rentosertib (INS018_055) / Insilico Medicine - LARVOL DELTA

Incentivizing challenging drug discovery: from reducing failure to quantifying uncertainty. (PubMed, Expert Opin Drug Discov) - "It discusses the risk-uncertainty distinction, AI as a new layer in the computational drug-discovery stack, the cumulative nature of confidence (illustrated by KRAS, PCSK9 and the AI-discovered TNIK inhibitor rentosertib), discordant evidence, AI's limitations, and incentive design. Literature was identified from PubMed/MEDLINE, Scopus and Google Scholar to August 2026, with primary sources and trial registries; as an invited editorial, the search was narrative, not systematic. AI's deepest contribution is epistemic rather than algorithmic: unlikely to lower failure rates markedly, but by making uncertainty measurable it can improve portfolio decisions and render ambitious biology attemptable - given calibration, prospective validation, open negative data, and incentives that reward reducing uncertainty."

Journal • KRAS

Study Evaluation Rentosertib (INS018_055) Administered Orally in Patients With Idiopathic Pulmonary Fibrosis (IPF) (clinicaltrials.gov) - P3 | N=320 | Recruiting | Sponsor: InSilico Medicine Hong Kong Limited | Not yet recruiting ➔ Recruiting

Enrollment open • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Insilico Medicine…announced that it has dosed the first patient with Rentosertib (known as ISM001-055 / INS018_055) in GENESIS-IPF-3, a Phase III clinical trial (NCT07687459, CTR20262475) at Peking Union Medical College Hospital, while Shanghai Pulmonary Hospital has also enrolled its first patient on the same day (PRNewswire) - "The 52-week prospective, randomized, multi-center, double-blind, placebo-controlled, parallel-group Phase III study in patients with idiopathic pulmonary fibrosis is expected to enroll a total of 320 participants across 47 centers in China."

Trial status • Idiopathic Pulmonary Fibrosis

Integration of proteomic aging clocks in a phase 2a clinical trial supports simultaneous geroprotective assessment. (PubMed, Nat Biotechnol) - "We addressed this issue indirectly through pathway analyses that identified potential anti-aging shifts in senescence and metabolic processes alongside the anti-fibrotic activity of rentosertib. This work supports the goal of dual-purpose clinical trial designs that integrate aging endpoints into studies for specific disease indications."

Journal • P2a data • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Artificial Intelligence-Driven Natural Product Drug Discovery: From Computational Genome Mining to Clinical Translation. (PubMed, Med Res Rev) - "Representative case studies, including the synthetic AI-designed clinical benchmark rentosertib, illustrate the current evidence spectrum from discovery-level validation to early clinical benchmarking, while also highlighting that most AI-enabled NP discovery workflows remain at the preclinical or proof-of-concept stage, with limited quantitative evidence of improved clinical productivity...This operational focus fills a critical gap between algorithmic capability and clinically actionable NP-derived leads. Importantly, while AI has demonstrably accelerated several early discovery steps, quantitative comparisons with classical NP workflows remain limited, and most reported advances are supported by preclinical or proof-of-concept studies rather than systematic evidence of improved time-to-lead, cost reduction, or clinical success rates."

Journal • Review • Cognitive Disorders

A multistage computational pipeline integrating ligand-based and structure-based screening with ADMET evaluation, molecular dynamic simulation and free energy calculations for the discovery of potential TNIK inhibitors. (PubMed, Talanta) - "MM/PBSA free energy calculations revealed favorable binding energies, comparable to clinical-phase TNIK inhibitor INS018_055. This LBVS-SBVS-ADMET-MD pipeline effectively identified three promising TNIK inhibitors, providing a solid foundation for future experimental validation and potential development of targeted therapies for Wnt-driven malignancies."

Journal • Colorectal Cancer • Hematological Malignancies • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Pain • Solid Tumor • Squamous Cell Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CTNNB1 • TCF4

Insilico Initiates Phase III Clinical Trial for Rentosertib, Its AI-Empowered TNIK Inhibitor for Idiopathic Pulmonary Fibrosis (Insilico Medicine Press Release) - "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."

Trial status • Idiopathic Pulmonary Fibrosis • Immunology

Study Evaluation Rentosertib (INS018_055) Administered Orally in Patients With Idiopathic Pulmonary Fibrosis (IPF) (clinicaltrials.gov) - P3 | N=320 | Not yet recruiting | Sponsor: InSilico Medicine Hong Kong Limited

New P3 trial • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

TNIK EXPANDS LEUKEMIC STEM CELLS BY ACTIVATING NF-ΚB SIGNALING AND REPRESENTS A NOVEL THERAPEUTIC TARGET IN ACUTE MYELOID LEUKEMIA (EHA 2026) - "Pharmacologic TNIK inhibition (INS018-055) was used to evaluate the effects and therapeutic potential of TNIK blockade on LSC function and leukemia progression...Summary/Conclusion TNIK is a critical regulator of LSC self-renewal, proliferation, and survival in myeloid leukemias, acting in part through NF- κ B activation. Targeting TNIK selectively impairs leukemic stem cells while preserving normal hematopoiesis, identifying TNIK inhibition as a promising therapeutic strategy to improve outcomes in AML."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Solid Tumor • ABL1 • BCR • TNIK

TRAF2 AND NCK INTERACTING KINASE SIGNALING DRIVES MULTIPLE MYELOMA DEVELOPMENT AND PROGRESSION (EHA 2026) - "Pharmacologic TNIK inhibition using INS018-055 reduced proliferation and induced apoptosis in TNIK- proficient MM cells...Summary/Conclusion TNIK acts as a central regulator of multiple myeloma cell growth and survival by promoting MAPK/ERK and Wnt/ β -catenin signaling. Genetic depletion or pharmacologic inhibition of TNIK suppresses myeloma cell proliferation and tumor growth in vitro and in vivo, highlighting TNIK as a promising therapeutic target in multiple myeloma."

IO biomarker • Chronic Myeloid Leukemia • Colorectal Cancer • Endocrine Disorders • Hematological Malignancies • Leukemia • Metabolic Disorders • Multiple Myeloma • Plasmacytoma • Solid Tumor • SDC1 • TNIK

Comparative efficacy and safety of monotherapy and combination pharmacotherapies for idiopathic pulmonary fibrosis: a network meta-analysis of randomized controlled trials. (PubMed, BMC Pulm Med) - "RHP, rentosertib, and nintedanib showed consistent signals for preserving FVC versus placebo. However, comparative effects on progression, mortality, and safety remain uncertain due to sparse data and limited head-to-head evidence. Large, well-designed trials with harmonized endpoints and longer follow-up are needed to validate these exploratory rankings and define optimal treatment sequencing and combinations."

Journal • Monotherapy • Retrospective data • Review • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Insilico's Rentosertib Inhalation Solution Receives IND Clearance for the World's First AI-Driven Candidate to Enter Direct-to-Lung Clinical Study (PRNewswire) - "The IND clearance supports a Phase I study to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of Rentosertib inhalation solution. The study will consist of two parts: (1) a randomized, double-blind, placebo-controlled Phase I trial in healthy participants involving single ascending dose (SAD) and multiple ascending dose (MAD) cohorts; and (2) a non-randomized, open-label evaluation in patients with Idiopathic Pulmonary Fibrosis (IPF) receiving multiple doses. Approximately 80 subjects are expected to be enrolled."

IND • New P1 trial • Idiopathic Pulmonary Fibrosis

Inhaled Rentosertib (ISM018_055), a Selective TNIK Inhibitor, Improves Lung Function and Reduces Fibrosis and Inflammation in Animal Models of Pulmonary Fibrosis (ATS 2026) - No abstract available

Preclinical • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Inhaled Rentosertib (INS018_055) Achieves High and Specific Pulmonary Exposure in Healthy And Fibrotic Lungs (ATS 2026) - No abstract available

Clinical • Fibrosis

Study Design of a Phase 1, Randomized, Double Blind, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of Inhaled Rentosertib (INS018_055) (ATS 2026) - No abstract available

Clinical • P1 data • PK/PD data • Interstitial Lung Disease

Inhaled Rentosertib (INS018_055) Exhibits High Safety and Tolerability in Animal Models (ATS 2026) - No abstract available

Preclinical • Interstitial Lung Disease

Artificial intelligence in the development of Rentosertib: A novel TNIK inhibitor for idiopathic pulmonary fibrosis - A letter to editor. (PubMed, Pulm Pharmacol Ther) - No abstract available

Journal • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Leading artificial intelligence-driven drug discovery platforms: 2025 landscape and global outlook. (PubMed, Pharmacol Rev) - "Key developments since 2024 include positive phase IIa results for Insilico Medicine's Traf2- and Nck-interacting kinase inhibitor, ISM001-055, in idiopathic pulmonary fibrosis...In addition, advancement of the Nimbus-originated tyrosine kinase 2 inhibitor, zasocitinib (TAK-279), into phase III clinical trials exemplifies Schrödinger's physics-enabled design strategy reaching late-stage clinical testing...Robotics tightly integrated with AI now enables self-driving laboratories that accelerate design-make-test-learn cycles and improve reproducibility. Together, these advances chart a forward-looking roadmap in which multimodal foundation models, robotics-led platforms, and hybrid physics-AI strategies are poised to accelerate translation, derisk development, and establish trustworthy AI as a cornerstone of modern drug discovery."

Journal • Review • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • TYK2

Study Evaluating INS018_055 Administered Orally to Subjects With Idiopathic Pulmonary Fibrosis (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: InSilico Medicine Hong Kong Limited | N=60 ➔ 40

Enrollment change • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

GENESIS-IPF: PHASE 2A COHORT CHARACTERISTICS AND LUNG IMAGING INDICATE CORRELATES OF RESPONSE TO ISM001-055 (RENTOSERTIB) IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS (CHEST 2025) - P2 | " High-resolution computed tomography (HRCT) was obtained at baseline (week 0) for 69 of 71 participants in INS018-055-003 (NCT05938920), a randomized, double-blind, placebo-controlled Phase 2a study in patients with IPF conducted at 22 clinical sites in China. The enrollment profile and baseline severity of disease in GENESIS-IPF participants and individual treatment arms is typical of the UK IPF patient population. The timing and methods for evaluating lung function is appropriate, as evidenced by the strong correlation between FVC and lung volume, which aligns with the expected physiological relationship. Changes in FVC and ppFVC from baseline to week 12 suggest that the best outcomes may occur in patients with the lowest level of fibrosis and the highest rentosertib treatment dose."

Clinical • P2a data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • COL1A1 • CTNNB1 • IL10 • MMP10 • TGFB1

Artificial Intelligence in Small-Molecule Drug Discovery: A Critical Review of Methods, Applications, and Real-World Outcomes. (PubMed, Pharmaceuticals (Basel)) - "Notable achievements include baricitinib (BenevolentAI/Eli Lilly, an existing drug repurposed through AI-assisted analysis for COVID-19 and rheumatoid arthritis), halicin (MIT, preclinical antibiotic), DSP-1181 (Exscientia, discontinued after Phase I), and ISM001-055/rentosertib (Insilico Medicine, positive Phase IIa results). We provide practical insights for integrating AI into drug discovery workflows, emphasizing hybrid human-AI approaches and the emergence of agentic AI systems that can autonomously navigate discovery pipelines. A critical evaluation of current limitations and future opportunities reveals that while AI offers significant potential as a complementary technology, realistic expectations and careful implementation are crucial for delivering innovative therapeutics."

Journal • Real-world evidence • Review • Immunology • Infectious Disease • Inflammatory Arthritis • Novel Coronavirus Disease • Rheumatoid Arthritis • Rheumatology

Comparison of the baseline clinical and HRCT characteristics of Insilico's ISM001_055 phase 2a trial cohort in China with real-world IPF datasets (ERS 2025) - P2 | "These results demonstrate that NCT05938920 has recruited patients whose baseline characteristics are representative of the broader IPF population. They provide promise that the positive results of NCT05938920 could be replicated in an ongoing ISM001_055 trial in the USA (NCT05975983)."

Clinical • P2a data • Real-world • Real-world evidence • Idiopathic Pulmonary Fibrosis

Rentosertib, a generative AI-discovered TNIK inhibitor improves lung function in IPF patients (ERS 2025) - "Figure 1: Change from baseline in FVC ± 95% CI after 12 weeks of treatment (excluding outliers*). *n=1 in placebo group and n=1 in 30mg QD group with >600 mL difference between screening and baseline FVC measurements."

Clinical • Idiopathic Pulmonary Fibrosis • Immunology

Traf2- and Nck-interacting kinase inhibitors: a patent review（2008 - 2024）. (PubMed, Expert Opin Ther Pat) - "Despite over 10 patents disclosing multiple scaffolds since 2008, only one inhibitor, INS018_055, has advanced to clinical trials to treat idiopathic pulmonary fibrosis. For the oncology indications, this is largely due to complexities in the relationship between TNIK and oncogenic pathways. Additionally, key characteristics of the molecules, such as kinase selectivity, physicochemical properties and pharmacokinetic profiles, have played significant roles in determining whether the molecules are drug-like enough to advance to clinical trials."

Journal • Review • CNS Disorders • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • CTNNB1

Insilico Medicine Announces Nature Medicine Publication of Phase IIa Results Evaluating Rentosertib, the Novel TNIK Inhibitor for Idiopathic Pulmonary Fibrosis (IPF) Discovered and Designed with a Pioneering AI Approach (PRNewswire) - P2a | N=71 | GENESIS-IPF (NCT05938920) | Sponsor: InSilico Medicine Hong Kong Limited | "The results demonstrated that Rentosertib exhibited a manageable safety and tolerability profile, with similar rates of treatment-emergent adverse events (TEAEs) observed across all treatment groups, thereby meeting the primary endpoint. Most adverse events (AEs) were mild to moderate in severity, and serious adverse events (SAEs) were rare. Notably, all adverse events resolved following discontinuation of treatment. Promising outcomes were also observed for the secondary efficacy endpoint, with a dose-dependent improvement in forced vital capacity (FVC), the gold-standard metric assessing lung function in IPF patients. Patients receiving 60 mg QD Rentosertib showed the greatest mean improvement in lung function, with a mean FVC increase of +98.4 mL, compared to a mean decline of -20.3 mL in the placebo group."

P2a data • Idiopathic Pulmonary Fibrosis