Early Clinical Development, Ophthalmology, Metabolism, Neurology, Immunology (OMNI), Genentech, Inc., South San Francisco, California, USA.
Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, California, USA.
Allergy. 2024 Nov;79(11):2993-3004. doi: 10.1111/all.16309. Epub 2024 Sep 9.
Tryptase, 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.
Phase 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.
MTPS9579A 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.
The 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.
糜蛋白酶，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。我们评估了 MTPS9579A（一种抗糜蛋白酶抗体）在一项 2a 期随机临床试验中的疗效、安全性、药代动力学和药效学，该试验针对的是未得到控制的哮喘患者，以及一项 1c 期试验，以了解下呼吸道的活性。
2a 期患者（n=134）接受每 4 周静脉注射 1800mg MTPS9579A 或安慰剂，共 48 周。主要终点是首次复合加重事件的时间。1c 期患者（n=27）接受 300 或 1800mg MTPS9579A 或安慰剂静脉注射一次。两项试验均测量 MTPS9579A 浓度及其对血清和鼻衬液中糜蛋白酶的影响；1c 期还分析了支气管衬液。
MTPS9579A 未达到主要终点（风险比=0.90；95%CI：0.55-1.47；p=0.6835）；安慰剂组的加重率较低。血清和鼻 MTPS9579A 药代动力学和糜蛋白酶水平与健康志愿者的数据一致。然而，在 1c 期患者中，与鼻水平相比，MTPS9579A 支气管浓度低 6.8 倍，支气管活性和总糜蛋白酶水平分别高 119 倍和 30 倍。药代动力学/药效学模型预测，需要每 4 周静脉注射 3800mg 的剂量才能从基线达到 95%的活性糜蛋白酶抑制。
2a 期研究中测试的 MTPS9579A 剂量不足以抑制支气管衬液中的糜蛋白酶，这可能是观察到的疗效缺乏的原因。
