# A hepatocyte-specific R-spondin mimetic bispecific fusion protein to stimulate hepatocyte regeneration in patients with acute alcoholic hepatitis

> **NIH NIH U01** · SURROZEN OPERATING, INC. · 2022 · $505,000

## Abstract

Abstract
Alcoholic hepatitis (AH) is characterized by inflammatory liver injury with impaired hepatocyte regeneration, with
high rates of morbidity and mortality. Currently, steroids are the only treatment option for patients with severe
AH, however, they have limited efficacy (no treatment benefit demonstrated beyond 28 days) and many patients
have contra-indications to steroid use (e.g. active infections) and cannot be treated. There is a clear unmet need
for new therapeutic approaches in AH. Wnt signaling plays an important role in liver development, metabolic
zonation, homeostatic turnover of hepatocytes, hepatocyte differentiation and maturation, and normal function
and regulation of hepatocytes. Furthermore, Wnt/β-catenin signaling is critical to hepatocyte regeneration
following various forms of liver injury. Deletion or overactivation of β-catenin has been shown to have a key
impact on hepatocyte regeneration following partial hepatectomy, acetaminophen, CCl4, or alcohol-induced
injuries in animal models. R-spondins (RSPOs) play an important role in liver homeostasis and hepatocyte
regeneration following injury such as partial hepatectomy. RSPOs enhance Wnt signaling, and RSPO function
depends on the presence of endogenous Wnt ligands; endogenous Wnt ligands tend to be upregulated and
localized in injured tissues. Importantly in human AH patients, lack of hepatocyte regeneration and maturation is
a major issue. Surrozen has developed SZN-043, a bi-specific fusion protein which is an R-spondin mimetic
targeted to the hepatocyte receptor ASGR1 for liver-specific enhancement of Wnt signaling and tissue
regeneration and repair. Our studies suggest that the effects of SZN-043, in contrast to RSPO2, are highly
specific to hepatocytes, and can improve liver function and reduce fibrosis in rodent disease models. Our
preclinical studies in mice and non-human primates have demonstrated that SZN-043 induces Wnt-target gene
activation in the liver and selectively stimulates proliferation and maturation of hepatocytes. We are interested in
exploring whether SZN-043 is capable of improving liver function and/or fibrosis in AH. In this grant, we propose
first moving forward to develop cell line and material manufacturing process for SZN-043. This will be followed
by IND-enabling studies, including, pharmacology, toxicology, pharmacokinetics, and biomarker information to
inform and enable safe and effective administration of SZN-043 for testing in humans. We will then conduct
Phase 1 single- and multiple-ascending dose studies in human patients to assess pharmacokinetics,
pharmacodynamics, and safety of SZN-043 for the treatment of AH.

## Key facts

- **NIH application ID:** 10488068
- **Project number:** 6U01AA028951-03
- **Recipient organization:** SURROZEN OPERATING, INC.
- **Principal Investigator:** Jay Tibbitts
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $505,000
- **Award type:** 6
- **Project period:** 2020-09-25 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488068

## Citation

> US National Institutes of Health, RePORTER application 10488068, A hepatocyte-specific R-spondin mimetic bispecific fusion protein to stimulate hepatocyte regeneration in patients with acute alcoholic hepatitis (6U01AA028951-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10488068. Licensed CC0.

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