# TREATMENT OF LIVER INJURY AND FIBROSIS: SAFETY PHARMACOLOGY AND TOXICOLOGY

> **NIH NIH R44** · XFIBRA, INC. · 2020 · $1,136,111

## Abstract

Activation of liver myofibroblasts (LMF) of different origins is responsible for the development of liver fibrosis in
chronic liver diseases of all causes and remarkably, LMF clearance by apoptosis may prevent development of
liver fibrosis and liver injury, and possibly allow recovery from reversal of liver fibrosis. Inhibiting o reversing
myofibroblast activation (the therapeutic cellular target) is critical for the treatment of liver fibrosis. Both
preventing progression of liver fibrosis as well as possibly, regression of liver fibrosis despite continued liver
injury, as we documented in our pre-clinical studies, are considered important clinical targets for patients with
advanced liver fibrosis and cirrhosis. Finally, blocking the progression of liver fibrosis would decrease
development of primary liver cancer since most hepatocellular carcinomas arise in cirrhotic livers. The basis for
our Research and Development is the development of a novel ‘humanized’ therapeutic peptide (XFB-19). We
created a library using analog synthesis to improve potential pitfalls for human therapy. We have performed in
a step-wise manner assays to select the safest and most efficient ‘humanized’ peptide (including medicinal
chemistry, stability assays in human plasma and human liver microsomes, apoptosis assays in activated
primary human liver myofibroblasts, cell-free caspase 8 activation assays, liver injury/fibrogenesis models,
pharmacokinetics, bioassay, CYP-450 inhibition studies, immunogenicity assays in human T-cells and in mice,
cardiotoxicity assays in human stem cell-derived cardiomyocytes, and toxicology assays in HCV-infected
primary human hepatocytes and in normal and cirrhotic mice).
In an animal model of decompensated cirrhosis, the XFB-19 peptide rescues hepatocyte cell death and liver
failure, and remarkably prevents by 45 % animal mortality from week-16 to week-32.
We have developed a novel (first-in-class inhibitor of a site-specific phosphorylation) and highly effective anti-
fibrotic peptide in animal models, with no evidences of immunogenicity, and with exceptional stability in human
microsomal systems and human plasma. XFB-19 has excellent solubility in water. These features should
facilitate administration by subcutaneous injection with excellent bioavailability during clinical trials judging by
the steady-state release in plasma of XFB-19 from the PEG-XFB-19. The PEG-XFB-19 was not toxic to mice
at 100-fold the therapeutic dose. There was no evidence of cardiotoxicity or inhibition of CYP-450 isoenzymes.
The aims that are proposed for this SBIR are to complete IND-enabling, FDA-mandated studies. There is no
FDA-approved medication for the treatment of liver fibrosis, and none of the drugs currently in Clinical Studies
target directly activated myofibroblasts.

## Key facts

- **NIH application ID:** 10095347
- **Project number:** 4R44DK122903-02
- **Recipient organization:** XFIBRA, INC.
- **Principal Investigator:** MARTINA BUCK
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,136,111
- **Award type:** 4N
- **Project period:** 2019-08-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10095347

## Citation

> US National Institutes of Health, RePORTER application 10095347, TREATMENT OF LIVER INJURY AND FIBROSIS: SAFETY PHARMACOLOGY AND TOXICOLOGY (4R44DK122903-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10095347. Licensed CC0.

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