Activated PI3Kδ Syndrome (APDS) is a rare inherited inborn error of immunity caused by mutations that constitutively activate the p110 delta isoform of phosphoinositide 3-kinase (PI3Kδ), resulting in recurring pulmonary infections. Currently no licensed therapies are available. Here we report the results of an open-label trial in which five subjects were treated for 12 weeks with nemiralisib, an inhaled inhibitor of PI3Kδ, to determine safety, systemic exposure, together with lung and systemic biomarker profiles (Clinicaltrial.gov: NCT02593539).

Induced sputum was captured to measure changes in phospholipids and inflammatory mediators, and blood samples were collected to assess pharmacokinetics of nemiralisib, and systemic biomarkers.

Nemiralisib was shown to have an acceptable safety and tolerability profile, with cough being the most common adverse event, and no severe adverse events reported during the study. No meaningful changes in phosphatidylinositol (3,4,5)-trisphosphate (PIP3; the enzyme product of PI3Kδ) or downstream inflammatory markers in induced sputum, were observed following nemiralisib treatment. Similarly, there were no meaningful changes in blood inflammatory markers, or lymphocytes subsets. Systemic levels of nemiralisib were higher in subjects in this study compared to previous observations.

While nemiralisib had an acceptable safety profile, there was no convincing evidence of target engagement in the lung following inhaled dosing and no downstream effects observed in either the lung or blood compartments. We speculate that this could be explained by nemiralisib not being retained in the lung for sufficient duration, suggested by the increased systemic exposure, perhaps due to pre-existing structural lung damage.

In this study investigating a small number of subjects with APDS, nemiralisib appeared to be safe and well-tolerated. However, data from this study do not support the hypothesis that inhaled treatment with nemiralisib would benefit patients with APDS.

激活的 PI3Kδ 综合征 (APDS) 是一种罕见的遗传性先天性免疫错误，由组成型激活磷酸肌醇 3-激酶 (PI3Kδ) 的 p110 δ 亚型的突变引起，导致反复发生的肺部感染。目前没有获得许可的疗法。在这里，我们报告了一项开放标签试验的结果，其中五名受试者接受了 nemiralisib（一种吸入的 PI3Kδ 抑制剂）治疗 12 周，以确定安全性、全身暴露以及肺和全身生物标志物概况（Clinicaltrial.gov：NCT02593539） .

捕获诱导痰以测量磷脂和炎症介质的变化，并收集血液样本以评估 nemiralisib 的药代动力学和全身生物标志物。

Nemiralisib 被证明具有可接受的安全性和耐受性，咳嗽是最常见的不良事件，在研究期间没有报告严重的不良事件。nemiralisib 治疗后，未观察到磷脂酰肌醇 (3,4,5)-三磷酸（PIP3；PI3Kδ 的酶产物）或诱导痰中的下游炎症标志物发生有意义的变化。同样，血液炎症标志物或淋巴细胞亚群也没有发生有意义的变化。与之前的观察结果相比，本研究中受试者的 nemiralisib 全身水平更高。

虽然 nemiralisib 具有可接受的安全性，但没有令人信服的证据表明吸入给药后靶点参与肺部，也没有在肺部或血液室中观察到下游效应。我们推测这可以解释为 nemiralisib 没有在肺中保留足够长的时间，这表明全身暴露增加，可能是由于预先存在的结构性肺损伤。

在这项调查少数 APDS 受试者的研究中，nemiralisib 似乎是安全且耐受性良好的。然而，这项研究的数据不支持吸入治疗尼米拉里斯会使 APDS 患者受益的假设。