insitro Presents New Data Demonstrating Its AI-Discovered MASH Candidate Shows Anti-Fibrotic Signal Beyond Liver-Fat Reduction at the American Diabetes Association 86th Scientific Sessions

• Findings from insitro’s lead therapeutic CTRO-1013 program demonstrate that liver-targeted silencing of IRS1 lowered circulatory biomarkers associated with fibrosis progression and hepatocyte injury in an industry-standard fibrogenic preclinical mouse model of MASH
• Data presented today at ADA provide converging evidence from human genetics and preclinical models supporting IRS1’s effect on liver fat and liver fibrosis
• The findings extend insitro’s AI-driven discovery of IRS1 – the strongest of 480 genetic signals for liver fat – and support the development of CTRO-1013 toward first-in-human trials this year

NEW ORLEANS--(BUSINESS WIRE)--insitro, the physical AI company unlocking causal human biology, today presented new preclinical data from its metabolic dysfunction-associated steatohepatitis (MASH) therapeutic development program during a podium presentation at the American Diabetes Association (ADA) 86th Scientific Sessions. The data demonstrate that liver-targeted silencing of IRS1 reduced fibrosis progression and injury-associated circulatory biomarkers in an industry-standard fibrogenic preclinical mouse model, with effects that appear partly independent of reductions in liver fat. The findings support the continued advancement of CTRO-1013, the company’s liver-targeted IRS1 candidate, through IND-enabling studies toward first-in-human trials this year.

The presentation, “Hepatic IRS1 as a Therapeutic Target in MASLD: AI/ML Driven Genetic Discovery and In Vivo Therapeutic Validation,” was delivered by Santhosh Satapati, Ph.D., Senior Director of Metabolic Diseases at insitro.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disease marked by excess fat accumulation in the liver. MASH is the progressive form of MASLD in which fat accumulation is accompanied by inflammation, liver injury, and fibrosis. Fibrosis – the scarring that can progress to cirrhosis, liver failure, and liver cancer – is one of the strongest predictors of poor outcomes for patients with MASH. Yet finding high-confidence targets has been difficult because the most relevant liver phenotypes, fibrosis among them, are hard to measure at the scale needed for human genetic discovery.

Human genetic analyses revealed an IRS1-associated fibrosis signal that persists even after adjusting for liver fat, suggesting a fibrotic mechanism independent of steatosis. To evaluate this genetic hypothesis, insitro tested liver-targeted IRS1 silencing in preclinical models. Data presented today showed significant reductions in TIMP-1 and CK-18 levels, key biomarkers associated with fibrosis progression and hepatocyte injury. IRS1 inhibition also reduced liver fat in AMLN-DIO mice. Together, these results reinforce prior insitro data demonstrating improvements in liver-injury endpoints and fibrosis-related gene expression, establishing a consistent role for IRS1 across both human genetics and preclinical models.

“MASH remains an area of significant unmet need, with a dearth of interventions capable of fundamentally shifting the disease trajectory,” said Daphne Koller, Ph.D., founder and CEO of insitro. “The primary obstacle has been bridging the gap between early metabolic indicators, like de novo lipogenesis, and the fibrotic processes that dictate clinical outcomes. Utilizing our Virtual Human™ platform, we applied AI-derived liver fat and fibrosis phenotypes from multimodal human data to identify causal targets, such as IRS1, where metabolic stress and fibrosis biology appear to converge.”

To translate this target discovery into clinical development, insitro is advancing CTRO-1013, an investigational liver-targeted siRNA therapeutic designed to selectively silence IRS1.

“IRS1 stands out because it bridges what have often been treated as two separate problems: metabolic dysfunction and fibrotic scarring,” said David Lloyd, Ph.D., Senior Vice President of Metabolic Disease and Translational Pharmacology at insitro. “By targeting IRS1 with CTRO‑1013, we see improvements in liver fat alongside encouraging shifts in biomarkers linked to fibrosis progression. While still preclinical, these data suggest that IRS1 inhibition could offer a path to meaningfully altering the trajectory toward severe, end‑stage liver disease.”

insitro identified IRS1 through analysis of human phenotypic, biomarker, and genetic data, including UK Biobank imaging and clinical datasets linked to liver fat and adipose biology. Genetic analyses prioritized IRS1 as a therapeutic target associated with liver fat biology and revealed a fibrosis-associated signal that persisted after adjustment for fat.

The company then validated the target experimentally. A potent, selective, liver-targeted siRNA against IRS1 suppressed lipid accumulation in human hepatocytes. In diet-induced obese mice, a single dose reduced hepatic IRS1 expression by 85%, de novo lipogenesis by 59%, and hepatic triglycerides by 45% after one month, while significantly improving NAS score versus vehicle.

Liver-targeted IRS1 silencing also led to significant reductions in TIMP-1 (37%) and CK-18 (68%) after 16 weeks of treatment (1 mg/kg, Q4W) in a standard fibrogenic preclinical mouse model compared to vehicle-treated controls. In cynomolgus monkeys, liver-targeted IRS1 silencing produced sustained target reduction over 90 days without affecting glucose homeostasis.

"The strength of these findings lies in the consistency of the signal – from human cells to preclinical models and non-human primates – across lipogenesis, liver injury, and fibrosis,” said Philip Tagari, Chief Scientific Officer of insitro. “This breadth of evidence is critical; it indicates that IRS1 modulation impacts disease pathology through pathways that are distinct from simple fat clearance, reinforcing our therapeutic rationale as we advance CTRO-1013 toward the clinic."

CTRO-1013 was designed from the outset for tissue-selective delivery to the liver, concentrating activity where it is needed while limiting systemic exposure.

According to Satapati, the integration of AI-derived phenotypes, human genetic data, clinical imaging, and rigorous preclinical testing provides a clearer, more human-relevant view of IRS1 inhibition than traditional animal models alone. “The anti-fibrotic signals observed in the data appear to function through mechanisms that are partially independent of liver-fat reduction, providing a vital insight the team is continuing to investigate.”

Additional mechanistic and histological analyses are ongoing. insitro is continuing IND-enabling studies for CTRO-1013 and expects the program to enter first-in-human clinical trials this year.

Presentation Details

Title: Hepatic IRS1 As a Therapeutic Target in MASLD: AI/ML Driven Genetic Discovery and In Vivo Therapeutic Validation

Abstract Number: 1331-OR

Presenter: Santhosh Satapati, PhD

Meeting: American Diabetes Association 86th Scientific Sessions

Location: New Orleans, Louisiana

About insitro

insitro is the physical AI company unlocking causal human biology, founded and led by AI pioneer Daphne Koller. By generating the world’s largest integrated multimodal corpus of human and cellular data, we’ve built the Virtual Human™ – a genetically anchored causal AI engine that reveals how disease begins, progresses, and can be resolved. Our platform enables us to precisely identify causal genetic drivers and deploy our TherML AI platform to design optimal medicines, advancing a broad pipeline of therapeutics for neuroscience and metabolic diseases. This industrialized architecture creates a self-learning loop: with every biology we onboard, our predictive models grow smarter, accelerating discovery across scales of biology. Backed by more than $750M in capital from world-class investors like a16z, ARCH, BlackRock, Casdin, CPP, Foresite, GV, SoftBank, Temasek, Third Rock, T. Rowe Price – including ~$140M in revenue from collaborations with BMS, Lilly, and Gilead – insitro is rebuilding drug discovery from an unpredictable journey into an industrialized, repeatable process with scalable impact for patients and the world.