Baxalta Innovations GmbH, a Member of the Takeda Group of Companies, Vienna, Austria.
Baxalta Innovations GmbH, a Member of the Takeda Group of Companies, Vienna, Austria
J Pharmacol Exp Ther. 2019 Oct;371(1):95-105. doi: 10.1124/jpet.119.260067. Epub 2019 Jul 31.
Extended half-life (EHL) factor therapies are needed to reduce the burden of prophylaxis and improve treatment adherence in patients with hemophilia. BAX 826 is a novel polysialylated full-length recombinant factor VIII [polysialyic acid (PSA) rFVIII] with improved pharmacokinetics (PK), prolonged pharmacology, and maintained safety attributes to enable longer-acting rFVIII therapy. In factor VIII (FVIII)-deficient hemophilic mice, PSArFVIII showed a substantially higher mean residence time (>2-fold) and exposure (>3-fold), and prolonged efficacy in tail-bleeding experiments (48 vs. 30 hours) compared with unmodified recombinant FVIII (rFVIII), as well as a potentially favorable immunogenicity profile. Reduced binding to a scavenger receptor (low-density lipoprotein receptor-related protein 1) and von Willebrand factor (VWF) as well as a largely VWF-independent circulation time in mice provide a rationale for prolonged BAX 826 activity. The significantly improved PK profile versus rFVIII was confirmed in cynomolgus monkeys [mean residence time: 23.4 vs. 10.1 hours; exposure (area under the curve from time 0 to infinity): 206 vs. 48.2 IU/ml⋅h] and is in line with results from rodent studies. Finally, safety and toxicity evaluations did not indicate increased thrombogenic potential, and repeated administration of BAX 826 to monkeys and rats was well tolerated. The favorable profile and mechanism of this novel experimental therapeutic demonstrated all of the requirements for an EHL-rFVIII candidate, and thus BAX 826 was entered into clinical assessment for the treatment of hemophilia A. SIGNIFICANCE STATEMENT: Prolongation of FVIII half-life aims to reduce the burden of prophylaxis and improve treatment outcomes in patients with hemophilia. This study shows that polysialylation of PSArFVIII resulted in prolongations of rFVIII circulation time and procoagulant activity, together with a favorable nonclinical safety profile of the experimental therapeutic.
需要延长半衰期（EHL）因子疗法，以减轻预防负担并提高血友病患者的治疗依从性。BAX 826 是一种新型的多聚唾液酸化全长重组凝血因子 VIII [多聚唾液酸（PSA）rFVIII]，具有改善的药代动力学（PK）、延长的药理学和维持的安全性特征，可实现更长效的 rFVIII 治疗。在缺乏凝血因子 VIII（FVIII）的血友病小鼠中，与未修饰的重组凝血因子 VIII（rFVIII）相比，PSArFVIII 表现出显著更高的平均停留时间（>2 倍）和暴露量（>3 倍），以及在尾部出血实验中的延长疗效（48 小时 vs. 30 小时），并且具有潜在有利的免疫原性特征。与 rFVIII 相比，其与清道夫受体（低密度脂蛋白受体相关蛋白 1）和血管性血友病因子（VWF）的结合减少，以及在小鼠中的 VWF 独立循环时间延长，为 BAX 826 活性的延长提供了依据。在食蟹猴中，与 rFVIII 相比，PK 特征得到了显著改善[平均停留时间：23.4 小时 vs. 10.1 小时；暴露量（从 0 到无穷大的曲线下面积）：206 IU/ml·h vs. 48.2 IU/ml·h]，与啮齿动物研究结果一致。最后，安全性和毒性评估并未表明增加血栓形成的潜力，并且 BAX 826 在猴子和大鼠中的重复给药也具有良好的耐受性。这种新型实验治疗的有利特征和机制满足了 EHL-rFVIII 候选药物的所有要求，因此 BAX 826 已进入用于治疗血友病 A 的临床评估。意义声明：延长 FVIII 半衰期旨在减轻预防负担并改善血友病患者的治疗结果。本研究表明，PSArFVIII 的多聚唾液酸化导致 rFVIII 循环时间和促凝血活性延长，同时具有实验治疗的有利非临床安全性特征。
