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

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.