Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Catalyst Biosciences, South San Francisco, California, United States of America.
PLoS One. 2020 Oct 28;15(10):e0240896. doi: 10.1371/journal.pone.0240896. eCollection 2020.
The rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy.
This study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs.
Two hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted.
There was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days.
The increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B.
因子 IX 的快速清除需要频繁进行静脉注射，才能为乙型血友病患者提供有效的预防治疗。历史上，皮下给药受到生物利用度和效价低的限制。Dalcinonacog alfa 采用合理的设计方法开发，是一种皮下给予的、新一代的凝血预防因子 IX 治疗药物。
本研究旨在研究皮下给予乙型血友病犬 Dalcinonacog alfa 的药代动力学、药效学和安全性特征。
两只乙型血友病犬接受了六天每日一次的皮下 Dalcinonacog alfa 单次剂量注射。在不同时间点测量因子 IX 抗原和活性、全血凝血时间和活化部分凝血活酶时间。此外，还进行了临床不良事件的安全性评估和实验室检查结果的评估。
每日皮下给予 Dalcinonacog alfa 可增加血浆因子 IX 抗原。乙型血友病犬皮下给予 Dalcinonacog alfa 的生物利用度为 10.3%。每日皮下给予 Dalcinonacog alfa 可在四天后达到足以纠正重度血友病至正常的稳定状态活性，从而表现出生物利用度、达峰时间和半衰期的效果。
Dalcinonacog alfa 的效力增加促进了乙型血友病患者皮下给药的 1/2 期研究的启动和完成。
