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

Abstract

Key Points• BAX 855, a pegylated fulllength rFVIII with extended half-life, was highly effective in the prevention and treatment of bleeding events.• No subjects receiving BAX 855 developed FVIII inhibitory antibodies nor experienced unexpected adverse events.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 (T 1/2 ) 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 ondemand 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.

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

“…With 1 or 2 injections, efmoroctocog alfa controlled 97.7% of bleeding episodes, moroctocog alfa (Refacto) controlled 88% (of 677 bleeding events across 2 studies), and rurioctacog alfa pegol (Adynovate) controlled 95.9% of bleeding episodes. 6,7,19 Of the patients on prophylaxis with rVIII-SingleChain, 43% achieved a zero bleed rate during the study. This is comparable to individualized prophylaxis with efmoroctocog alfa (45%) and twice-weekly prophylaxis with rurioctacog alfa pegol (39.6%).…”

“…This is comparable to individualized prophylaxis with efmoroctocog alfa (45%) and twice-weekly prophylaxis with rurioctacog alfa pegol (39.6%). 6,7 Treatment with rVIII-SingleChain during all surgical procedures resulted in very good control of bleeding, with hemostatic efficacy rated as excellent in 94% of procedures. These results are in line with those reported recently for other novel rFVIII products.…”

“…6,15,17,18 rVIII-SingleChain was also analogous in terms of the numbers of injections needed to achieve hemostatic control; 93.5% of bleeds were controlled with 1 or 2 injections. With 1 or 2 injections, efmoroctocog alfa controlled 97.7% of bleeding episodes, moroctocog alfa (Refacto) controlled 88% (of 677 bleeding events across 2 studies), and rurioctacog alfa pegol (Adynovate) controlled 95.9% of bleeding episodes.…”

“…4,5 Recently, several new recombinant FVIII (rFVIII) products with extended half-life have completed phase 3 studies. 6,7 Although (glycol) pegylation and Fc fusion have prolonged the half-life of rFVIII, this extension is limited to only 1.5 to 1.7 times the normal half-life of endogenous FVIII. This is largely due to the dependence of FVIII on the half-life of von Willebrand factor (VWF) in the circulation.…”

Production of recombinant coagulation factors: Are humans the best host cells?

“…21 In the phase I clinical trial, the half-life of Adynovate Ò was 1.4-1.5 times-higher when compared with Advate Ò . 22 No clear increase in the incidence of FVIII inhibitor has been reported up to date for the rFVIII pegylated products. Indeed, pegylation has been shown to obliterate the immunogenicity of recombinant proteins after administration into animals, as compared with the non-pegylated counterparts.…”