Key Points Seletalisib, a PI3Kδ inhibitor, was evaluated in seven patients with APDS1 and APDS2. Following treatment, patients had improvements in clinical and immunological features. Seletalisib had a favorable risk–benefit profile in a phase 1b study up to 96 wk. Mutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b 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 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b 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 1b 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 1b 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 1b 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 ≤96 wk.

中文翻译：

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用于激活 PI3Kδ 综合征的 Seletalisib：开放标签阶段 1b 和扩展研究

关键点 Seletalisib 是一种 PI3Kδ 抑制剂，在 7 名 APDS1 和 APDS2 患者中进行了评估。治疗后，患者的临床和免疫学特征有所改善。在长达 96 周的 1b 期研究中，Seletalisib 具有良好的风险-收益特征。两个基因的突变可导致激活的 PI3Kδ 综合征 (APDS)，这是一种治疗选择有限的罕见免疫缺陷疾病。Seletalisib 是一种有效的选择性 PI3Kδ 抑制剂，已在 APDS1 和 APDS2 患者中进行了评估。在 1b 期研究（欧洲临床试验数据库 2015-002900-10）中，遗传和临床确认 APDS1 或 APDS2 的患者接受 15-25 mg/d seletalisib 治疗 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，具有探索性功效和免疫学终点。7 名患者（中位年龄 15 岁；APDS1 n = 3；APDS2 n = 4）接受了 seletalisib；五人完成了1b期研究。对于扩展研究，四名患者进入，一名撤回同意（第 24 周），三名完成≥84 周的治疗。在 1b 期研究中，患者的外周淋巴结病（n = 2）、肺功能（n = 1）、血小板计数（n = 1）和慢性肠病（n = 1）均有改善。总体而言，扩展中保持了效果。在 1b 期研究中，过渡 B 细胞的百分比下降，幼稚 B 细胞增加，衰老的 CD8 T 细胞减少（人类细胞）；效果在扩展中普遍保持。7 名患者中有 4 名发生了 Seletalisib 相关的不良事件（1b 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、烦躁、肌腱紊乱和潜在的药物性肝损伤），四名患者中有一名在扩展过程中出现不良事件（口疮性溃疡）。7 名患者中有 3 名发生了严重不良事件（1b 期研究：住院、结肠炎和潜在的药物性肝损伤），4 名患者中有 1 名在扩展期间出现了不良事件（口腔炎）。接受 seletalisib 的 APDS 患者在不同的临床和免疫学特征方面都有所改善，并且在≤96 周内保持了良好的风险-收益特征。住院、结肠炎和潜在的药物性肝损伤）和四名患者中的一名在延长期间出现不良事件（口腔炎）。接受 seletalisib 的 APDS 患者在不同的临床和免疫学特征方面都有所改善，并且在≤96 周内保持了良好的风险-收益特征。住院、结肠炎和潜在的药物性肝损伤）和四名患者中的一名在延长期间出现不良事件（口腔炎）。接受 seletalisib 的 APDS 患者在不同的临床和免疫学特征方面都有所改善，并且在≤96 周内保持了良好的风险-收益特征。