Division of Hematology/Oncology, Department of Medicine, University of California San Diego, San Diego, CA.
Center for Inherited Blood Disorders, Orange, CA.
Blood Adv. 2023 Oct 10;7(19):5671-5679. doi: 10.1182/bloodadvances.2022008886.
Etranacogene dezaparvovec (AMT-061) is a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) transgene with a liver-specific promoter. Here, we report 3-year outcomes from a phase 2b, open-label, single-dose, single-arm, multicenter trial conducted among adults with severe or moderately severe hemophilia B (FIX ≤2%). All participants (n = 3) received a single intravenous dose (2 × 1013 gene copies per kg) and will be followed up for 5 years. The primary end point of FIX activity ≥5% at 6 weeks was met. Secondary end points included bleed frequency, FIX concentrate use, joint health, and adverse events (AEs). All participants required routine FIX prophylaxis and had neutralizing antibodies to AAV5 before etranacogene dezaparvovec treatment. After administration, FIX activity rose to a mean of 40.8% in year 1 and was sustained in year 3 at 36.9%. All participants discontinued FIX prophylaxis. Bleeding was completely eliminated in 2 out of 3 participants. One participant required on-demand FIX replacement therapy per protocol because of elective surgical procedures, for 2 reported bleeding episodes, and twice for a single self-administered infusion because of an unreported reason. One participant experienced 2 mild, self-limiting AEs shortly after dosing. During the 3-year study period, there were no clinically significant elevations in liver enzymes, no requirement for steroids, no FIX inhibitor development, and no late-emergent safety events in any participant. Etranacogene dezaparvovec was safe and effective in adults with hemophilia B over 3 years after administration. This trial was registered at www.clinicaltrials.gov as #NCT03489291.
依特兰基因疗法（AMT-061）是一种腺相关病毒血清型 5（AAV5）载体，包含一个经过密码子优化的帕多瓦变异人凝血因子 IX（FIX）转基因，带有一个肝脏特异性启动子。在这里，我们报告了一项 2b 期、开放标签、单剂量、单臂、多中心试验的 3 年结果，该试验在患有严重或中度严重血友病 B（FIX≤2%）的成年人中进行。所有参与者（n=3）均接受单次静脉注射（每公斤 2×1013 个基因拷贝），并将随访 5 年。6 周时FIX 活性≥5%的主要终点得到满足。次要终点包括出血频率、FIX 浓缩物使用、关节健康和不良事件（AE）。所有参与者在接受依特兰基因疗法治疗前均需要常规 FIX 预防治疗，且均具有针对 AAV5 的中和抗体。给药后，FIX 活性在第 1 年上升至平均 40.8%，并在第 3 年持续稳定在 36.9%。所有参与者均停止了 FIX 预防治疗。在 3 名参与者中，有 2 名完全消除了出血。1 名参与者因根据方案规定的择期手术而需要按需接受 FIX 替代治疗，有 2 次因 2 次报告的出血事件，以及 1 次因未报告的原因而接受单次自我输注。1 名参与者在给药后不久经历了 2 次轻度、自限性 AE。在 3 年的研究期间，没有任何参与者出现临床上显著的肝酶升高、无类固醇需求、无 FIX 抑制剂产生，以及任何新出现的安全事件。依特兰基因疗法在接受治疗 3 年后对血友病 B 成人是安全有效的。该试验在 www.clinicaltrials.gov 上注册为 #NCT03489291。
