Lack of efficacy is the leading reason drug candidates fail in clinical trials. A 2024 analysis by Olesya Razuvayevskaya and colleagues, published in Nature Genetics, applied natural language processing to 28,561 trial stoppage records on ClinicalTrials.gov and found that trials halted for efficacy failures showed consistently weaker genetic support for the drug-target hypothesis; stronger genetic evidence roughly halved the odds of early stoppage. The preclinical testing that cleared those failed candidates relied largely on animal models that do not replicate human disease biology.
VivoSim Labs, a pharmaceutical and biotechnology services company, announced the extension of its NAMkind platform to include human disease models for drug efficacy testing in the liver and gastrointestinal (GI) tract. The new service lines add metabolic dysfunction-associated steatohepatitis (MASH) and inflammatory bowel disease (IBD) efficacy testing to the toxicology services at the core of VivoSim's business. The expansion aligns with a regulatory shift: in April 2025, the FDA published a strategy to phase down animal testing in preclinical safety studies, followed in March 2026 by a draft guidance outlining NAM validation requirements for new approach methodologies (NAMs), a category covering human cell-based models, three-dimensional tissues, microphysiological systems, and computational approaches.
MASH and IBD: why rodent models cannot close the translational gap
Species-specific biology is the core failure of animal models in MASH and IBD: progressive fibrosis, immune dysregulation, and inter-individual variation in treatment response are either absent or artificially induced in murine systems. Resmetirom, a thyroid hormone receptor beta-selective agonist, became the first FDA-approved therapy for MASH in March 2024, achieving fibrosis improvement of at least one stage in 24 to 26 percent of treated participants in the MAESTRO-NASH Phase 3 trial. Despite that milestone, the vast majority of MASH drug candidates have failed in Phase 2 or Phase 3 trials; a 2025 review in Advanced Biology found that dietary and genetic rodent models capture neither the full spectrum of human disease etiology nor the progressive fibrotic response that defines clinical MASH.
In IBD, the mechanistic heterogeneity of ulcerative colitis and Crohn's disease, which determines why some patients respond to JAK inhibitors while others do not, is equally invisible to animal models that lack the genetic and cellular architecture of human disease. In studies showing organoids predict drug responsiveness presented at Digestive Disease Week, organoids from ulcerative colitis patients stratified by tofacitinib sensitivity tracked closely with actual clinical outcomes in those same individuals. The FDA's 2026 draft NAM guidance explicitly positioned human tissue-based models as capable of supporting investigational new drug (IND) applications without traditional animal efficacy data in some contexts, a formal signal that human-first preclinical testing is gaining regulatory traction.
How NAMkind tests MASH and IBD compounds in human disease tissue
The NAMkind MASH model uses liver tissue that is already diseased, not tissue chemically induced into a disease state. It co-cultures primary human hepatocytes with hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells from a donor with histologically confirmed MASH, generating spontaneous steatosis and fibrosis across 14 or 21 days of repeated compound dosing. Fibrosis, liver function, and cell health markers are measured in the same study, separating genuine anti-fibrotic activity from cytotoxicity, with resmetirom as the clinical reference benchmark in every run.
The NAMkind IBD model uses colon and small-intestine organoids from 12 donors with ulcerative colitis or Crohn's disease. Barrier integrity, inflammation, and fibrosis are measured simultaneously in the same well, with results reported per donor to preserve inter-individual variability. Reference compounds include tofacitinib and upadacitinib; VivoSim has documented that JAK inhibitors appearing pharmacologically equivalent diverge in their fibrosis, barrier, and inflammation effects in donor-derived colonoids, consistent with published ex vivo mucosal data showing site-specific JAK inhibitor responses differ between colonic and ileal tissue.
A sponsor can confirm both functional efficacy and drug mechanism within a single study using the five readouts below.
- MASH liver model: co-culture of hepatocytes, stellate, Kupffer, and endothelial cells from a histologically confirmed MASH donor; 14- or 21-day repeated dosing; resmetirom as clinical reference benchmark
- IBD intestinal model: colon and small-intestine organoids from 12 ulcerative colitis and Crohn's disease donors; barrier integrity, inflammation, and fibrosis endpoints; per-donor reporting; healthy tissue comparator arm included
- Pharmacodynamic and target biomarker profiling: gene expression panels, cytokine profiling, extracellular matrix markers, target engagement assays, dose-response characterization
- Reference benchmarking: approved or clinically validated reference compound run alongside the client compound in every donor tissue
- Combined safety and efficacy: toxicology testing available on the same liver and GI platform, enabling both readouts within a single study design
"By leveraging patient-derived donor tissues, our disease platforms preserve the complex multiomic signatures and heterogeneous phenotypes seen in real-world clinical populations," said Amar Sethi, M.D., Ph.D., Chief Scientific Officer of VivoSim Labs. "Crucially, we can now evaluate candidate compounds not only for primary disease endpoints like fibrosis and barrier repair, but also for target-specific pharmacodynamic biomarkers. This dual capability allows drug developers to confirm both functional human efficacy and underlying drug mechanism on the exact same platform before entering clinical trials."
Does tissue sourcing change what a preclinical MASH model can tell you?
Whether the assay substrate carries the genetic and epigenetic architecture of human disease or approximates it through external stimuli depends entirely on tissue sourcing. Several academic groups and commercial contract research organizations (CROs) offer liver spheroid or organoid services for MASH using healthy hepatocytes stimulated with fatty acids or lipopolysaccharide; these platforms have demonstrated screening utility and validated against clinical candidates, but cannot replicate the donor-specific variation in disease progression, immune activation, and fibrogenic signaling that drives differential treatment response. Research on primary human tissue models confirmed patient-derived MASH tissue reproduces disease-relevant molecular signatures, including altered extracellular matrix organization and cholesterol biosynthesis pathways, at a level that diet-induced models do not match.
Tissue source is the variable that most determines what each platform can predict: the further the model is from patient-derived diseased tissue, the less it captures the inter-individual variation that drives differential treatment response in the clinic.
| Testing approach | Primary tissue source | Supported indications | Published evidence base | Key characteristics |
|---|---|---|---|---|
| Patient-derived diseased-donor 3D co-culture (NAMkind) | Primary human donor cells from histologically confirmed disease | MASH liver, IBD intestine; combined toxicology and efficacy | Digestive Disease Week Poster of Distinction (IBD, May 2025); aligned with FDA NAM roadmap | Per-donor reporting; spontaneous disease phenotype without chemical inducers |
| Commercial 3D liver spheroid platforms (healthy-donor induced) | Primary human hepatocytes from healthy donors, disease induced by fatty acids or lipopolysaccharide | MASH, general hepatotoxicity | Multiple peer-reviewed publications; validated against clinical MASH candidates | High-throughput screening capacity; disease state requires induction protocol |
| Academic patient-derived organoid biobanks | Patient biopsy-derived (IBD and other disease states) | IBD epithelial barrier function and drug response | Published in Scientific Reports, iScience, Inflamm Bowel Dis, and others | Foundational science; not standardized or available as a commercial CRO service at scale |
| Traditional rodent models (diet-induced or genetic) | Murine primary cells or genetically modified animals | MASH, IBD, metabolic and inflammatory diseases broadly | Established regulatory acceptance; FDA roadmap accelerating transition | Species-specific gaps limit clinical translation; fail to capture human inter-individual variability |
"Our customers often need help with whether a candidate is likely to work, because that is where many drugs fall short in the clinic," said Keith Murphy, Executive Chairman of VivoSim Labs. "Disease models let us address that question on the same human tissue platform we already use for safety, leveraging patient-derived diseased cell sources so customers learn more before committing a program to clinical trials. We believe disease models could more than double our addressable market."
FDA's NAM roadmap is accelerating the case for human tissue efficacy data
The FDA's April 2025 roadmap identified monoclonal antibody INDs as the first class where human-relevant alternatives could formally replace animal efficacy requirements. Its March 2026 draft guidance then provided a structured validation framework for NAM-based data in regulatory filings. In October 2025, the agency approved the first oncology IND backed solely by human vascularized organoid efficacy data, the first time human tissue evidence served as the basis for first-in-human trials without animal proof-of-concept testing.
For MASH specifically, this shift matters because the liver fibrosis endpoint requires demonstrating at least one stage of improvement without worsening disease activity, the FDA's accepted threshold for accelerated approval. Human tissue models with spontaneous disease phenotypes can test that threshold more faithfully than rodent systems where fibrosis must be chemically induced. Resmetirom's approval validated the endpoint; patient-derived platforms now offer a way to calibrate compound confidence against that same standard before Phase 2 entry.
Patient-derived NAMs reduce attrition risk, but prospective validation remains the open question
Patient-derived human disease models directly address the leading cause of clinical trial failure by exposing drug candidates to tissue carrying the molecular architecture of actual disease before a single participant is enrolled. VivoSim's NAMkind platform brings that approach to the MASH and IBD indications with the longest history of preclinical-to-clinical translation failures, combining spontaneous disease phenotype, per-donor reporting, and pharmacodynamic biomarker profiling within a single study design aligned with the FDA's evolving NAM guidance. Whether platforms of this type can durably reduce a drug attrition rate that has remained above 90 percent for decades depends on the prospective validation evidence needed for human tissue efficacy data to inform regulatory submissions and portfolio decisions across the industry.
This article is based on a GlobeNewswire announcement from VivoSim Labs and was produced under Drug Discovery News' AI Editorial Guidelines.
