BDDrFVIII [moroctocog alfa (AF-CC), Xyntha] for Surgical Hemostasis in Patients with Hemophilia A: Results from a Pivotal Study.

BDDrFVIII [moroctocog alfa (AF-CC), Xyntha] is manufactured by a modified process designed to enhance viral safety relative to currently licensed ReFacto. Efficacy and safety of BDDrFVIII for management of surgical hemostasis has been evaluated in a completed, open-label study of previously treated patients, age 12 years or older, with severe hemophilia A (FVIII:C ≤ 2%) undergoing elective major surgery. BDDrFVIII was to be administered for at least 6 postoperative days by bolus injection (BI) or by continuous infusion (CI) at the investigator’s discretion, and up to a maximum of 6 weeks following surgery. Twenty-two (22) patients treated by BI received a median of 42 infusions per patient (range 16 to 72) for a median total dose of 85,008 IU per patient (range 36,500 to 231,044) over a median 33 total exposure days (EDs) per patient (range 15 to 40). Eight (8) patients designated for treatment by CI, including 1 patient who received 1 dose for PK assessment only, received a median total dose of 74,409 IU per patient (range 4,405 to 96,251) over a median 29 total EDs per patient (range 1 to 37). Of the 30 patients treated with BDDrFVIII, 29 patients underwent major surgery and completed the study; 25 were evaluable for hemostatic efficacy. These 25 patients had the following procedures: 11 total knee replacements, 5 synovectomies, 1 left ulnar nerve transposition/release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 stapes replacement, 1 ankle arthrodesis, 1 pseudotumor excision, 1 hip arthroplasty, 1 hip arthroplasty revision, and 1 revision/debridement of the knee after total knee replacement. Investigator ratings for surgical hemostasis efficacy at the end of surgery, the primary efficacy endpoint, were 72% excellent (18/25) and 28% good (7/25). At the end of the initial postoperative period, postsurgical day 7, the surgical hemostasis efficacy ratings were 92% excellent (23/25) and 8% good (2/25). Blood loss was assessed for the intra- and post-operative periods. Twenty-four (24) efficacy-evaluable patients had intraoperative blood loss; for all subjects, blood loss was rated normal. Thirteen (13) efficacy-evaluable patients had postoperative blood loss; in 10 cases the postoperative blood loss was rated normal, 1 case was rated abnormal due to hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood loss after hip replacement surgery and 1 after an elbow synovectomy, but the blood loss could not be quantitated by the investigator. Nine (9) of 25 efficacy-evaluable patients were prospectively predicted to require transfusions during the intraoperative period; of those 9 only 1 was transfused. Of the other 16 efficacy-evaluable patients, 2 had intraoperative transfusions of packed red blood cells (PRBCs), for both, blood loss was reported as normal. During the postoperative period 4 efficacy-evaluable patients received transfusions, including 1 patient who received PRBCs following excessive hemorrhage associated with trauma to the epigastric artery during surgery. All 30 patients were assessed for safety. Treatment emergent adverse events (AEs) reported in 3 or more patients were fever, pain, infection, headache, flu syndrome, hypertension, nausea, anemia, thrombocythemia, peripheral edema, arthralgia, upper respiratory infection, and local reaction to procedure. The general AE profile was considered consistent with AEs reported in the surgical setting. Three (3) AEs were reported as related to BDDrFVIII. There was an AE of hemorrhage at the operative site during the postoperative period in 1 patient, and clinically silent low titer inhibitors were detected in two patients during routine protocol-specified surveillance testing. One inhibitor was detected pre-operatively (maximum observed titer 1.51 BU/mL) and the other inhibitor (0.63 BU/mL) was detected only on the patient’s final study visit with corresponding negative ELISA tests for anti- Factor VIII antibodies. This study has demonstrated that BDDrFVIII is effective and safe when used for surgical prophylaxis in hemophilia A patients undergoing major surgery.