BackgroundTryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti‐tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract.MethodsPhase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid.ResultsMTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55–1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8‐fold lower, and bronchial active and total tryptase levels were higher (119‐fold and 30‐fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline.ConclusionsThe MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

中文翻译：

---

气道类胰蛋白酶水平表明类胰蛋白酶抑制剂MTPS9579A在哮喘中缺乏临床疗效


背景类胰蛋白酶是一种肥大细胞蛋白酶，已被确定为管理难治性哮喘患者的潜在治疗靶点。我们在一项针对未控制的哮喘患者的 2a 期随机试验和一项 1c 期试验中评估了 MTPS9579A（一种抗类胰蛋白酶抗体）的疗效、安全性、药代动力学和药效学，以了解下呼吸道内的活动。方法2a 期患者 （n = 134） 每 4 周静脉注射 1800 mg MTPS9579A 或安慰剂，持续 48 周。主要终点是首次复合恶化事件的时间。1c 期患者 （n = 27） 接受一次静脉注射剂量的 300 或 1800 mg MTPS9579A 或安慰剂。两项试验都测量了血清和鼻内壁液中MTPS9579A浓度和对类胰蛋白酶的影响;1C 期还分析了支气管内膜液。结果MTPS9579A 未达到主要终点 （风险比 = 0.90;95% CI： 0.55–1.47;p = 0.6835）;安慰剂组的恶化率较低。血清和鼻MTPS9579A药代动力学和类胰蛋白酶水平与健康志愿者的数据一致。然而，在 1c 期患者中，与鼻腔水平相比，MTPS9579A支气管浓度低 6.8 倍，支气管活性和总类胰蛋白酶水平较高（分别为 119 倍和 30 倍）。药代动力学/药效学模型预测每 4 周静脉注射 3800 毫克对于达到基线 95% 的活性类胰蛋白酶抑制是必要的。结论在 2a 期研究中测试的 MTPS9579A 剂量不足以抑制支气管内衬液中的类胰蛋白酶，这可能是观察到疗效不佳的原因。