# Development of a Novel Hyaluronan Inhibitor for the Treatment of Group 3 Pulmonary Hypertension (PH)

> **NIH NIH R44** · HALO BIOSCIENCES, INC. · 2024 · $1,957,305

## Abstract

PROJECT SUMMARY
Group 3 pulmonary hypertension due to interstitial lung disease (PH-ILD) is a devastating disease. Patients with
PH-ILD are perpetually short of breath and often unable to walk or even to speak in full sentences without gasping
for air. Characterized by extensive changes in the extracellular matrix (ECM) and the vasculature, PH is observed
in up to 80% of patients with ILD. The severity of PH is the most significant predictor of mortality in these patients,
who have an average life expectancy of only 3-4 years. Existing therapies are often ineffective, in part because
they target individual cells and not the tissue remodeling that drives the disease. We desperately need new
therapies for PH-ILD.
There is strong evidence from in vitro and animal models of PH that hyaluronan (HA) drives disease progression.
HA, a prominent component of the ECM that fills the space between cells is overexpressed in the lungs of
patients with PH and is associated with vascular remodeling, inflammation, and fibrosis. Given the role of HA
and the ECM in PH-ILD pathogenesis, HA is an attractive target, one that is currently not targeted by approved
drugs or other drugs in development.
4-MU (4-methylumbelliferone) is a small molecule inhibitor of HA synthesis with the potential to treat PH-ILD. 4-
MU has shown dramatic preclinical efficacy in multiple mouse models of PH. Unfortunately, 4-MU has poor
pharmacokinetics, characterized by extensive 1st pass metabolism and poor bioavailability. While 4-MU works in
animal models at high dosages, we need improved formulations of 4-MU to be able to treat human PH-ILD.
We have developed an approach to the formulation of 4-MU that enhances systemic delivery, reduces 1st pass
metabolism, and promotes bioavailability (H1614). Our vision is that this formulation will result in reduced dose
burden and improved efficacy. To advance our program to deliver a proprietary agent for Phase 2 clinical
assessment we are proposing three specific aims for this grant application:
In Aim 1 we will manufacture 4-MU as an orally disintegrating tablet (ODT) using proprietary Zydis® technology
and evaluate the pharmacokinetics of the new formulation in an animal model.
Then, in Aim 2 we will perform preclinical studies to identify the optimal dose of 4-MU in a rat model of PH and
lung fibrosis and to define its toxicology profile to current FDA standards.
Finally, in Aim 3 we will validate assays to quantitate the levels of 4-MU and HA in human serum, in order to
ensure compliance with FDA standards to support the Phase 2 human clinical trial.
Completion of these studies will result in a proprietary, optimized formulation of 4-MU ready for manufacturing
to support a Phase 2 clinical trial in PH-ILD (WHO Group 3). Complementary studies of toxicology,
pharmacology, and human PK are to be undertaken directly by Halo Biosciences. This project has the potential
to transform the treatment not only of PH-ILD, but of other diseases characterize...

## Key facts

- **NIH application ID:** 10821542
- **Project number:** 1R44HL169052-01A1
- **Recipient organization:** HALO BIOSCIENCES, INC.
- **Principal Investigator:** Rudy Paladini
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,957,305
- **Award type:** 1
- **Project period:** 2024-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821542

## Citation

> US National Institutes of Health, RePORTER application 10821542, Development of a Novel Hyaluronan Inhibitor for the Treatment of Group 3 Pulmonary Hypertension (PH) (1R44HL169052-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10821542. Licensed CC0.

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