Insilico Medicine initiates Phase III trial of rentosertib, an AI‑discovered TNIK inhibitor, in idiopathic pulmonary fibrosis following Phase IIa data showing safety and lung‑function improvement.
Written By: Farha Farheen, PharmD
Reviewed By: Pharmacally Editorial Team
Insilico Medicine has initiated a Phase III clinical trial evaluating rentosertib for the treatment of idiopathic pulmonary fibrosis (IPF), advancing what the company describes as the first AI-discovered therapy to reach late-stage clinical development. The investigational oral small-molecule TNIK inhibitor will be evaluated in patients with IPF following positive Phase IIa data demonstrating a favorable safety profile and improvements in lung function.
Formerly known as ISM001-055 (INS018_055), rentosertib was identified and optimized using Insilico’s Pharma.AI platform. The program combined AI-powered target discovery through PandaOmics with generative molecular design using Chemistry42 and clinical development support from Medicine42. Its discovery process was previously published in Nature Biotechnology, while Phase IIa clinical findings appeared in Nature Medicine.
Novel AI-Discovered Therapy Targets Fibrosis Biology
Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease characterized by irreversible scarring of lung tissue, resulting in declining respiratory function and a median survival of approximately two to four years after diagnosis. Although currently approved antifibrotic therapies slow disease progression, they do not reverse established fibrosis, highlighting the need for treatments with new mechanisms of action.
Rentosertib inhibits Traf2- and NCK-interacting kinase (TNIK), a serine/threonine kinase involved in multiple profibrotic and inflammatory signaling pathways, including Wnt, TGF-β, Hippo/YAP-TAZ, JNK, and NF-κB. Using multi-omics datasets and aging biology analyses, PandaOmics identified TNIK as a previously underexplored therapeutic target for pulmonary fibrosis.
Phase III Trial Builds on Encouraging Phase IIa Results
The pivotal Phase III study is a randomized, double-blind, placebo-controlled, parallel-group trial expected to enroll 320 patients across 47 centers in China. Participants will receive once-daily rentosertib or placebo over 52 weeks. The primary endpoint is the annual rate of decline in forced vital capacity (FVC), while a key secondary endpoint evaluates time to first disease progression event.
The study follows the multicenter GENESIS-IPF Phase IIa trial (NCT05938920) involving 71 patients with IPF across 22 clinical sites. The trial met its primary objective by demonstrating manageable safety and tolerability across treatment groups. Patients receiving the 60 mg once-daily dose experienced a mean improvement of 98.4 mL in FVC after 12 weeks compared with a 20.3 mL decline in the placebo arm. Exploratory biomarker analyses also supported antifibrotic and anti-inflammatory activity consistent with TNIK inhibition.
Leadership Highlights Scientific Progress
Leading principal investigator Professor Zuojun Xu of Peking Union Medical College Hospital said the Phase IIa trial demonstrated a dose-dependent efficacy trend that attracted broad scientific interest and justified evaluation in a larger, longer-duration study. He emphasized the importance of maintaining consistent study standards and data quality across participating centers during Phase III.
Feng Ren, PhD, Co-Chief Executive Officer and Chief Scientific Officer of Insilico Medicine, said the program originated from an AI-driven biology-first approach that linked TNIK to fibrosis and aging-related mechanisms before generative AI produced a clinically suitable drug candidate. Carol Satler, MD, PhD, Senior Vice President for Clinical Development, added that the pivotal trial will determine whether the lung-function improvements observed in Phase IIa translate into clinically meaningful benefits for patients with IPF.
Phase III Marks a Milestone for AI-Driven Drug Discovery
Rentosertib is Insilico Medicine’s first investigational therapy to enter Phase III development and remains an investigational drug without regulatory approval. The U.S. FDA previously granted Orphan Drug Designation for IPF in 2023. Beyond the clinical program, the company continues to expand its AI-driven pipeline, reporting 31 preclinical candidate nominations, 13 investigational new drug clearances, and eight ongoing Phase I studies. If successful, the Phase III trial could establish rentosertib as a first-in-class oral TNIK inhibitor and provide further evidence for AI-enabled drug discovery in late-stage clinical development.
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About the Writer
Farha Farheen, PharmD (LinkedIn) is a pharmacy professional with a strong interest in pharmacovigilance and clinical research. She has completed her Doctor of Pharmacy (Pharm.D) along with her internship as a Clinical Pharmacist. She has hands-on experience in adverse drug reaction (ADR) reporting, safety data documentation, and pharmacovigilance workflows, and is proficient in using VigiFlow. She is also a patent holder for an antibacterial formulation enriched with bioactive substances, granted by the German Patent and Trademark Office.