SBIR-STTR Award

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 ?4?7) 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 ?4?7 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 ?4?1, allowing recruitment of inflammatory cells into the gut. The dual ?4?1 and ?4?7 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 ?4?1 and ?4?7 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 ?4?7 and ?4?1. 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 ?4-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.

Public Health Relevance Statement:
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.

Project Terms:
6-Mercaptopurine; Address; Adopted; Adrenal Cortex Hormones; Affinity; Aminosalicylate; angiogenesis; Animal Model; Antibodies; Azathioprine; base; Benefits and Risks; Biological; Caring; Cell Adhesion Molecules; Cells; Characteristics; Chronic; Clinical; Clinical Trials; Coagulation Process; Colitis; Complex; cost; Crohn's disease; Data; Development; Disease; Dose; drug candidate; Drug Kinetics; Drug Targeting; dysbiosis; efficacy study; Environmental Risk Factor; Etiology; Family; Future; Genetic; Goals; Gut associated lymphoid tissue; Hematopoietic Stem Cell Mobilization; Homing; Immunity; Immunologic Factors; immunomodulatory therapies; immunoregulation; improved; Inflammatory; Inflammatory Bowel Diseases; inflammatory milieu; Inflammatory Response; Integrin alpha4; Integrin alpha4beta1; integrin alpha4beta7; Integrins; Interleukin-12; Intestinal Mucosa; JC Virus; Lead; Libraries; Link; Lymphocyte; Lymphocytosis; Modeling; Molecular Conformation; Monoclonal Antibodies; mouse model; Mus; natalizumab; Nature; novel strategies; Oral; Oral Administration; Outcome; outcome forecast; patient population; patient subsets; Patients; Pharmaceutical Preparations; pharmacokinetics and pharmacodynamics; Phase; phase 2 study; pill; Play; preclinical development; programs; Progressive Multifocal Leukoencephalopathy; Property; reactivation from latency; receptor; recruit; response; Role; Safety; Secondary to; Small Business Technology Transfer Research; small molecule; Specificity; Structure; T-Lymphocyte; Testing; TNF gene; trafficking; Treatment Cost; treatment response; treatment strategy; Ulcerative Colitis; Up-Regulation; wound healing

Inflammatory bowel disease (IBD) is comprised mainly of Crohn's Disease (CD) and Ulcerative Colitis (UC), and ischaracterized by a chronic non-resolving inflammatory response in the intestinal mucosa. Although the exact etiology isunknown, dysbiosis, genetic, environmental, and immunologic factors are all thought to play roles in this multifactorialdisease. There are no cures, and in most cases, lifelong treatment is required. Current first line standards of care maybenefit 50% of patients, with non-responders being prescribed more aggressive corticosteroid and immunomodulatorytherapies that include many different classes of biologics. Although biologics like mAbs targeting TNF, IL-12/23, andvedolizumab (which targets the gut homing receptor integrin α4β7) have been a welcome addition in the treatment ofIBDs, they present unique issues. With respect to vedolizumab, this includes subsets of patients that lack a response totreatment, cost, and high rates of secondary loss of response. There is a clear need for new approaches to treat IBDpatients that offer better long-term prognosis and improved risk-benefit profiles. Vedolizumab selectively targets integrinα4β7 and is currently indicated for use in patients with moderate to severe CD or UC who have not responded to currentfirst and second line treatments. However, not all patients respond and secondary loss of response to vedolizumab can beas high as 39% in UC patients. A mechanism that could explain this is the upregulation of compensatory cell traffickingmolecules, like the integrin α4β1, allowing recruitment of inflammatory cells into the gut. The dual α4β1 and α4β7antagonist natalizumab could address this from an efficacy standpoint, however, despite being approved for Crohn'sdisease, the significant safety concerns around progressive multifocal leukoencephalopathy (PML) preclude its use in thispatient population. Development of an effective dual α4β1 and α4β7 antagonist, that is not biologic in nature but rather asmall molecule drug administered orally once-a-day and devoid of the safety concerns surrounding PML, would betransformative 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 ina T cell transfer model of colitis but does not induce hematopoietic stem cell mobilization or B cell lymphocytosis, whichare linked to the development of PML with natalizumab treatment. The lead class of compounds are orally available, withpharmacokinetic parameters indicative of once-a-day dosing. In this phase II proposal, we will perform IND-enablingstudies, including safety pharmacology, ADME, toxicology/toxicokinetics, and biomarker development that will lead toeventual clinical candidate selection and submission of an IND for testing in IBD patients.

Public Health Relevance Statement:
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.

Project Terms:
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