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

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). 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. 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. 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.