A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome.
A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome.
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DOI：
10.1182/blood.2022018546
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发表时间：
2023-03-02
期刊：
影响因子：
20.3
通讯作者：
Uzel, Gulbu
中科院分区：
文献类型：
--
作者：
Rao, V. Koneti;Webster, Sharon;Sediva, Anna;Plebani, Alessandro;Schuetz, Catharina;Shcherbina, Anna;Conlon, Niall;Coulter, Tanya;Dalm, Virgil A.;Trizzino, Antonino;Zharankova, Yulia;Kulm, Elaine;Koerholz, Julia;Lougaris, Vassilios;Rodina, Yulia;Radford, Kath;Bradt, Jason;Kucher, Klaus;Relan, Anurag;Holland, Steven M.;Lenardo, Michael J.;Uzel, Gulbu
口服PI 3 K δ抑制剂leniolisib可减少APDS患者的淋巴结病并使免疫细胞亚群正常化，APDS是一种先天性免疫缺陷。Leniolisib在APDS患者中耐受性良好，大多数为1级AE，无与研究治疗相关的严重AE。活化磷脂酰肌醇3-激酶δ综合征（Activated phosphoinositide 3-kinase delta，PI 3 K δ）是一种先天性免疫缺陷综合征，临床表现包括感染、淋巴细胞增生、自身免疫、肠病、支气管扩张、淋巴瘤风险增加和早期死亡。过度活跃的PI 3 K δ信号传导导致APDS，并被leniolisib（一种PI 3 K δ的口服小分子抑制剂）选择性靶向。在此，31例年龄≥12岁的APDS患者入组了一项全球、III期、三盲试验，并以2：1的比例随机接受70 mg leniolisib或安慰剂，每日两次，持续12周。共同主要结局是指淋巴结大小和外周血幼稚B细胞百分比与基线的差异，作为免疫失调和免疫缺陷的替代指标进行评估。两个主要结局均得到了满足：淋巴结大小方面，肾结石B组与安慰剂组之间的校正平均变化（95%置信区间[CI]）差异为−0.25（−0.38，−0.12; P = 0.0006; N = 26），幼稚B细胞百分比为37.30（24.06，50.54; P = 0.0002; N = 13）。与安慰剂相比，Leniolisib减少了脾脏体积（三维体积[cm 3]的校正平均差异为-186; 95%CI为-297至-76.2; P = 0.0020），并改善了关键免疫细胞亚群。接受leniolisib治疗的患者报告的研究治疗相关不良事件（AE;大多数为1-2级）少于接受安慰剂治疗的患者（23.8% vs 30.0%）。总体而言，肾结石B耐受性良好，与安慰剂相比，共同主要终点显著改善，淋巴结病减少，幼稚B细胞百分比增加，反映了对APDS患者中观察到的免疫失调和免疫缺陷的有利影响。本试验在www.clinicaltrials.gov上注册为#NCT02435173。活化磷酸肌醇3-激酶δ综合征（APDS）是一种先天性免疫缺陷综合征，与感染、淋巴细胞增生、肺和胃肠道并发症、淋巴瘤风险和早期死亡相关。它是由PI 3 K δ异二聚体的任一亚基突变引起的，导致PI 3 K δ信号传导增加。在这篇全体会议论文中，Rao等人报告了一项在31例APDS患者中进行的PI 3 K δ抑制剂leniolisib的随机、安慰剂对照III期试验。尽管队列较小，反映了这种疾病的罕见性，但该药物可减少淋巴结肿大和脾肿大，并改善免疫细胞特征。
The oral PI3Kδ inhibitor leniolisib reduced lymphadenopathy and normalized immune cell subsets in patients with APDS, an inborn error of immunity. Leniolisib was well tolerated in patients with APDS, with mostly grade 1 AEs and no serious AEs related to study treatment. Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was −0.25 (−0.38, −0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], −186; 95% CI, −297 to −76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173. Activated phosphoinositide 3-kinase delta syndrome (APDS) is a congenital immunodeficiency syndrome associated with infections, lymphoproliferation, pulmonary and gastrointestinal complications, risk of lymphoma, and early mortality. It is caused by mutations in either subunit of the PI3Kδ heterodimer, leading to increased PI3Kδ signaling. In this Plenary Paper, Rao et al report on a randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib in 31 patients with APDS. Despite the small cohort, reflecting the rarity of this disorder, the agent reduces adenopathy and splenomegaly and improves immune cell profiles.
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影响因子：
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发表时间：
2013-11-15
期刊：
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Angulo I;Vadas O;Garçon F;Banham-Hall E;Plagnol V;Leahy TR;Baxendale H;Coulter T;Curtis J;Wu C;Blake-Palmer K;Perisic O;Smyth D;Maes M;Fiddler C;Juss J;Cilliers D;Markelj G;Chandra A;Farmer G;Kielkowska A;Clark J;Kracker S;Debré M;Picard C;Pellier I;Jabado N;Morris JA;Barcenas-Morales G;Fischer A;Stephens L;Hawkins P;Barrett JC;Abinun M;Clatworthy M;Durandy A;Doffinger R;Chilvers ER;Cant AJ;Kumararatne D;Okkenhaug K;Williams RL;Condliffe A;Nejentsev S
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Nejentsev S