Pipe Steven, Poma Allen, Rajasekhar Anita, Everington Tamara, Sankoh Serap, Allen Jack, Cataldo Jason, Crombez Eric
Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI.
Ultragenyx Pharmaceutical Inc, Novato, CA.
Blood Adv. 2025 Jun 24;9(12):2980-2987. doi: 10.1182/bloodadvances.2024015184.
Hemophilia B is a rare, X-linked bleeding disorder that predominantly affects males and is caused by factor IX (FIX) gene variants, leading to spontaneous bleeding and impaired ability to clot after injury or surgeries. Standard of care is prophylaxis to increase FIX levels. DTX101 is a nonreplicating adeno-associated viral serotype rh10 gene transfer vector containing a codon-optimized wild-type human FIX coding sequence. The phase 1/2 open-label, single-arm, multicenter, dose-finding 101HEMB01 study examined the safety/efficacy of DTX101 in adult males with hemophilia B; the 101HEMB02 follow-up study assessed long-term outcomes. Participants received DTX101 as 1.6 × 1012 (cohort 1; n = 3) or 5.0 × 1012 genome copies/kg (cohort 2; n = 3) at baseline and were monitored through week 44 (cohort 2) or 52 (cohort 1) in 101HEMB01, and 4 additional years in 101HEMB02. The primary end point of 101HEMB01, peak plasma FIX level at week 6, showed median levels of 7.0 (range, 5.0-8.0) and 10.0 IU/dL (range, 6.0-16.0) in cohorts 1 and 2, respectively. Levels failed to reach the 20 IU/dL target criteria; all participants required adjunct FIX replacement therapy based on low FIX activity at intermediate time points. In 101HEMB01, 4 of 6 participants experienced treatment-related adverse events of elevated transaminase levels (n = 3) and fatigue (n = 1), and 1 experienced fatigue in 101HEMB02; none experienced related serious adverse events. Elevated transaminase levels were asymptomatic and resolved with steroids in all participants. The DTX101 program was halted for insufficient treatment response; however, from its completion, lessons can be learned regarding the design and execution of gene therapy clinical trials, including additional optimization of transgene sequence and immunosuppression protocols. The 101HEMB01 and 101HEMB02 studies were registered at www.ClinicalTrials.gov as #NCT02618915 and #NCT02971969, respectively.
血友病B是一种罕见的X连锁出血性疾病，主要影响男性，由凝血因子IX（FIX）基因变异引起，导致自发性出血以及受伤或手术后凝血能力受损。护理标准是进行预防性治疗以提高FIX水平。DTX101是一种非复制型腺相关病毒血清型rh10基因转移载体，包含一个密码子优化的野生型人FIX编码序列。1/2期开放标签、单臂、多中心剂量探索性101HEMB01研究考察了DTX101在成年男性血友病B患者中的安全性/有效性；101HEMB02随访研究评估了长期结局。在基线时，参与者接受1.6×10¹²（队列1；n = 3）或5.0×10¹²基因组拷贝/千克（队列2；n = 3）的DTX101，并在101HEMB01中接受监测至第44周（队列2）或52周（队列1），在101HEMB02中再额外监测4年。101HEMB01的主要终点，即第6周时的血浆FIX峰值水平，在队列1和队列2中的中位数水平分别为7.0（范围5.0 - 8.0）和10.0 IU/dL（范围6.0 - 16.0）。这些水平未达到20 IU/dL的目标标准；所有参与者在中间时间点因FIX活性低而需要辅助FIX替代治疗。在101HEMB01中，6名参与者中有4名经历了与治疗相关的不良事件，即转氨酶水平升高（n = 3）和疲劳（n = 1），在101HEMB02中有1名经历了疲劳；无人经历相关严重不良事件。所有参与者的转氨酶水平升高均无症状，且用类固醇治疗后症状缓解。DTX101项目因治疗反应不足而停止；然而，从其完成情况中，可以吸取关于基因治疗临床试验设计和实施的经验教训，包括转基因序列和免疫抑制方案的进一步优化。101HEMB01和101HEMB02研究分别在www.ClinicalTrials.gov上注册为#NCT02618915和#NCT02971969。
