Summary

A cohort of 79 previously untreated patients (PUPs) with moderateseverehaemophilia A (baseline Factor VIII 2%) were enrolled ina study to evaluate the safety, efficacy and immunogenicity of recombinantfactor VIII (r-FVIII, Recombinate ™). Blood samples wereobtained retrospectively from a total 55 PUPs who were investigatedfor the spectrum of FVIII gene mutations responsible for their haemophilia.FVIII gene inversion mutations were found in 27 (49%) patients.Two patients had partial gene deletions. The remaining 26 patientswere then screened for mutations in the FVIII gene coding region usingconformation sensitive gel electrophoresis. Point mutations wereidentified in 22 (85%) of the patients and 14 of these mutations werenovel. Study subjects were monitored for the development of FVIIIinhibitors throughout the study. A total of 23 of the 73 evaluablesubjects (including one subject with a low inhibitor titer at baseline)demonstrated an inhibitor on one or more occasions; 11 (15%) werepersistent. Inhibitors were detected in patients with partial genedeletions and inversions and in three of eight patients with missensemutations. No inhibitors were found in 11 patients with small insertionsor deletions resulting in an alteration of the protein translation readingframe (frameshift mutations). The results corroborate the observationthat mutation type is an important determinant of the propensity todevelop inhibitory anti-FVIII antibody.