<br>TRK-250（一种基于 siRNA 的新型寡核苷酸）在特发性肺纤维化患者中的 I 期研究。,Journal of Aerosol Medicine and Pulmonary Drug Delivery

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TRK-250（一种基于 siRNA 的新型寡核苷酸）在特发性肺纤维化患者中的 I 期研究。
Journal of Aerosol Medicine and Pulmonary Drug Delivery ( IF 2.0 ) Pub Date : 2023-09-22 , DOI: 10.1089/jamp.2023.0014
Hiroyuki Doi ₁ , Jun Atsumi ₁ , David Baratz ₂ , Yohei Miyamoto ₁

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目的：TRK-250 是一种新型单链寡核苷酸，带有由两个脯氨酸接头连接的人类转化生长因子-β1 靶向 siRNA 基序。非临床研究表明 TRK-250 可能具有预防肺纤维化进展的功效。在此，进行了一项 I 期研究，以调查 TRK-250 在特发性肺纤维化（IPF）患者中的安全性和药代动力学（PK）。方法：在 I 期研究中，34 名 IPF 患者部分随机接受安慰剂或 TRK-250，分 4 次单剂量 2、10、30 和 60 mg 或多次递增剂量 10、30 和 60 mg，每次 1 次。每周口服吸入4周。对于单剂量和多剂量研究，主要终点是安全性，次要终点是 PK。结果：在所有口服 TRK-250 的 IPF 患者中，未观察到明显的药物相关不良事件（AE）。除 1 例急性加重的严重病例外，AE 均为轻度或中度。最常见的 AE 之一是咳嗽。一名患者在最后一次服药前因咳嗽而停止治疗。基于临床实验室数据（临床化学、血液学或尿液分析）、生命体征数据、心电图数据、体格检查结果、脉搏血氧饱和度数据、肺活量测定数据或肺弥散能力，没有发现与安全性终点相关的医学上重要的发现。一氧化碳数据。血液中PK的所有生物分析结果均低于定量下限。结论：在 IPF 患者中进行的第一项研究中，单剂量和多剂量 TRK-250 都是安全的且耐受性良好。此外，吸入后在体循环中未检测到 TRK-250，表明全身暴露量较低或几乎不存在。该研究已在 ClinicalTrials.gov 上注册，识别号为 NCT03727802。

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A Phase I Study of TRK-250, a Novel siRNA-Based Oligonucleotide, in Patients with Idiopathic Pulmonary Fibrosis.

Purpose: TRK-250 is a novel single-stranded oligonucleotide carrying a human Transforming growth factor-beta 1-targeting siRNA motif tethered by two proline linkers. Nonclinical studies have shown that TRK-250 may have potency to prevent the progression of pulmonary fibrosis. Herein, a phase I study was conducted to investigate the safety and pharmacokinetics (PKs) of TRK-250 in patients with idiopathic pulmonary fibrosis (IPF). Method: In the phase I study, 34 IPF patients were partially randomized to receive a placebo or TRK-250 in 4 single doses of 2, 10, 30, and 60 mg or multiple rising doses of 10, 30, and 60 mg once per week for 4 weeks by oral inhalation. For both the single- and multiple-dose studies, the primary endpoint was safety, and the secondary endpoint was PKs. Result: In all IPF patients who orally inhaled TRK-250, no significant drug-related adverse events (AEs) were observed. The AEs were mild or moderate, except for one severe case with acute exacerbation. One of the more common AEs was coughing. One patient discontinued treatment before the last dose because of coughing. There were no medically important findings related to safety endpoints based on clinical laboratory data (clinical chemistry, hematology, or urinalysis), vital signs data, electrocardiogram data, physical examination findings, pulse oximetry data, spirometry data, or diffusing capacity of the lung for carbon monoxide data. All the bioanalytical results of PKs in the blood were below the lower limit of quantification. Conclusions: Both the single and multiple doses of TRK-250 were safe and well tolerated in this first study done in IPF patients. Furthermore, TRK-250 was not detected in the systemic circulation following inhalation, indicating low or virtually nonexistent systemic exposure. This study is registered at ClinicalTrials.gov with identifier number NCT03727802.

更新日期：2023-09-22

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