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

选择性靶向高亲和力 α4 整合素作为 IBD 的安全治疗策略

• 批准号: 10697576
• 负责人: Ronald J Biediger
• 金额: $ 103.66万
• 依托单位: AVIARA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697576
• 关键词: 6-Mercaptopurine; Address; Adopted; Adrenal Cortex Hormones; Affinity; Aminosalicylate; Antibodies; Azathioprine; B-Lymphocytes; Benefits and Risks; Binding Proteins; Biodistribution; Biological; Biological Assay; Biological Availability; Biological Products; Blood; CD34 gene; Canis familiaris; Caring; Cell Adhesion Molecules; Cells; Chronic; Clinical; Clinical Trials; Colitis; Complex; Crohn' s disease; Cytochrome P450; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Environmental Risk Factor; Etiology; Evaluation; Family; Funding; Future; Genetic; Goals; Grant; Gut associated lymphoid tissue; Hematopoietic Stem Cell Mobilization; Homing; Human; Immunologic Factors; Industry; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Integrin alpha4; Integrin alpha4beta1; Integrins; Interleukin-12; Intestinal Mucosa; JC Virus; Lead; Link; Lymphocyte; Lymphocytosis; Macaca fascicularis; Metabolic; Modeling; Monitor; Monoclonal Antibodies; Mus; Mutagenesis; Nature; Oral; Oral Administration; Outcome; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Play; Prognosis; Progressive Multifocal Leukoencephalopathy; Property; Rattus; Research; Role; Route; Safety; Selection Criteria; Small Business Technology Transfer Research; T-Lymphocyte; TNF gene; Testing; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Ulcerative Colitis; Up-Regulation; antagonist; biomarker development; candidate selection; clinical candidate; clinical development; cost; design; drug candidate; dysbiosis; efficacy evaluation; first-in-human; genotoxicity; gut inflammation; immunomodulatory therapies; immunoregulation; improved; in vivo; inflammatory milieu; integrin alpha4beta7; lead candidate; natalizumab; nonhuman primate; novel strategies; patient population; patient subsets; pharmacodynamic biomarker; pharmacologic; phase 1 study; programs; reactivation from latency; receptor; receptor binding; recruit; response; safety study; scale up; screening; small molecule; stem cells; trafficking; treatment response; treatment strategy

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.

炎症性肠病（IBD）主要由克罗恩病（CD）和溃疡性结肠炎（UC）组成，IS 其特征是肠道粘膜中慢性非分辨炎症反应。虽然确切的病因是 未知，营养不良，遗传，环境和免疫学因素都被认为在此多因素中起着作用 疾病。没有治疗方法，在大多数情况下，需要终身治疗。当前的一线护理标准可能 受益于50％的患者，而无反应的患者被处方更具侵略性的皮质类固醇和免疫调节性 包括许多不同类别的生物制剂的疗法。尽管靶向TNF，IL-12/23和 Vedolizumab（靶向肠道受体整联蛋白α4β7）在治疗中已成为可喜的添加 IBD，他们提出了独特的问题。关于Vedolizumab，这包括缺乏反应的患者子集 治疗，成本和高度响应损失率很高。显然需要新方法来治疗IBD 提供更好的长期预后和改善风险效果的患者。 Vedolizumab选择性地靶向整合素 α4β7，目前用于用于中度至重度CD或UC的患者，他们对电流没有反应 第一线和第二行处理。但是，并非所有患者都反应，对Vedolizumab的次要丧失可以是 UC患者高达39％。可以解释这一点的机制是补偿性细胞运输的上调 像整联蛋白α4β1一样，分子允许将炎性细胞募集到肠道中。双α4β1和α4β7 纳塔尔苏单抗可以从有效的角度来解决这一问题，但是，dospite被批准为克罗恩 疾病，围绕进行性多灶性白斑脑病（PML）的重大安全问题排除了其在此方面的使用 患者人数。开发有效的双α4β1和α4β7拮抗剂，本质上不是生物学的 小分子药物每天口服一次，没有PML的安全问题，将是 IBD治疗方面的变革性。这是这里提出的I阶段STTR计划的目标。 第一阶段研究已经确定了整合素α4β7和α4β1的潜在铅候选者 结肠炎的T细胞转移模型，但不会诱导造血干细胞动员或B细胞淋巴细胞增多 与Natalizumab治疗有关PML的发展。化合物的铅类口服，并带有 药代动力学参数指示每天一次给药。在此阶段II提案中，我们将执行索引 研究，包括安全药理学，ADME，毒理学/毒理学和生物标志物开发，将导致 最终的临床候选候选和提交IBD患者的IND进行测试。