Konkle Barbara A, Walsh Christopher E, Escobar Miguel A, Josephson Neil C, Young Guy, von Drygalski Annette, McPhee Scott W J, Samulski R Jude, Bilic Ivan, de la Rosa Maurus, Reipert Birgit M, Rottensteiner Hanspeter, Scheiflinger Friedrich, Chapin John C, Ewenstein Bruce, Monahan Paul E
BloodWorks Northwest, Seattle, WA.
Division of Hematology, University of Washington School of Medicine, Seattle, WA.
Blood. 2021 Feb 11;137(6):763-774. doi: 10.1182/blood.2019004625.
Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)-based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 × 1011; 1.0 × 1012; or 3.0 × 1012 vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua-directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of ∼20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. This trial was registered at www.clinicaltrials.gov as #NCT01687608.
基因疗法有潜力通过将功能性人类F9基因导入肝细胞，来维持B型血友病患者治疗性凝血因子IX（FIX）的水平。这项1/2期开放标签剂量递增研究，在B型血友病患者中调查了BAX 335（AskBio009，AAV8.sc-TTR-FIXR338Lopt），一种基于8型腺相关病毒（AAV8）的FIX帕多瓦基因疗法。本报告重点关注给药参与者的安全性、药代动力学变量、对FIX活性的影响以及免疫反应的12个月中期分析。八名成年男性参与者（年龄20 - 69岁；FIX活性范围为0.5%至2.0%）接受了3种BAX 335静脉注射剂量中的1种：2.0×10¹¹；1.0×10¹²；或3.0×10¹²载体基因组/千克。三名（37.5%）参与者发生了4起严重不良事件，均被认为与BAX 335无关。没有严重不良事件导致死亡。未报告临床血栓形成、抑制剂或其他针对FIX帕多瓦的免疫反应。8名参与者中有7名可检测到FIX表达；FIX活性峰值呈现剂量依赖性（队列3中为32.0%至58.5%）。一名参与者在4年时间里实现了约20%的持续治疗性FIX活性，且无出血或替代治疗；在其他参与者中，FIX活性在5至11周后未能持续。与之前的一些研究不同，皮质类固醇治疗未能稳定FIX活性丧失。我们推测转基因表达的丧失可能是由先天免疫反应的刺激引起的，包括通过密码子优化引入BAX 335编码序列的CpG寡脱氧核苷酸。该试验在www.clinicaltrials.gov上注册为#NCT01687608。
