Xyntha ® is effective and safe in previously treated patients with severe haemophilia A: Final results of a pivotal phase III study

Background:  Xyntha® (albumin‐free cell culture process) is a BDDrFVIII manufactured using an albumin‐free cell culture process and purified using a chemically synthesized peptide affinity ligand instead of a murine monoclonal antibody. A virus‐retaining filtration step has been included as an additional safety precaution during manufacture. The potency assignment of Xyntha® has been aligned to the one‐stage clotting assay, to permit routine clinical monitoring, as for other rFVIII products, without specialized standards. Objectives:  The primary objectives were to demonstrate inhibitor safety for Xyntha® and to demonstrate pharmacokinetic (PK) equivalence of Xyntha® with Advate® by standard bioequivalence criteria using the one‐stage assay. Other objectives included characterizing the PK of Xyntha® over time, and to determine efficacy of Xyntha® for prevention and treatment of bleeding episodes. Adverse events and consumption over time in patients treated with Xyntha® were also assessed. Methods:  PK profiles of Xyntha® and Advate® were assessed in a randomized double‐blind crossover fashion, in 30 previously treated patients (PTPs) (≥12 years; FVIII:C ≤1%) using the standard bioequivalence approach based upon the one‐stage clotting assay. Safety and efficacy of Xyntha® were also assessed in 94 PTPs (FVIII:C ≤2%), which included the PK subjects, during 6 months of open label routine prophylaxis supplemented with on‐demand treatment as necessary. A follow‐up PK assessment with Xyntha® was performed in PK subjects after 6 months. Summary:  Two patients had transient, low‐titre, clinically silent inhibitors (0.98 BU mL −1 and 1.21 BU mL −1 ), each detected by routine surveillance on a single occasion (both with negative follow‐up testing); this rate met prespecified safety goals. Corresponding ELISAs for FVIII antibodies were negative for both patients. No patient had a positive ELISA immune response to CHO cell protein or to the peptide affinity ligand used for Xyntha® purification. Pharmacokinetic equivalence of Xyntha® and Advate® was demonstrated ( n  = 30). Ratios of geometric least‐square means for K‐value, AUC t , AUC∞ were 100%, 89.8% and 88.0%, respectively, and associated 90% confidence intervals were within the bioequivalence window of 80–125%. Twenty‐five subjects had a baseline and 6 month follow‐up PK assessment with Xyntha®. Mean K ‐value and t 1/2 for Xyntha® were 2.23 (±0.39) IU dL −1 per IU kg −1 and 11.8 (±5.1) hours, respectively at baseline and the 6 month follow‐up PK profile was unchanged. Eighty‐nine of 94 patients accrued at least 50 Xyntha® exposure days. Median routine prophylaxis dose was 30.2 IU kg −1 . During routine prophylaxis, the median annualized bleed rate was 1.9 (mean 3.9, range 0–42.1), and 43 of 94 (45.7%) patients experienced no bleeding episodes. One hundred and eighty‐seven bleeding episodes were treated on‐demand with a median dose of 30.6 IU kg −1 and 92.5% resolved with one or two infusions. The overall adverse event (AE) profile was consistent with the AE profile of ReFacto and other rFVIII products. Conclusions:  Inhibitor safety results show no evidence of neoantigenicity and the AE profile demonstrates safety in PTPs with haemophilia A. Xyntha® is pharmacokinetically equivalent to Advate® based on one‐stage FVIII activity assessments, and Xyntha® PK is stable over 6 months of use. The product is effective in the prevention and treatment of bleeding episodes.