Saxena K, Lalezari S, Oldenburg J, Tseneklidou-Stoeter D, Beckmann H, Yoon M, Maas Enriquez M
Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
National Haemophilia Centre, Chaim Sheba Medical Centre, Tel-Hashomer, Israel.
Haemophilia. 2016 Sep;22(5):706-12. doi: 10.1111/hae.12952. Epub 2016 Jun 24.
BAY 81-8973 (Kovaltry(®) ) is a full-length, unmodified recombinant human factor VIII (FVIII) with the same amino acid sequence as sucrose-formulated recombinant FVIII and is produced using additional advanced manufacturing technologies.
To demonstrate efficacy and safety of BAY 81-8973 for treatment of bleeds and as prophylaxis based on two different potency assignments.
In LEOPOLD I (ClinicalTrials.gov identifier, NCT01029340), males aged 12-65 years with severe haemophilia A and ≥150 exposure days received BAY 81-8973 20-50 IU kg(-1) two or three times per week for 12 months. Potency was based on chromogenic substrate assay per European Pharmacopoeia and label adjusted to mimic one-stage assay potency. Patients were randomized for potency sequence and crossed over potency groups after 6 months, followed by an optional 12-month extension. Primary efficacy endpoint was annualized bleeding rate (ABR). Patients also received BAY 81-8973 during major surgeries.
Sixty-two patients received BAY 81-8973 prophylaxis and were included in the analysis. Median ABR was 1.0 (quartile 1, 0; quartile 3, 5.1) without clinically relevant differences between potency periods. Median ABR was similar for twice-weekly vs. three times-weekly dosing (1.0 vs. 2.0). Haemostasis was maintained during 12 major surgeries. Treatment-related adverse event (AE) incidence was ≤7% overall; no patient developed inhibitors. One patient with risk factors for cardiovascular disease developed a myocardial infarction.
BAY 81-8973 was efficacious in preventing and treating bleeding episodes, irrespective of the potency assignment method, with few treatment-related AEs. Caution should be used when treating older patients with cardiovascular risk factors.
BAY 81-8973（Kovaltry(®)）是一种全长、未修饰的重组人凝血因子VIII（FVIII），其氨基酸序列与蔗糖配方的重组FVIII相同，采用了额外的先进制造技术。
基于两种不同的效价赋值，证明BAY 81-8973治疗出血和预防出血的有效性和安全性。
在LEOPOLD I研究（ClinicalTrials.gov标识符，NCT01029340）中，年龄在12至65岁、患有严重甲型血友病且暴露天数≥150天的男性患者，每周接受2至3次BAY 81-8973，剂量为20-50 IU kg(-1)，持续12个月。效价基于欧洲药典的显色底物测定法，标签根据模拟一步法测定效价进行调整。患者被随机分配效价顺序，并在6个月后交叉效价组，随后进行为期12个月的可选延长治疗。主要疗效终点是年化出血率（ABR）。患者在大手术期间也接受BAY 81-8973治疗。
62例患者接受了BAY 81-8973预防治疗并纳入分析。中位ABR为1.0（四分位数1，0；四分位数3，5.1），效价期之间无临床相关差异。每周两次给药与每周三次给药的中位ABR相似（分别为1.0和2.0）。12例大手术期间均维持了止血效果。总体治疗相关不良事件（AE）发生率≤7%；无患者产生抑制剂。1例有心血管疾病危险因素的患者发生了心肌梗死。
无论效价赋值方法如何，BAY 81-8973在预防和治疗出血发作方面均有效，治疗相关AE较少。治疗有心血管危险因素的老年患者时应谨慎。
