Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Clin Transl Sci. 2024 Aug;17(8):e13891. doi: 10.1111/cts.13891.
Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil-derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single-rising-dose study (NCT03414008) and two multiple-rising-dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug-drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug-related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra-proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose-dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co-administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).
需要新的治疗方法来减轻炎症、改善症状、解决恶化问题并减缓支气管扩张症的疾病进展。组织蛋白酶 C（CatC）抑制有望通过减少中性粒细胞衍生的丝氨酸蛋白酶（包括中性粒细胞弹性蛋白酶[NE]和蛋白酶 3 [PR3]）的激活来实现这一目标。在这里，我们介绍了新型 CatC 抑制剂 BI 1291583 的 I 期特征。呈现了五项在健康受试者中进行的 BI 1291583 I 期试验：一项单次递增剂量研究（NCT03414008）和两项多次递增剂量研究（NCT03868540 和 NCT04866160），评估了 BI 1291583 的安全性、耐受性、药效学和药代动力学；一项食物影响研究（NCT03837964）；以及 BI 1291583 和伊曲康唑的药物相互作用研究（NCT03890887）。在这些试验中，BI 1291583 在测试剂量范围内均安全且耐受良好。大多数不良事件（AE）为轻度或中度，没有严重的 AE、特殊关注的 AE 或任何试验中报告的死亡。与安慰剂相比，接受 BI 1291583 治疗的受试者中没有更频繁地报告与药物相关的皮肤剥落。BI 1291583 易于吸收，药代动力学在评估的剂量范围内呈超比例。此外，BI 1291583 以剂量依赖性方式抑制 CatC，抑制下游 NE 活性，并降低 PR3 水平。未观察到食物效应。多次给予伊曲康唑可使 BI 1291583 的暴露量增加约两倍。由于这些有希望的 I 期结果，一项针对支气管扩张症成年患者的 BI 1291583 的多中心 II 期计划正在进行中（Airleaf™[NCT05238675]、Clairafly™[NCT05865886]和 Clairleaf™[NCT05846230]）。
