Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase lb and Extension Studies
Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase lb and Extension Studies
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DOI：
10.4049/jimmunol.2000326
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发表时间：
2020-12-01
影响因子：
4.4
通讯作者：
Kracker, Sven
中科院分区：
文献类型：
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作者：
Diaz, Nieves;Juarez, Maria;Kracker, Sven
两个基因的突变可导致活化的PI 3 K δ综合征（APDS），这是一种治疗选择有限的罕见免疫缺陷疾病。在APDS 1和APDS 2患者中评价了一种强效、选择性PI 3 K δ抑制剂Seletalisib。在Ib期研究（欧洲临床试验数据库2015-002900-10）中，具有APDS 1或APDS 2的遗传和临床确认的患者接受15-25 mg/d司来他昔布12周。患者可以进入扩展研究（欧洲临床试验数据库2015-005541）。主要终点是安全性和耐受性，以及探索性疗效和免疫学终点。7名患者（中位年龄15岁; APDS 1 n = 3; APDS 2 n = 4）接受司来他利昔布; 5名完成Ib期研究。对于扩展研究，4名患者进入，1名患者撤回同意（第24周），3名患者完成>= 84周的治疗。在Ib期研究中，患者具有改善的外周淋巴结病（n = 2）、肺功能（n = 1）、血小板计数（n = 1）和慢性肠病（n = 1）。总体而言，延长期的效果得以维持。在Ib期研究中，过渡性B细胞的百分比降低，初始B细胞增加，并且衰老的CD 8 T细胞减少（人细胞）;在延长期中通常保持效果。7名患者中有4名发生了司来他利相关不良事件（Ib期研究：肝酶升高、头晕、口疮性溃疡、关节痛、关节炎、食欲增加、体重增加、坐立不安、肌腱疾病和潜在的药物诱导的肝损伤），4名患者中有1名在扩展期发生了不良事件（口疮性溃疡）。七名患者中有三名发生严重不良事件（Ib期研究：住院、结肠炎和潜在的药物诱导的肝损伤），四名患者中有一名在扩展期发生不良事件（口腔炎）。接受seletalisib治疗的APDS患者在可变的临床和免疫学特征方面有所改善，
Mutations in two genes can result in activated PI3K delta syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3K delta inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase lb study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15-25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase lb study. For the extension study, four patients entered, one withdrew consent (week 24), three completed >= 84 wk of treatment. In the phase lb study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase lb study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase lb study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase lb study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk-benefit profile was maintained for