Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A

Abstract

Current management of hemophilia A includes prophylaxis with factor VIII (FVIII) replacement every 2 to 3 days. BAX 855, Baxalta's pegylated full-length recombinant FVIII (rFVIII), was designed to increase half-life and, thus, reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy. BAX 855 was evaluated in previously treated patients with severe hemophilia A who were aged 12 to 65 years. A phase 1 study compared the pharmacokinetic (PK) profile of BAX 855 with that of licensed rFVIII (Advate). In a pivotal study, the annualized bleeding rate (ABR), PK parameters, and efficacy of bleeding treatment were assessed. In the phase 1 study, the mean half-life (T1/2) and the mean residence time of BAX 855 compared with Advate were 1.4- to 1.5-fold higher. These results were confirmed in the pivotal study. The pivotal study met its primary endpoint: Prophylaxis with BAX 855 resulted in an ABR that was significantly lower than half the ABR of on-demand treatment (P < .0001). The median ABR was 1.9, and 39.6% of compliant subjects had no bleeding episodes during prophylaxis, whereas subjects treated on-demand had a median ABR of 41.5. BAX 855 was also efficacious for the treatment of bleeding episodes, with 95.9% of bleeding episodes treated with 1 to 2 infusions and 96.1% having efficacy ratings of excellent/good. No FVIII inhibitory antibodies or safety signals were identified. These studies provide evidence that BAX 855 was safe and efficacious for on-demand treatment and prophylaxis administered twice weekly in patients with hemophilia A. The trials were registered at www.clinicaltrials.gov as #NCT01736475 and #NCT01599819.

Figure 1

Both clinical studies were open label with no randomization. In the phase 1 study (A), the sequence of treatment was Advate first, followed by BAX 855 for each subject in each cohort. Nine subjects in the 30 IU/kg group were treated first. After review of the data from the first cohort and approval by the Data Monitoring Committee, treatment of 10 subjects in the 60 IU/kg group commenced. Only 1 treated subject was excluded from the PK analysis set as a result of a bleeding episode within 4 days of infusion. In the pivotal study (B), treatment assignment depended on the subjects’ prior treatment: Subjects previously receiving prophylaxis were assigned to the prophylaxis group. The first 17 subjects who previously received on-demand treatment were assigned to the on-demand group, then additional subjects were assigned to the prophylaxis arm. The PK subset comprised 26 subjects in the prophylaxis group. Twelve subjects discontinued during prophylaxis: 1 for a surgical procedure, 1 because of screen failure, 2 because of discontinuation by the subject, 4 because of an adverse event, and 4 for protocol violation.

Figure 2

In a descriptive analysis of 118 subjects in the PPAS, the median (Q1; Q3) and mean (SD) ABRs were computed for the prophylactic group vs the on-demand group, for all, joint and spontaneous bleeding episodes.

Figure 3

Mean annualized bleeding rates (ABRs) in subjects who received prophylactic treatment with BAX 855 are depicted by target joint status at screening. There were 101 subjects in the PPAS, including 69 subjects with no target joints at screening and 32 subjects with target joints at screening. Median ABR values are also presented.

Figure 4

The 1-stage clotting assay data shown represent median (Q1; Q3) FVIII plasma levels and the nominal sampling times as indicated on the linear x axis. BAX 855 (dashed gray line) demonstrated an extended half-life compared with Advate (solid black line). The PK assessments shown were conducted in 26 subjects at their first exposure to BAX 855.

Figure 5

Scatterplots and Spearman rank correlation analysis of T_1/2 are displayed. The T_1/2 of BAX 855 was positively correlated to preinfusion VWF antigen plasma concentrations (A) and negatively correlated with ABR (B). The T_1/2 values for these analyses were derived from PK assessments conducted in 26 subjects at their first exposure to BAX 855, using the 1-stage clotting assay. The circles represent individual subject values. An apparent outlier appears in A for a subject with a very low T_1/2 and a high ABR; it is of note that no inhibitory antibodies to FVIII were detected in this subject.