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

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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.