Whalen John, Chandra Anita, Kracker Sven, Ehl Stephan, Seidel Markus G, Gulas Ioana, Dron Louis, Velummailum Russanthy, Nagamuthu Chenthila, Liu Sichen, Tutein Nolthenius Joanne, Maccari Maria Elena
Pharming Group N.V., Leiden, The Netherlands.
Department of Medicine, University of Cambridge, Cambridge, UK.
Clin Exp Immunol. 2025 Jan 21;219(1). doi: 10.1093/cei/uxae107.
Leniolisib, an oral, targeted phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, was well-tolerated and efficacious versus placebo in treating individuals with activated PI3Kδ syndrome (APDS), an ultra-rare inborn error of immunity (IEI), in a 12-week randomised controlled trial. However, longer-term comparative data versus standard of care are lacking. This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum immunoglobulin M (IgM) levels versus current standard of care, using data from the leniolisib single-arm open-label extension study 2201E1 (NCT02859727) and the European Society for Immunodeficiencies (ESID) registry. The endpoints were chosen following feasibility assessment considering comparability and availability of data from both sources. Baseline characteristics between groups were balanced through inverse probability of treatment weighting. The leniolisib-treated group included 37 participants, with 62 and 49 participants in the control group for the respiratory tract infections and serum IgM analyses, respectively. Significant reductions in the annual rate of respiratory tract infections (rate ratio: 0.34; 95% confidence interval [CI]: 0.19, 0.59) and serum IgM levels (treatment effect: -1.09 g/L; 95% CI: -1.78, -0.39, P = 0.002) were observed in leniolisib-treated individuals versus standard of care. The results were consistent across all sensitivity analyses, regardless of censoring, baseline infection rate definition, missing data handling, or covariate selection. These novel data provide an extended comparison of leniolisib treatment versus standard of care, highlighting the potential for leniolisib to deliver long-term benefits by restoring immune system function and reducing infection rate, potentially reducing complications and treatment burden.
在一项为期12周的随机对照试验中，口服靶向磷酸肌醇3-激酶δ（PI3Kδ）抑制剂来尼利昔布在治疗活化PI3Kδ综合征（APDS）患者时耐受性良好，与安慰剂相比疗效显著。APDS是一种极为罕见的先天性免疫缺陷病（IEI）。然而，目前尚缺乏与标准治疗方案的长期对比数据。这项外部对照研究利用来尼利昔布单臂开放标签扩展研究2201E1（NCT02859727）和欧洲免疫缺陷学会（ESID）登记处的数据，比较了来尼利昔布与当前标准治疗方案相比，对呼吸道感染年发生率和血清免疫球蛋白M（IgM）水平变化的长期影响。在考虑到两个来源数据的可比性和可用性进行可行性评估后选择了终点指标。通过治疗权重的逆概率平衡了各组之间的基线特征。来尼利昔布治疗组包括37名参与者，呼吸道感染和血清IgM分析的对照组分别有62名和49名参与者。与标准治疗方案相比，来尼利昔布治疗的个体呼吸道感染年发生率（率比：0.34；95%置信区间[CI]：0.19，0.59）和血清IgM水平（治疗效果：-1.09 g/L；95% CI：-1.78，-0.39，P = 0.002）显著降低。无论在删失、基线感染率定义、缺失数据处理或协变量选择方面如何，所有敏感性分析的结果均一致。这些新数据提供了来尼利昔布治疗与标准治疗方案的扩展对比，突出了来尼利昔布通过恢复免疫系统功能和降低感染率从而提供长期益处的潜力，这可能会减少并发症和治疗负担。
