Insilico Medicine announced the initiation of the Phase III clinical trial for Rentosertib, its potentially first-in-class oral small-molecule inhibitor targeting TNIK for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive, age-related fibrotic lung disease with high unmet medical need.
Rentosertib, formerly known as ISM001-055 / INS018_055, was discovered and designed through Insilico's Pharma.AI platform. The program combines a novel fibrosis target prioritized by Biology42: PandaOmics, Insilico's AI-powered biology engine, with a novel small molecule generated and optimized through Chemistry42, Insilico's generative chemistry platform. Insilico leverages PandaOmics for indication prioritization and Medicine42's inClinico platform to predict and improve the program's clinical trial outcomes. The program's discovery-to-clinic path was published in Nature Biotechnology, while randomized Phase IIa clinical results were published in Nature Medicine and presented at the American Thoracic Society (ATS) 2025 International Conference.
The initiation of Rentosertib's Phase III clinical trial marks a major late-stage milestone for AI-driven drug discovery: a medicine whose target was identified with AI, whose chemical structure was designed with generative AI, and whose clinical development is aimed at a severe age-related disease in which current approved antifibrotic therapies can slow progression but do not reverse the degenerative course of disease.
To evaluate Rentosertib in this next stage of development, the upcoming Phase III clinical trial is a prospective, randomized, double-blind, placebo-controlled, parallel-group Phase III study. It will be led by Professor Zuojun Xu of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences as the Leading Principal Investigator (Leading PI), with Academician Nanshan Zhong of the Chinese Academy of Engineering, a renowned expert in respiratory medicine, and President Chang Chen of Shanghai Pulmonary Hospital serving as Co-Leading Principal Investigators (Co-Leading PIs). The study is expected to enroll 320 patients with idiopathic pulmonary fibrosis (IPF) and is designed to systematically evaluate the efficacy and safety of once-daily Rentosertib administered over 52 weeks.
As Leading PI of the study, Professor Zuojun Xu from Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, commented: "Interstitial lung disease (ILD) has always been a key focus of research. From basic science to disease mechanisms and potential therapeutics, research in this area is continuously improving and has achieved several encouraging clinical-stage breakthroughs. In the Phase IIa trial of Rentosertib, we were pleased to observe a dose-dependent efficacy trend, which attracted widespread attention and anticipation from research institutions globally. For the Phase III study at a larger scale with longer duration, we look forward to enhanced collaboration across all parties regarding study standards, risk mitigation, and cross-center data consistency, so as to realize an objective and comprehensive evaluation of Rentosertib, benefiting patients in need."
IPF is a chronic, progressive lung-scarring disease that disproportionately affects older adults. As fibrosis accumulates, lung tissue becomes stiff and scarred, making breathing increasingly difficult and leading to irreversible decline in lung function. The median survival after diagnosis is commonly reported at approximately two to four years, and there remains a substantial need for disease-modifying treatments that can meaningfully alter the clinical course.
TNIK is a serine/threonine kinase implicated in fibrosis-driving and inflammation-related pathways including Wnt, TGF-β, Hippo/YAP-TAZ, JNK and NF-κB signaling. Insilico identified TNIK as a high-priority fibrosis target using PandaOmics by integrating multi-omics data from fibrotic tissues, biological network analysis, causal inference, pathway analysis, literature and patent intelligence, and aging-relevant target scoring. In the Nature Biotechnology paper, TNIK was reported as the top-ranked candidate in the protein and receptor kinase discovery scenario, representing a previously underexplored target class for IPF compared with the receptor tyrosine kinase biology addressed by existing antifibrotic drugs.
"IPF is one of the clearest clinical examples of an age-related disease in which fibrosis, chronic inflammation, extracellular matrix remodeling and cellular senescence intersect," said Feng Ren, PhD, Co-CEO and Chief Scientific Officer of Insilico Medicine. "Rentosertib was not discovered by starting from a conventional target and simply screening more compounds. It came from a biology-first, aging-informed AI workflow that connected TNIK to fibrotic and inflammatory disease mechanisms, and then used generative chemistry to create a drug candidate with the properties required for clinical development."
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