Ivens Inge A, Banczyk David, Gutberlet Katrin, Jackman Shawna, Vauléon Stéphanie, Frisk Anna-Lena
1 Bayer HealthCare, San Francisco, CA, USA.
2 Bayer AG, Berlin, Germany.
Toxicol Pathol. 2019 Jul;47(5):585-597. doi: 10.1177/0192623319852300. Epub 2019 May 27.
BAY 94-9027 (Jivi) is a site-specifically PEGylated human B-domain-deleted (BDD) recombinant factor VIII (FVIII), with a 60 kDa branched PEG molecule attached. The nonclinical safety of BAY 94-9027 was evaluated in a toxicology program that included 2 weeks intravenous (IV) toxicity studies in rats and rabbits, a juvenile toxicity study in rats as well as a 26-week chronic study in rats. Doses of 75, 750, or 2250 IU/kg given every other day for 2 weeks did not elicit any findings related to BAY 94-9027. Specifically, no thrombus formation or histological changes such as cellular vacuolation were seen. In the chronic toxicity study, 40, 400, and 1200 IU/kg of BAY 94-9027 given twice weekly did not induce adverse effects related to BAY 94-9027, and no tissue vacuolation was observed. There was no PEG detected in choroid plexus or other areas of the brain, cerebrospinal fluid or in spleen or kidneys. These results were supported by toxicity studies in rats and rabbits treated with PEG 60 kDa attached to the maleimide linker (PEG-60-Mal-Cys). No findings related to PEG-60-Mal-Cys were seen. These results demonstrate the safety of BAY 94-9027 for long-term use.
BAY 94-9027（Jivi）是一种位点特异性聚乙二醇化的人B结构域缺失（BDD）重组因子VIII（FVIII），连接有一个60 kDa的分支聚乙二醇分子。在一项毒理学研究中评估了BAY 94-9027的非临床安全性，该研究包括对大鼠和兔子进行的为期2周的静脉内（IV）毒性研究、对大鼠进行的幼年毒性研究以及对大鼠进行的为期26周的慢性研究。每隔一天给予75、750或2250 IU/kg的剂量，持续2周，未发现任何与BAY 94-9027相关的结果。具体而言，未观察到血栓形成或组织学变化，如细胞空泡化。在慢性毒性研究中，每周两次给予40、400和1200 IU/kg的BAY 94-9027未诱发与BAY 94-9027相关的不良反应，也未观察到组织空泡化。在脉络丛或大脑的其他区域、脑脊液、脾脏或肾脏中未检测到聚乙二醇。用连接有马来酰亚胺接头的60 kDa聚乙二醇（PEG-60-Mal-Cys）处理的大鼠和兔子的毒性研究支持了这些结果。未发现与PEG-60-Mal-Cys相关的结果。这些结果证明了BAY 94-9027长期使用时的安全性。
