Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
Haemophilia. 2014 May;20 Suppl 4:29-35. doi: 10.1111/hae.12413.
The primary major issue in haemophilia treatment remains the development of inhibitors. Recently two novel bypassing products have been developed. First, a humanized bispecific antibody against FIXa and FX, termed hBS23, was produced utilizing these two molecules placed into a spatially appropriate position to mimic FVIIIa, and recently this mimetic activity and the pharmacokinetics of the original antibody were improved by engineering the charge properties of the variable region within the immunoglobulin. Using the new antibody, termed ACE910, a phase 1 study in 64 Japanese and Caucasian healthy adults was performed and data from this trial suggested that the product had medically acceptable safety and tolerability profiles. The other new bypassing agent is named MC710, and consists of a mixture of plasma-derived FVIIa and FX. Preclinical studies using in vitro and in vivo haemophilia B inhibitor monkey models indicated that the haemostatic effects of FVIIa and FX were enhanced by simultaneous administration. Results from phase I and II clinical studies suggested that MC710 had equal or greater pharmacokinetic (PK), pharmacodynamic (PD), efficacy and safety profiles than conventional bypassing agents in the treatment of joint bleeding in haemophilia patients with inhibitors. Another significant current issue in this context is the increased medical cost of conventional treatment due to the higher consumption of concentrates. Biosimilar products may offer advantages in these circumstances and may offer a less expensive alternative. Regulatory issues, however, together with acceptability of biosimilar materials and reimbursement policies as well as supply and demand incentives remain to be considered. Rare bleeding disorders (RBDs) have attracted less attention from the pharmaceutical industry than haemophilia or von Willebrand disease due to the limited number of patients involved. Many cases of this type have been treated, therefore, using fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs) which carry serious risks of infections, allergic reactions and fluid overload. Several specific plasma-derived or recombinant products including fibrinogen, FVIIa, FXI and FXIII have now become available, however, and a phase III clinical study of recombinant FXIIIa has recently been completed demonstrating safety and efficacy of substances of this nature.
血友病治疗的主要问题仍然是抑制剂的发展。最近开发了两种新型旁路产品。首先，一种针对 FIXa 和 FX 的人源化双特异性抗体，称为 hBS23，是利用这两种分子放置在适当的空间位置来模拟 FVIIIa 而产生的，最近通过工程改造免疫球蛋白可变区的电荷特性，提高了这种模拟活性和原始抗体的药代动力学。使用称为 ACE910 的新型抗体，在 64 名日本和高加索健康成年人中进行了 1 期研究，该试验的数据表明该产品具有可接受的安全性和耐受性。另一种新型旁路剂称为 MC710，由血浆衍生的 FVIIa 和 FX 混合物组成。使用体外和体内血友病 B 抑制剂猴模型的临床前研究表明，同时给予 FVIIa 和 FX 可增强止血作用。I 期和 II 期临床研究结果表明，MC710 在治疗有抑制剂的血友病患者关节出血方面，其药代动力学（PK）、药效学（PD）、疗效和安全性与传统旁路剂相当或更优。在这种情况下，另一个当前的重要问题是由于浓缩物消耗增加，常规治疗的医疗成本增加。生物类似物产品在这种情况下可能具有优势，并提供更便宜的替代方案。然而，监管问题、生物类似物材料的可接受性和报销政策以及供应和需求激励因素仍有待考虑。由于涉及的患者数量有限，与血友病或血管性血友病相比，罕见出血性疾病（RBD）较少受到制药行业的关注。因此，许多此类病例使用新鲜冷冻血浆（FFP）或凝血酶原复合物浓缩物（PCC）治疗，这些方法存在严重的感染、过敏反应和液体超负荷风险。然而，现在已经有几种特定的血浆衍生或重组产品，包括纤维蛋白原、FVIIa、FXI 和 FXIII，最近完成了重组 FXIIIa 的 III 期临床试验，证明了这种物质的安全性和有效性。
