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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DK127869-01
Agency Tracking Number: R41DK127869
Amount: $296,724.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 300
Solicitation Number: PA19-270
Timeline
Solicitation Year: 2019
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-09-16
Award End Date (Contract End Date): 2021-09-15
Small Business Information
7000 FANNIN ST, STE 2130
Houston, TX 77030-5501
United States
DUNS: 965002301
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 DARREN WOODSIDE
 (832) 355-9084
 dwoodside@texasheart.org
Business Contact
 GEORGE HOLLAND
Phone: (713) 894-6742
Email: gholland@aviarapharma.com
Research Institution
 TEXAS HEART INSTITUTE
 
BOX 20345, MC 3-116
HOUSTON, TX 77225-0345
United States

 Domestic Nonprofit Research Organization
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.We have identified a structural class of small molecule compounds that are potent dual antagonists of integrins
α4β7 and α4β1. They are orally available with a pharmacokinetic profile indicative of once-a-day dosing. Notably, they
are selective for the high affinity integrin conformations. Recent data suggests that selectively targeting the high affinity
conformation of α4-integrins may result in decreased potential for development of PML. In this proposal, we will test this
hypothesis along with proof-of-concept efficacy studies in the T Cell transfer model or murine colitis. Future phase II
studies will expand pre-clinical development toward submission of an IND for testing in IBD patients.We are proposing the development of an orally available small molecule drug that targets inflammatory cell trafficking to
the gut as a safe alternative to current treatments strategies in inflammatory bowel disease that either are associated with
significant safety concerns, like the development of progressive multifocal leukoencephalopathy, or are associated with
high numbers of primary and secondary non-responders to therapy.

* Information listed above is at the time of submission. *

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