ATS 2021 will feature presentations of original research from accepted abstracts. Mini Symposia and Thematic Poster Sessions are abstract based sessions.
Please use the form below to browse scientific abstracts and case reports accepted for ATS 2021. Abstracts presented at the ATS 2021 will be published in the Online Abstract Issue of the American Journal of Respiratory and Critical Care Medicine, Volume 203, May 3, 2021.
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Safety, Tolerability and Pharmacokinetics/Pharmacodynamic Assessment of an Oral, Selective Prolyl-tRNA Synthetase Inhibitor, DWN12088, for the Treatment of Idiopathic Pulmonary Fibrosis in Healthy Subjects
Session Title
TP28 - TP028 APPROACH TO THERAPY IN FIBROSING AND NON-FIBROSING ILD
Abstract
A1897 - Safety, Tolerability and Pharmacokinetics/Pharmacodynamic Assessment of an Oral, Selective Prolyl-tRNA Synthetase Inhibitor, DWN12088, for the Treatment of Idiopathic Pulmonary Fibrosis in Healthy Subjects
Author Block: M. Park1, J. Heo1, Y. Kim1, J. Han1, D. Kim2, C. Lee2, M. Cho2, J. Park2; 1Clinical Development Center, Daewoong Pharmatheutical Co., Ltd., Seoul, Korea, Republic of, 2Drug Discovery Center, Daewoong Pharmatheutical Co., Ltd., Seoul, Korea, Republic of.
Introduction: Glutamyl-Prolyl-tRNA synthetase (EPRS) is an enzyme that conjugates proline to its tRNA. Excessive deposition of collagen is the pathological hallmark of fibrosis, and proline is one of the major constituents of collagen. Thus, EPRS plays an essential role in de novo collagen synthesis. In our previous studies, EPRS expression was significantly increased in Idiopathic Pulmonary Fibrosis (IPF) patients’ lung tissues. Daewoong is developing a novel, proprietary first-in-class prolyl-tRNA synthetase (PRS) inhibitor, DWN12088, and previous studies have shown anti-fibrotic effects by down-regulating collagen synthesis in various cellular and mouse pulmonary fibrosis models. In this study, safety, tolerability, pharmacokinetic and pharmacodynamic profiles of DWN12088 were assessed in healthy volunteers. Method: DW_DWN12088101 is a phase 1, double-blind, placebo-controlled, randomized study in healthy volunteers. In Single Ascending Dose (SAD) studies, including sentinel dosing, 40 healthy subjects received DWN12088 or placebo at 100 - 600 mg. In Multiple Ascending Dose (MAD) studies, 32 healthy subjects received DWN12088 or placebo 25 - 200 mg b.i.d. for two weeks. Results: Oral administration of DWN12088 demonstrated safety with no serious adverse event (SAE) in single and multiple ascending dose studies. The most common Treatment Emergent Adverse Events (TEAE) were gastrointestinal (GI) disorders. DWN12088 pharmacokinetic profiles showed dose linearity and plasma DWN12088 exposures were increased dose-dependently across the single and multiple doses. As a preliminary pharmacodynamic marker study, Type III Procollagen Peptide (PIIINP) levels were investigated in blood samples. PIIINP is a fragment generated when mature type III collagen is formed, and it has been shown that PIIINP levels are increased in IPF patient’s serum. Thus, oral administration of DWN12088 was expected to lower PIIINP levels. As a preliminary result, our study showed dose-dependent reduction of PIIINP, which suggests DWN12088 may be able to show anti-fibrotic efficacy by successfully down-regulating collagen synthesis in IPF patients. Conclusion: Daewoong’s proprietary PRS inhibitor, DWN12088, is a first-in-class small molecule inhibitor that is being developed as a therapeutic agent for IPF. In this study, we showed oral administration of DWN12088 has safety, tolerability, and favorable pharmacokinetic profiles in healthy volunteers, which supports further clinical development for IPF. DWN12088 has completed Phase I study in healthy volunteers, and is expected to proceed to Phase II clinical trial in 2021.
Author Block: M. Park1, J. Heo1, Y. Kim1, J. Han1, D. Kim2, C. Lee2, M. Cho2, J. Park2; 1Clinical Development Center, Daewoong Pharmatheutical Co., Ltd., Seoul, Korea, Republic of, 2Drug Discovery Center, Daewoong Pharmatheutical Co., Ltd., Seoul, Korea, Republic of.
Introduction: Glutamyl-Prolyl-tRNA synthetase (EPRS) is an enzyme that conjugates proline to its tRNA. Excessive deposition of collagen is the pathological hallmark of fibrosis, and proline is one of the major constituents of collagen. Thus, EPRS plays an essential role in de novo collagen synthesis. In our previous studies, EPRS expression was significantly increased in Idiopathic Pulmonary Fibrosis (IPF) patients’ lung tissues. Daewoong is developing a novel, proprietary first-in-class prolyl-tRNA synthetase (PRS) inhibitor, DWN12088, and previous studies have shown anti-fibrotic effects by down-regulating collagen synthesis in various cellular and mouse pulmonary fibrosis models. In this study, safety, tolerability, pharmacokinetic and pharmacodynamic profiles of DWN12088 were assessed in healthy volunteers. Method: DW_DWN12088101 is a phase 1, double-blind, placebo-controlled, randomized study in healthy volunteers. In Single Ascending Dose (SAD) studies, including sentinel dosing, 40 healthy subjects received DWN12088 or placebo at 100 - 600 mg. In Multiple Ascending Dose (MAD) studies, 32 healthy subjects received DWN12088 or placebo 25 - 200 mg b.i.d. for two weeks. Results: Oral administration of DWN12088 demonstrated safety with no serious adverse event (SAE) in single and multiple ascending dose studies. The most common Treatment Emergent Adverse Events (TEAE) were gastrointestinal (GI) disorders. DWN12088 pharmacokinetic profiles showed dose linearity and plasma DWN12088 exposures were increased dose-dependently across the single and multiple doses. As a preliminary pharmacodynamic marker study, Type III Procollagen Peptide (PIIINP) levels were investigated in blood samples. PIIINP is a fragment generated when mature type III collagen is formed, and it has been shown that PIIINP levels are increased in IPF patient’s serum. Thus, oral administration of DWN12088 was expected to lower PIIINP levels. As a preliminary result, our study showed dose-dependent reduction of PIIINP, which suggests DWN12088 may be able to show anti-fibrotic efficacy by successfully down-regulating collagen synthesis in IPF patients. Conclusion: Daewoong’s proprietary PRS inhibitor, DWN12088, is a first-in-class small molecule inhibitor that is being developed as a therapeutic agent for IPF. In this study, we showed oral administration of DWN12088 has safety, tolerability, and favorable pharmacokinetic profiles in healthy volunteers, which supports further clinical development for IPF. DWN12088 has completed Phase I study in healthy volunteers, and is expected to proceed to Phase II clinical trial in 2021.
