plasma‐derived activated factor VII (FVIIa) and factor X (FX) at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In this study, pharmacokinetic (PK), pharmacodynamic (PD) parameters and safety of single doses of MC710 were investigated in 11 male haemophilia patients with inhibitors in a non‐bleeding state. This was a multi‐centre, open‐labelled, non‐randomized, active controlled crossover, dose‐escalation study of five doses (20–120 μg kg⁻¹ of FVIIa) with re‐administration of different MC710 dosages to the same subjects. The active controls were NovoSeven (120 μg kg⁻¹) and/or FEIBA (50 and 75 U kg⁻¹) which were used to compare PD parameters. The area under the curve (AUC) and maximum plasma concentration (C_max) of MC710 active ingredients increased dose‐dependently within the range of 20 and 120 μg kg⁻¹. After administration of MC710, activated partial thromboplastin time (APTT) was dose‐dependently improved and prothrombin time (PT) was shortened to approximately 6 s at 10 min, and APTT improvement and PT shortening effects were maintained until 12 h after administration of MC710 at all doses. No serious or severe adverse event was observed after administration of MC710; furthermore, several diagnostic marker values and those changes did not indicate any signs of disseminated intravascular coagulation (DIC). These results suggest that MC710 would have haemostatic potential equal to or greater than NovoSeven and FEIBA and was be tolerable when given at doses up to 120 μg kg⁻¹.     

A Phase II clinical trial of a mixture of plasma‐derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: haemostatic efficacy,safety and pharmacokinetics/pharmacodynamics

MC710, a mixture of plasma‐derived activated factor VII and factor X at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In a Phase II trial, we evaluated the haemostatic efficacy and safety of single doses of MC710, and investigated pharmacokinetic and pharmacodynamic parameters in nine joint bleeding episodes in six male haemophilia patients with inhibitors. This trial was a multi‐centre, open‐label, non‐randomized study of two doses (60 and 120 μg kg^?1 as FVIIa dose), allowing the re‐administration of different MC710 dosages to the same subjects. Haemostatic efficacy was assessed by evaluating reduction in pain and swelling, as well as increase in range of motion in a bleeding joint. The results of the study showed that in nine bleeding episodes, seven treatments were rated as ‘excellent’ or ‘effective’ according to investigator's rating system of efficacy at 8 h after administration. No serious or severe adverse events were observed after administration; furthermore, measurement of several diagnostic markers revealed no signs or symptoms of disseminated intravascular coagulation (DIC). The haemostatic potential of MC710 was confirmed at doses of 60 and 120 μg kg^?1 in this trial. MC710 is thus expected to be a safe and efficacious novel bypassing agent for controlling bleeding in haemophilia patients with inhibitors.