garutadustat (ISM5411) / Insilico Medicine - LARVOL DELTA

ISM012-042 (ISM5411), A PHD1/2 INHIBITOR, PREVENTATIVELY AND THERAPEUTICALLY MITIGATES T CELL TRANSFER-INDUCED COLITIS IN MICE (CCCongress 2026) - "ISM012-042 , administered preventively or therapeutically, alone or with anti-TNF-α, effectively mitigated chronic T cell transfer-induced colitis by preserving colon integrity, and suppressing pro-inflammatory T cell subsets and cytokines, suggesting its potential as a versatile IBD therapy. References: 1. Fu, Y., Ding, X., Zhang, M. et al."

Preclinical • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • GATA3 • IFNG • IL17A • IL6

PRECLINICAL TOXICOLOGY EVALUATION OF ISM5411: 13-WEEK ORAL ADMINISTRATION IN RATS AND BEAGLE DOGS (CCCongress 2026) - "The 13-week oral administration of ISM5411 in both rats and Beagle dogs demonstrated a favorable safety profile, with no observed adverse effects at the highest tested doses of 1000 mg/kg. These results support clinical advancement of ISM5411 and inform dose selection and safety monitoring in human trials."

Preclinical • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Ophthalmology • HIF1A

ISM5411, A NOVEL GUT-RESTRICTED PHD1/2 INHIBITOR FOR INFLAMMATORY BOWEL DISEASE: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, FIRST-IN-HUMAN PHASE I STUDY TO EVALUATE SAFETY, TOLERABILITY AND PK PROFILES (CCCongress 2026) - P1 | "ISM5411 tablets were safe and well-tolerated at all doses administered and demonstrated good gut restriction, consistent with preclinical findings and potential disease-localized activity. Phase 2a proof-of-concept testing of ISM5411 is ongoing in patients with UC to explore the safety, PK, and clinical efficacy. References: 1."

Clinical • First-in-human • P1 data • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

First-in-human Phase 1 (Australia): safety, tolerability, and pharmacokinetics consistent with gut restriction (Citybizlist) - "Key findings reported in the abstract include: 76 subjects dosed; no serious adverse events (SAEs) or deaths reported at any dose; One discontinuation due to a grade 1 rectal hemorrhage, judged not related to ISM5411...Pharmacokinetics: Oral ISM5411 resulted in very low plasma exposure and >30% excreted in feces in prototypic form, supporting a gut-restricted profile; Biomarkers: Post-dose erythropoietin (EPO) changes largely within or near normal range; no clear trend observed in systemic VEGF across cohorts; both support a gut-restricted profile with minimal expression of systemic HIF-1α stabilization biomarkers."

First-in-human • P1 data • PK/PD data • Inflammatory Bowel Disease

Chronic T cell transfer-induced colitis model: preventive and therapeutic mitigation, including with anti-TNF (Citybizlist) - "Preventive ISM012-042 (10 or 30 mpk, PO QD) or anti-TNF-α reduced disease severity across endpoints including body weight loss, disease activity index (DAI), and colon morphology, and reduced inflammatory mucosal cytokines such as IFN-γ, TNF-α, and IL-6, along with decreases in inflammatory T cell subsets in mesenteric lymph nodes; Histology showed less crypt damage, inflammatory infiltration, and fibrosis with administration of ISM012-042 (ISM5411) with and without anti-TNF-α; Therapeutic dosing post-induction (and combination with anti-TNF-α) reduced DAI, colon density, and mucosal cytokines including IL-6, IFN-γ, TNF-α, and IL-17A."

Preclinical • Inflammatory Bowel Disease • Ulcerative Colitis

13-week repeat-dose toxicology (rats and dogs): favorable profile and NOAEL at highest dose tested (Citybizlist) - "ISM5411 was well tolerated in both species, with no test article-related adverse findings; Findings were limited to moderate, reversible increases in erythroid parameters in dogs (≤+30.34% in RBC count, hemoglobin, hematocrit), which fully resolved after recovery and were not considered adverse based on lack of associated pathology/histopathology; ISM5411 demonstrates approximately 100-fold higher exposure in colon tissue versus plasma across preclinical species, supporting a gut-restricted, localized pharmacology profile with minimal systemic exposure; No observed adverse effect level (NOAEL): 1000 mg/kg/day in both species, supporting clinical advancement and informing dose selection and safety monitoring."

Preclinical • Inflammatory Bowel Disease

Insilico Medicine Completes First Patient First Dose in BETHESDA: A Phase II Trial for Garutadustat (ISM5411), the Gut-restricted AI-driven PHD Inhibitor for the Treatment of Inflammatory Bowel Disease (PRNewswire) - "In approximately 80 participants with ulcerative colitis, BETHESDA plans to assess the safety, tolerability, and pharmacokinetics (PK) of Garutadustat, and efficacy signals will be monitored through clinical remission/response, endoscopy, histopathology, and biomarker exploration."

Trial status • Inflammatory Bowel Disease • Ulcerative Colitis

Study Evaluating ISM5411 Administered Orally to Subjects With Active Ulcerative Colitis (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: InSilico Medicine Hong Kong Limited

New P2 trial • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

THERAPEUTIC EFFICACY OF ISM012-042(ISM5411)IN T CELL TRANSFER-INDUCED COLITIS IN MICE (UEGW 2025) - "ISM012-042, administered preventively or therapeutically, alone or with anti-TNF-α, effectively mitigated chronic T cell transfer-induced colitis by preserving colon integrity, and suppressing pro-inflammatory T cell subsets and cytokines, suggesting its potential as a versatile IBD therapy."

Preclinical • Crohn's disease • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • GATA3 • IFNG • IL17A • IL6

ISM5411, A NOVEL GUT-RESTRICTIVE PROLYL HYDROXYLASE-2 INHIBITOR FOR INFLAMMATORY BOWEL DISEASE: RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED FIRST-IN-HUMAN PHASE I STUDY TO EVALUATE SAFETY, TOLERABILITY AND PK PROFILES (UEGW 2025) - "ISM5411 tablets were safe and well-tolerated and demonstrated good gut-restrictive property, consistent with the intended PK profile. Another Phase I study in China was also completed. Phase 2a proof of concept study of ISM5411 is under planned in patients with ulcerative colitis to explore the safety, PK and clinical efficacy."

Clinical • First-in-human • P1 data • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • HIF1A

Insilico Received Positive Topline Results from Two Phase 1 Trials of ISM5411, New Drug Designed Using Generative AI for the Treatment of Inflammatory Bowel Disease (PRNewswire) - P1 | N=79 | NCT06012578 | Sponsor: InSilico Medicine Hong Kong Limited | N=48 | CTR20241789 | Sponsor: Insilicon Intelligence Technology (Shanghai) Co., Ltd. | "The data indicates that ISM5411 was generally safe and well tolerated across all dose groups of two Phase I studies, with no reports of serious adverse events or treatment-related adverse events (TRAEs) leading to discontinuation...The observed human PK of ISM5411 in healthy volunteers was in line with the Company's preclinical modeling, with no significant drug accumulation observed after 14 days of multiple administration across all dosing groups. ISM5411 also exhibited a favorable PK profile....Based on these results, Insilico Medicine expects to initiate a Phase 2 proof-of-concept study evaluating ISM5411 in active ulcerative colitis patients in the second half of 2025."

New P2 trial • P1 data • Inflammatory Bowel Disease • Ulcerative Colitis

Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor. (PubMed, Nat Biotechnol) - "Here we used a multimodel multimodal generative artificial intelligence platform to design an orally gut-restricted selective PHD1 and PHD2 inhibitor that exhibits favorable safety and pharmacokinetic profiles in preclinical studies. ISM012-042 restores intestinal barrier function and alleviates gut inflammation in multiple experimental colitis models."

Journal • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease

Nature Biotechnology | Generative Chemistry Enables Insilico to Develop Gut-Restricted PHD Inhibitors Promising for Intestinal Mucosal Barrier Repair and Immunomodulation (PRNewswire) - "Recently, scientists at Insilico Medicine utilized the comprehensive generative chemistry engine Chemistry42 to discover a novel gut-restricted PHD inhibitor that shows promise for repairing the intestinal mucosal barrier and regulating immune responses in IBD. The study, published in Nature Biotechnology, highlights the role of Chemistry42 and its submodules in supporting drug candidate design and optimization....At the time of this publication, two Phase 1 clinical trials of ISM5411 for the treatment of IBD are being conducted in parallel in Australia and China."

Preclinical • Trial status • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Study Evaluating ISM5411 Administered Orally to Healthy Volunteers (clinicaltrials.gov) - P1 | N=79 | Completed | Sponsor: InSilico Medicine Hong Kong Limited | Recruiting ➔ Completed

Trial completion

Insilico Medicine Announces First-in-Human Study for Orally PHD Inhibitor ISM5411 for Inflammatory Bowel Disease (IBD) (PRNewswire-Asia) - "Insilico Medicine...announced that the company has initiated the first-in-human study for ISM5411, a potentially first-in-class PHD inhibitor for the treatment of inflammatory bowel disease (IBD)....The ongoing Phase I study is designed to evaluate the safety, tolerability, pharmacokinetics and food effects of ISM5411 at increasing oral doses in 76 healthy subjects, with the first dose in healthy volunteers now completed in Australia. To further evaluate ISM5411 in wider populations, Insilico plans to conduct global multi-center Phase Ib trials in patients with ulcerative colitis following the Phase Ia study."

Trial status • Immunology • Inflammatory Bowel Disease