Nonclinical work in fibrosis

Fibrosis is the replacement of functional tissue with scar, and it occurs in the liver, lung and kidney among other organs. For a development programme the defining feature is that the process is progressive and, once established, does not readily reverse. That shapes the nonclinical work: a compound intended to prevent fibrosis and one intended to reverse established fibrosis need different models, and a model in which fibrosis is still developing cannot answer the second question.

This is also an area where the relationship between animal results and clinical results is unusually well documented, and unusually discouraging. That is where this article starts, because it changes how a nonclinical result here should be read.

What the field says about its own models

An official workshop report of the American Thoracic Society, addressing the use of animal models for preclinical assessment of potential therapies for pulmonary fibrosis, states the position directly: numerous compounds have shown efficacy in limiting the development of pulmonary fibrosis using animal models, yet few of these compounds have replicated those beneficial effects in clinical trials.^[S1] This is not an argument against running the studies. It is an argument for being precise about what a positive result in one of them supports, and for designing the study so that a positive result is informative rather than merely favourable.

The models in common use

The models used are established and differ by organ. A published review covers the liver and kidney sets: carbon tetrachloride, bile duct ligation and dimethylnitrosamine induction for liver fibrosis, and unilateral ureteral obstruction for renal fibrosis.^[S3] In the lung, bleomycin administered into the airway is the standard. Each produces fibrosis by a defined injury, which is both their utility and their limitation: the injury is not the one patients sustain, and the time course is compressed from years into weeks.

One recent published example illustrates what a multi-organ anti-fibrotic programme looks like. A small-molecule inhibitor of TRAF2 and NCK-interacting kinase, identified through a machine learning approach and designated INS018_055, is reported to show anti-fibrotic activity across different organs in vivo by oral, inhaled and topical administration.^[S2] The paper is cited here for its content. It is not associated with any laboratory named on this site, and this article draws no conclusion about the compound clinical prospects.

A programme that reached clinical trials

A candidate developed by Nitto Denko Corporation, later carried forward in trials sponsored by Bristol Myers Squibb with Nitto Denko as a listed collaborator, illustrates the pattern.^[S5] The mechanism is described in a published pharmacokinetic and safety paper as a retinoid-conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47, a collagen-specific chaperone protein involved in fibrosis development.^[S4] That is a rational target: a protein required for collagen maturation, addressed by a modality that can be directed to the cells producing it.

What happened next

One of the clinical trials, in adults with compensated cirrhosis arising from steatohepatitis, was terminated. The reason recorded in the trial registry is that the trial was terminated because of lack of efficacy in the short term acute phase.^[S6] That is a clinical outcome and is reproduced here as a registry fact rather than an assessment. Its relevance to this article is what it illustrates: a target supported by mechanism, a delivery system characterized in published work, and nonclinical activity, none of which guaranteed the clinical result. That is the pattern the workshop report describes.^[S1]

What to settle before placing the work

Whether fibrosis is established before dosing begins or develops during it. A compound given from the day of induction is being tested for prevention, whatever the study is called.', 'What the primary endpoint is. Histological scoring, collagen quantification and imaging can disagree, and the one that will decide the programme should be named in the protocol.', 'Who reads the histology, whether the reader is blinded to treatment group, and whether the scoring system is one used in published work.', 'What the historical control data look like for this model at this laboratory, since variability in the induction determines the effect size the study can detect.', 'Whether the study is exploratory pharmacology, which is normally conducted outside the good laboratory practice regulation, or part of the regulated package.^[S7]

Summary

Fibrosis remains an area with few approved options and substantial development activity across several mechanisms and organs. The nonclinical models are well established and widely available.

The practical conclusion for a sponsor is narrower than encouragement. In an area where the field has documented that animal efficacy has rarely carried into the clinic,^[S1] the value of a nonclinical study lies in how precisely it is designed and how conservatively it is interpreted, not in whether it produces a positive result.

About this article

This is an independent editorial article for people who commission nonclinical work in the United States. It does not discuss the efficacy of any product, and clinical trial outcomes are reproduced only as recorded in the public trial registry. It does not recommend any laboratory. Results in animal models describe the model; the workshop report cited above sets out how rarely they have carried into clinical results in this area. Last reviewed: September 3, 2026.

References

1. An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis. https://pubmed.ncbi.nlm.nih.gov/ (accessed 2026-09-03)
2. Ren F, et al. A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models. Nature Biotechnology. 2025 (PMID 38459338; DOI 10.1038/s41587-024-02143-0). https://pubmed.ncbi.nlm.nih.gov/38459338/ (accessed 2026-09-03)
3. Preclinical approaches to studying liver and kidney fibrosis: models and methodologies. https://pubmed.ncbi.nlm.nih.gov/ (accessed 2026-09-03)
4. Pharmacokinetics, safety, and tolerability of BMS-986263, a lipid nanoparticle containing HSP47 siRNA（PMID 37654022; DOI 10.1111/cts.13581）. https://pubmed.ncbi.nlm.nih.gov/37654022/ (accessed 2026-09-03)
5. ClinicalTrials.gov — Phase 1b/​2, Open Label, Repeat Dose, Dose Escalation Study of ND-L02-s0201 Injection in Subjects With Moderate to Extensive Fibrosis. https://clinicaltrials.gov/study/NCT02227459 (accessed 2026-09-03)
6. ClinicalTrials.gov — Safety and Effectiveness of BMS-986263 in Adults With Compensated Cirrhosis (Liver Disease) From Nonalcoholic Steatohepatitis (NASH). https://clinicaltrials.gov/study/NCT04267393 (accessed 2026-09-03)
7. 21 CFR Part 58 — Good Laboratory Practice for Nonclinical Laboratory Studies (§58.1 scope). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-58 (accessed 2026-09-03)