# Selective targeting of high affinity alpha4 integrins as a safe treatment strategy for IBD

> **NIH NIH R42** · AVIARA PHARMACEUTICALS, INC. · 2024 · $959,682

## Abstract

Inflammatory bowel disease (IBD) is comprised mainly of Crohn’s Disease (CD) and Ulcerative Colitis (UC), and is
characterized by a chronic non-resolving inflammatory response in the intestinal mucosa. Although the exact etiology is
unknown, dysbiosis, genetic, environmental, and immunologic factors are all thought to play roles in this multifactorial
disease. There are no cures, and in most cases, lifelong treatment is required. Current first line standards of care may
benefit 50% of patients, with non-responders being prescribed more aggressive corticosteroid and immunomodulatory
therapies that include many different classes of biologics. Although biologics like mAbs targeting TNF, IL-12/23, and
vedolizumab (which targets the gut homing receptor integrin α4β7) have been a welcome addition in the treatment of
IBDs, they present unique issues. With respect to vedolizumab, this includes subsets of patients that lack a response to
treatment, cost, and high rates of secondary loss of response. There is a clear need for new approaches to treat IBD
patients that offer better long-term prognosis and improved risk-benefit profiles. Vedolizumab selectively targets integrin
α4β7 and is currently indicated for use in patients with moderate to severe CD or UC who have not responded to current
first and second line treatments. However, not all patients respond and secondary loss of response to vedolizumab can be
as high as 39% in UC patients. A mechanism that could explain this is the upregulation of compensatory cell trafficking
molecules, like the integrin α4β1, allowing recruitment of inflammatory cells into the gut. The dual α4β1 and α4β7
antagonist natalizumab could address this from an efficacy standpoint, however, despite being approved for Crohn’s
disease, the significant safety concerns around progressive multifocal leukoencephalopathy (PML) preclude its use in this
patient population. Development of an effective dual α4β1 and α4β7 antagonist, that is not biologic in nature but rather a
small molecule drug administered orally once-a-day and devoid of the safety concerns surrounding PML, would be
transformative in the treatment of IBD. This is the goal of the Phase I STTR program proposed here.
 Phase I studies have identified a potential lead candidate antagonist of integrins α4β7 and α4β1 that is effective in
a T cell transfer model of colitis but does not induce hematopoietic stem cell mobilization or B cell lymphocytosis, which
are linked to the development of PML with natalizumab treatment. The lead class of compounds are orally available, with
pharmacokinetic parameters indicative of once-a-day dosing. In this phase II proposal, we will perform IND-enabling
studies, including safety pharmacology, ADME, toxicology/toxicokinetics, and biomarker development that will lead to
eventual clinical candidate selection and submission of an IND for testing in IBD patients.

## Key facts

- **NIH application ID:** 10871890
- **Project number:** 5R42DK127869-03
- **Recipient organization:** AVIARA PHARMACEUTICALS, INC.
- **Principal Investigator:** Ronald J Biediger
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $959,682
- **Award type:** 5
- **Project period:** 2020-09-16 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871890

## Citation

> US National Institutes of Health, RePORTER application 10871890, Selective targeting of high affinity alpha4 integrins as a safe treatment strategy for IBD (5R42DK127869-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10871890. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*