An Open-Label Study of the Safety and Efficacy of Morotocog Alfa (AF-CC) in Previously Untreated Patients Aged <6 Years in Usual Care Settings

Background: Moroctocog alfa (AF-CC) (ReFacto AF), a purified recombinant B-domain deleted factor VIII (FVIII) protein, is indicated for the treatment and prophylaxis of bleeding events in patients (pts) with hemophilia A and is manufactured in the absence of human albumin and purified using an affinity chromatography purification process along with additional filtration. It replaced the predecessor product moroctocog alfa, which was manufactured with human serum album and utilized murine monoclonal antibody purification. Data in previously untreated patients aged <6 years using moroctocog alfa (AF-CC) are lacking.

Aims: To fulfill a European Medicines Agency requirement for post-authorization safety surveillance and risk management that moroctocog alfa (AF-CC) was acceptable in terms of efficacy and safety (including inhibitor development) in the usual care setting.

Methods: This was a nonrandomized, open-label study that enrolled male patients with severe hemophilia A (FVIII activity <1%) aged <6 years and previously untreated patients (PUP) with a FVIII replacement product. The study was approved by an ethics committee and parents/guardians of all patients provided informed consent. The primary endpoint was the development of clinically significant inhibitors. Secondary endpoints focused on efficacy including the annualized bleeding rate (ABR), incidence of less-than-expected therapeutic effect (LETE), response to first on-demand treatment for new bleeding events (4-point rating scale), number of infusions to treat new bleeding events, and FVIII recovery. Moroctocog alfa (AF-CC) was dosed in accordance with the local prescribing information. Blood samples to test for inhibitors were collected at the 10 - 15 exposure day (ED) and 50 ED visits and at least every 6 months through the final visit. Recovery was performed during the enrolment visit (ED1), ED 10-15 visit, and at the ED 50 visit. Thereafter, recovery studies were recommended by at the investigators' discretion.

Results: Twenty-three patients aged <6 years (mean age ± SD 1.0±1.09 years) participated for a median study duration of 476 days (min-max 92 - 1876 days). Dosing and frequency of dosing was at the discretion of the primary investigator in accordance with the moroctocog alfa (AF-CC) package insert. Clinically significant inhibitors were found in 5 (21.7%) patients with inhibitor detection overall in 8 (34.8%) patients. The aggregate ABR of all subjects on the study was 5.9±8.08. The percentage LETE was 0.0 and 0.1 for on-demand and prophylaxis settings, respectively. One infusion led to resolution of 88% of bleeding events and 66.4% of first infusions were rated as excellent or good. Overall, the mean number of infusions for resolution of a bleeding episode was 1.3±1.28. At ED1, recovery was 1.32 ± 0.654 IU/dL/IU/kg in subjects between the ages of 28 days to <24 months and 1.749 and 1.776 IU/dL/IU/kg in the 2 children aged greater than 2 yrs, 2.7 and 5.3 yrs respectively, and generally remained constant over the duration of the study.

Conclusions: The clinical inhibitor rate along with the overall safety and efficiacy of moroctocog alfa (AF-CC) is similar to its predecessor product supporting that the change in manufacturing did not alter the overall clinical benefit. These data also support the use of moroctocog alfa (AF-CC) for the treatment of previously untreated hemophilia A patients less than 6 years of age.