Safety and initial clinical efficacy of three dose levels of recombinant activated factor VII (rFVIIa): results of a Phase I study

The safety and efficacy of recombinant DNA-produced factor Vila (rFVIIa) was investigated in 15 haemophilic patients in non-bleeding states and during bleeding episodes (mild to moderate joint bleed). Patients with severe haemophilia A without inhibitors (n = 4), haemophilia A with inhibitors (n = 10), and haemophilia B with inhibitor (n = 1) received one or more doses of rFVIIa during 32 non-bleeding study episodes and 23 bleeding episodes. The study was an open, uncontrolled, dose-escalation (17.5 μg/kg, 35 μg/kg, 70 μg/kg) trial. Physical evaluation, laboratory assessment, and immunology testing were conducted at baseline, monthly for 3 months and every 3 months thereafter. The immediate safety of rFVIIa was assessed by monitoring of D-dimer, fibrinogen, platelet count, antithrombin III, thrombin-antithrombin complex, and α2-antiplasmin 5 min before and at multiple times throughout the following 24 h. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) values were also obtained. Pain, swelling, joint circumference, and range of motion were recorded before administration of the initial dose of rFVIIa in bleeding patients and at 6, 12, and 24 h. Haemostatic response to rFVIIa was observed in patients with severe VIII and IX deficiency with and without inhibitors. Therapy with rFVIIa was judged effective in 19 of the 22 evaluable bleeding episodes at one or more time points. The 35 μg/kg and 70 μg/kg doses were associated with higher response rates at 6 and 12 h compared to the 17.5 μg/kg dose level. A second dose of rFVIIa was administered in 20 of the 22 bleeding episodes. Marked variation in the interval between first and second dose (2–29 h) precluded systematic assessment of the optimal dose schedule. No evidence of systemic activation of the coagulation system following administration of rFVIIa was found by laboratory evaluation and clinical signs of thromboembolic events were not observed. Adverse events were mild and occurred infrequently. Changes in physical, laboratory, and immunological parameters attributable to rFVIIa were not observed. Shortening of PT and aPTT values from baseline following rFVIIa administration was observed in bleeding and non-bleeding patients. In conclusion, rFVIIa demonstrated positive initial safety and efficacy for treatment of haemorrhagic episodes in severe haemophiliacs with and without antibodies to factor VIII and IX.