The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors
Haemophilia : the official journal of the World Federation of Hemophilia. 2021
INTRODUCTION Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.
PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding
Haemophilia : the Official Journal of the World Federation of Hemophilia. 2017;23((6):):832-843
INTRODUCTION Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. AIM: Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). METHODS A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 mug/kg or 225 mug/kg initial doses with 75 mug/kg subsequent doses by schedule were administered until clinical response. RESULTS The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 mug/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 mug/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. CONCLUSION The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.
A comparison of recombinant thrombin to bovine thrombin as a hemostatic ancillary in patients undergoing peripheral arterial bypass and arteriovenous graft procedures
Journal of Vascular Surgery. 2008;47((6):):1266-73.
OBJECTIVES Recombinant thrombin (rThrombin) is a potential hemostatic alternative to bovine and human plasma-derived thrombin. This report examines the clinical results for the vascular surgery subgroup of patients enrolled in a larger double-blind, randomized, multicenter trial, which evaluated the comparative safety and efficacy of rThrombin and bovine plasma-derived thrombin (bThrombin) when used as adjuncts to surgical hemostasis. METHODS Data from the 164 vascular patients who underwent either a peripheral arterial bypass (PAB) or arteriovenous graft (AV) procedure are included in this analysis. Time to hemostasis at proximal and distal anastomotic sites at 1. 5-, 3-, 6-, and 10-minute intervals was determined by procedure (PAB or AV) and overall (PAB + AV). Baseline and day 29 immunologic sera were analyzed. The incidences of postoperative adverse events were compared between treatment groups. Categorical adverse events were evaluated in relation to thrombin product antibody formation. RESULTS Patients were randomized to either bThrombin (n = 82) or rThrombin (n = 82). Procedures included PAB (n = 88) and AV (n = 76). The bThrombin and rThrombin groups were well matched for demographics and baseline characteristics. A comparable incidence of anastomotic hemostasis was observed in both treatment groups at 10 minutes (94% bThrombin, 91% rThrombin). The incidence of hemostasis was lower at all time points for PAB procedures compared with AV procedures. In the PAB group, a significantly greater proportion of patients receiving rThrombin (55%) achieved hemostasis at 3 minutes compared with bThrombin (39%; P < . 05). Adverse event profiles and laboratory findings were similar between groups. No patients in the rThrombin group developed anti-rThrombin product antibodies at day 29, whereas 27% of patients in the bThrombin group developed antibodies to bThrombin product (P < . 0001). CONCLUSIONS rThrombin or bThrombin used as a hemostatic ancillary for anastomotic bleeding was equally effective at 10 minutes; however, rThrombin compared with bThrombin may provide a more rapid onset of hemostasis at 3 minutes in PAB procedures. Adverse events were similar between the two thrombins. In patients undergoing vascular surgery, both treatments were similarly well tolerated, although rThrombin demonstrated a superior immunogenicity profile.