# Inhibition of Liver Fibrosis by Oxysterol Drug Candidates in a Mouse Model of NASH

> **NIH NIH R43** · MAX BIOPHARMA, INC. · 2020 · $223,696

## Abstract

ABSTRACT
Pathologic tissue fibrosis, impelled by uncontrolled wound healing responses to acute or chronic injury is a
significant problem in many organs including kidney, lung, and liver. Liver fibrosis is a major health problem
that causes morbidity and mortality in the affected patient population. Liver fibrosis occurs due to various
pathologies including non-alcoholic fatty liver disease (NAFLD), non-alcoholic liver steatohepatitis (NASH),
viral infection, and liver cancer. A number of molecular mechanisms have been scrutinized in an effort to
identify the root causes of liver fibrosis, often overlapping with the study of fibrosis in other organs. Among
these, prominent studies point to aberrant Hedgehog (Hh) signaling and inappropriate activation of TGFβ
signaling as prime factors underlying the pathogenesis of liver fibrosis, and hence extensively investigated.
At MAX BioPharma, we have identified semi-synthetic oxysterols that act as Hh pathway modulators, both as
agonists and antagonists. We found oxysterol Hh pathway antagonists that also have potent inhibitory effects
on TGFβ signaling in fibroblastic cells and in primary human liver stellate cells (HLS). Activated HLS are
considered to be the main mediators of liver fibrosis and a number of studies have shown that their activation
results in abundant extracellular matrix formation and fibrosis. Therefore, interference with HLS activation may
halt and reverse fibrotic processes in the liver. Based on preliminary in vitro studies and in vivo safety and
pharmacokinetic (PK) studies, we identified orally bioavailable Oxy210 as an oxysterol with potent Hh and
TGFβ pathway inhibitory activity when applied to NIH3T3 and HLS cells, and Oxy186 as a potent Hh pathway
inhibitor without any effect on TGFβ signaling. Oxy210 inhibits the expression of profibrogenic genes induced
by TGFβ in NIH3T3 fibroblasts and their expression in activated HLS. We propose that oxysterols might serve
as ideal drug candidates for development into orally bioavailable anti-fibrosis agents.
Our goal is to examine the efficacy of Oxy210 and Oxy186 in inhibiting liver fibrosis and to further identify the
relative roles of TGFβ and Hh signaling in pathogenesis of the disease. We propose to address the following
Specific Aims in the present Phase 1 SBIR application: Aim1. Optimization of oral delivery of Oxy210 and
Oxy186 to mice when mixed in food, compared to oral gavage for long term studies of liver fibrosis; Aim2.
Examination of the effect of Oxy210 and Oxy186 on liver fibrosis in vivo in “humanized” hyperlipidemic mice;
Aim 3. Examination of TGFβ and Hh signaling and the effect of Oxy210 and Oxy186 on these signaling
pathways during development of liver fibrosis in “humanized” hyperlipidemic mice.

## Key facts

- **NIH application ID:** 10076454
- **Project number:** 1R43DK125139-01A1
- **Recipient organization:** MAX BIOPHARMA, INC.
- **Principal Investigator:** FARHAD PARHAMI
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $223,696
- **Award type:** 1
- **Project period:** 2020-08-21 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076454

## Citation

> US National Institutes of Health, RePORTER application 10076454, Inhibition of Liver Fibrosis by Oxysterol Drug Candidates in a Mouse Model of NASH (1R43DK125139-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10076454. Licensed CC0.

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