# Developing novel inhibitors of the gut microbiome to modulate drug metabolism

> **NIH NIH R44** · SYMBERIX, INC. · 2020 · $625,834

## Abstract

The long-term objective of this project is a therapeutic adjunct to prevent adverse gastrointestinal events,
including life-threatening diarrhea, associated with Ofev® and Stivarga®, used to treat idiopathic pulmonary
fibrosis and metastatic colorectal cancer, respectively. Adverse GI events associated with both drugs is a major
reason for reducing, postponing, or stopping treatment, thus compromising efficacy. One fundamental and
common source of drug-dependent lower GI adverse events is microbiome-mediated drug metabolism, during
which commensal β-glucuronidase enzymes (GUS) reactivate drug metabolites in the gut. We previously
demonstrated the therapeutic efficacy of GUS enzyme inhibition as a novel “Symbiotic Drug” approach to
ameliorate gastrointestinal sequela associated with common anti-inflammatory drugs and the chemotherapeutic
agent, irinotecan. Here, we aim to identify novel symbiotic drugs to increase the efficacy of Ofev and Stivarga,
while simultaneously reducing the risk of side effects. We previously developed a rapid screening assay that
uses a clinically relevant source of GUS enzymes, and demonstrated that Ofev and Stivarga metabolites are
substrates for bacterial GUS enzymes. In Phase I we will optimize our assay for high-throughput screening for
novel GUS inhibitors. In Phase II, we will commence a high-throughput screen, identify lead candidate GUS
inhibitors, and define the symbiotic drug candidacy of each. A key deliverable in the proposed project is a lead
drug series for both Ofev and Stivarga, which will be evaluated for efficacy and safety in future pre-clinical animal
studies. We expect that the development and validation of a comprehensive class of GUS inhibitors will be
broadly applicable to improve the therapeutic index of many existing drugs.

## Key facts

- **NIH application ID:** 10073908
- **Project number:** 4R44TR002691-02
- **Recipient organization:** SYMBERIX, INC.
- **Principal Investigator:** Bret David Wallace
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $625,834
- **Award type:** 4N
- **Project period:** 2019-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073908

## Citation

> US National Institutes of Health, RePORTER application 10073908, Developing novel inhibitors of the gut microbiome to modulate drug metabolism (4R44TR002691-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073908. Licensed CC0.

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