From the Katharine Dormandy Haemophilia and Thrombosis Centre (P.C., M.P., A.R., M.R.P., E.T., A.N.), Health Services Laboratory, Sonic Healthcare (A.R.), and the Department of Hepatology and Liver Transplantation (D.W.P.), Royal Free Hospital, University College London (P.C., M.P., M.Q., A.N.), Guy's and St. Thomas' Hospital (G.D.), and Wstats (M.W.), London, Oxford University Hospitals Foundation Trust, Oxford NIHR Biomedical Research Centre, and Oxford University, Oxford (S.S.), the University of Sheffield, Sheffield (M.M.), East Kent Hospitals NHS University Foundation Trust, Canterbury (G.E.), University Hospital Southampton, Southampton (S.B.), Newcastle upon Tyne Hospitals NHS Trust, Newcastle (K.T.), and Freeline Therapeutics, Stevenage (A.D., A.N.) - all in the United Kingdom; St. Jude Children's Research Hospital, Memphis, TN (U.R.); and Freeline Therapeutics, New York (A.L.).
N Engl J Med. 2022 Jul 21;387(3):237-247. doi: 10.1056/NEJMoa2119913.
FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B.
In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26.
Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×10 vg, 6.40×10 vg, 8.32×10 vg, or 1.28×10 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels.
Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017-000852-24 and 2017-005080-40.).
FLT180a（verbrinacogene setparvovec）是一种靶向肝脏的腺相关病毒（AAV）基因疗法，它使用合成衣壳和功能获得性蛋白，使乙型血友病患者的因子 IX 水平正常化。
在这项多中心、开放标签、1-2 期临床试验中，我们评估了不同剂量的 FLT180a 在严重或中度严重乙型血友病（因子 IX 水平，≤正常值的 2%）患者中的安全性和疗效。所有患者均接受糖皮质激素联合或不联合他克莫司进行免疫抑制，以降低载体相关免疫反应的风险。26 周后，患者被纳入长期随访研究。主要终点是 26 周时的因子 IX 水平评估的安全性和疗效。
10 名患者接受了每公斤体重 4 种 FLT180a 剂量的载体基因组（vg）之一：3.84×10 vg、6.40×10 vg、8.32×10 vg 或 1.28×10 vg。接受输注后，所有患者的因子 IX 水平均呈剂量依赖性增加。在中位数为 27.2 个月（范围 19.1 至 42.4）的随访中，除 1 名患者恢复因子 IX 预防治疗外，所有患者均持续观察到因子 IX 活性。截至数据截止日期（2021 年 9 月 20 日），5 名患者的因子 IX 水平正常（范围 51 至 78%），3 名患者的水平为 23 至 43%，1 名患者的水平为 260%。报告的不良事件中，约 10%与 FLT180a 相关，24%与免疫抑制相关。肝转氨酶水平升高是最常见的与 FLT180a 相关的不良事件。在糖皮质激素减量后接受长期他克莫司治疗的患者中，出现了晚期转氨酶水平升高。一名因子 IX 水平较高的患者发生了严重的动静脉瘘血栓形成不良事件。
低剂量的 FLT180a 可使因子 IX 水平持续维持在正常范围内，但需要糖皮质激素联合或不联合他克莫司进行免疫抑制。（由 Freeline Therapeutics 资助；临床试验.gov 编号，NCT03369444 和 NCT03641703；EudraCT 编号，2017-000852-24 和 2017-005080-40。）
