Walsh Karin S, Mrakotsky Christine, Carcao Manuel, Chan Anthony K C, Nielsen Pernille Højlund, Holst Helle, Shapiro Kevin
Center for Neuroscience and Behavioral Medicine, Children's National Hospital and the George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Departments of Neurology & Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Res Pract Thromb Haemost. 2024 Feb 8;8(2):102341. doi: 10.1016/j.rpth.2024.102341. eCollection 2024 Feb.
Nonacog beta pegol (N9-GP) is an extended half-life PEGylated factor (F)IX product with established efficacy and short-term safety in persons with hemophilia B (HB). Long-term safety has been evaluated for polyethylene glycol exposure but not N9-GP.
To assess safety, neurodevelopmental, and efficacy outcomes of children with HB receiving N9-GP prophylaxis across 2 open-label, single-arm, phase 3 studies: paradigm5 (previously treated patients [PTPs]) and paradigm6 (previously untreated patients [PUPs]) in this interim analysis.
PTPs (aged ≤12 years) and PUPs (aged <6 years) with severe/moderate (≤2% FIX level) HB were recruited to N9-GP prophylaxis (40 IU/kg once weekly) in paradigm5 and paradigm6, respectively. Safety assessments included FIX inhibitor incidence, adverse events, neurocognitive and neurologic outcomes, polyethylene glycol concentration in plasma, and medical events of special interest. Efficacy endpoints included bleeds, N9-GP hemostatic effect, and FIX consumption.
Overall, 25 patients in paradigm5 and 50 patients in paradigm6 received N9-GP and were followed for up to 8 and 6 years, respectively. No inhibitory antibodies were reported in PTPs; 4 of the 50 PUPs developed inhibitors. Extensive evaluation revealed no neurocognitive or neurologic concerns with N9-GP use in children during the study period. Across both studies, few adverse events were reported as possibly related to N9-GP. High hemostatic response rate, high treatment adherence, low annualized bleeding rates, and no new target joints were reported.
These data provide the longest follow-up for an extended half-life FIX and confirm the long-term efficacy of N9-GP prophylaxis in children with HB with no observed neurocognitive or neurologic safety concerns.
非阿可凝血因子β聚乙二醇化产物（N9-GP）是一种半衰期延长的聚乙二醇化凝血因子IX产品，在B型血友病（HB）患者中已证实具有疗效和短期安全性。已对聚乙二醇暴露的长期安全性进行了评估，但未评估N9-GP的长期安全性。
在这项中期分析中，通过两项开放标签、单臂、3期研究——paradigm5（既往接受治疗的患者[PTPs]）和paradigm6（既往未接受治疗的患者[PUPs]），评估接受N9-GP预防治疗的HB儿童的安全性、神经发育和疗效结果。
分别将重度/中度（FIX水平≤2%）HB的PTPs（年龄≤12岁）和PUPs（年龄<6岁）纳入paradigm5和paradigm6的N9-GP预防治疗（每周一次，40 IU/kg）。安全性评估包括FIX抑制剂发生率、不良事件、神经认知和神经学结果、血浆中聚乙二醇浓度以及特别关注的医学事件。疗效终点包括出血、N9-GP的止血效果和FIX消耗量。
总体而言，paradigm5中的25例患者和paradigm6中的50例患者接受了N9-GP治疗，分别随访了长达8年和6年。PTPs中未报告抑制性抗体；50例PUPs中有4例产生了抑制剂。广泛评估显示，在研究期间，儿童使用N9-GP未出现神经认知或神经学问题。在两项研究中，报告的不良事件很少被认为可能与N9-GP有关。报告了高止血反应率、高治疗依从性、低年化出血率，且无新的靶关节。
这些数据提供了对半衰期延长的FIX最长时间的随访，并证实了N9-GP预防治疗对HB儿童的长期疗效，未观察到神经认知或神经学安全性问题。
