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

炎症性肠病(IBD)主要由克罗恩病(CD)和溃疡性结肠炎(UC)组成， 以肠粘膜的慢性非分解炎症反应为特征的。尽管确切的病原学是 未知的、生物失调、遗传、环境和免疫因素都被认为在这一多因素中起作用。 疾病。没有治愈的方法，在大多数情况下，需要终生治疗。目前的第一线护理标准可能 50%的患者受益，无反应者被开出更具侵略性的皮质类固醇和免疫调节剂 包括许多不同类别的生物制剂的疗法。尽管像靶向肿瘤坏死因子、白介素12/23和 Vedolizumab(靶向肠道归巢受体整合素α4β7)是一种受欢迎的治疗新药 IBDS，他们提出了独特的问题。关于vedolizumab，这包括对以下药物缺乏反应的患者亚群 治疗、费用和继发性反应丧失的高比率。治疗IBD的新方法显然是有必要的 提供更好的长期预后和改善风险-收益状况的患者。Vedolizumab选择性靶向整合素 α4β7，目前建议用于对CURRENT无反应的中到重度CD或UC患者 一线和二线治疗。然而，并不是所有的患者对vedolizumab都有反应，继发性的反应丧失可能是 UC患者高达39%。一种可以解释这一现象的机制是补偿性细胞贩运的上调 分子，如整合素α4β1，允许炎性细胞招募到肠道。Dualα4β1和α4β7 然而，拮抗剂Natalizumab可以从疗效的角度解决这个问题，尽管它被批准用于克罗恩病 疾病，进行性多灶性白质脑病(PML)的重大安全性问题阻碍了它的使用 病人群体。开发有效的双α4β1和α4β7拮抗剂，这不是生物性质的，而是 小分子药物每天口服一次，并且没有围绕PML的安全性问题，将是 在治疗IBD方面具有变革性。这就是这里提出的第一阶段STTR计划的目标。 I期研究已经确定了一种潜在的整合素α4β7和α4β1的主要候选拮抗剂，该拮抗剂在 一种结肠炎的T细胞转移模型，但不能诱导造血干细胞动员或B细胞淋巴细胞增多，这是一种 与使用那他珠单抗治疗的PML的发展有关。先导类化合物是口服的，具有 一天一次给药的药代动力学参数。在此阶段II提案中，我们将执行IND启用 研究，包括安全药理学、ADME、毒理学/毒物动力学和生物标记物的开发 最终选择临床候选人并提交IND用于IBD患者的测试。

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.