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）主要包括克罗恩病（CD）和溃疡性结肠炎（UC）， 其特征是肠粘膜出现慢性非消退性炎症反应，尽管确切的病因尚不清楚。 未知的、生态失调、遗传、环境和免疫因素都被认为在这种多因素中发挥作用 该疾病无法治愈，在大多数情况下，可能需要终身治疗。 使 50% 的患者受益，无反应者可服用更积极的皮质类固醇和免疫调节药物 包括许多不同类别的生物制剂的疗法，尽管针对 TNF、IL-12/23 和 IL-12/23 的单克隆抗体等生物制剂。 维多珠单抗（针对肠道归巢受体整合素 α4β7）已成为治疗以下疾病的受欢迎的补充 对于 IBD，它们提出了独特的问题，其中包括对维多珠单抗缺乏反应的患者亚群。 治疗、费用和高继发反应丧失率显然需要新的方法来治疗 IBD。 维多珠单抗选择性地针对整合素，提供更好的长期预后和改善的风险效益。 α4β7，目前适用于对当前药物没有反应的中度至重度 CD 或 UC 患者 然而，并非所有患者都对维多珠单抗有反应，并且可能出现继发性失去反应。 UC 患者中高达 39%，可以解释这一现象的机制是代偿性细胞运输的上调。 分子，如整合素α4β1，允许炎症细胞进入肠道双重α4β1和α4β7。 然而，拮抗剂那他珠单抗可以从功效的角度解决这个问题，尽管它已被批准用于克罗恩病 由于进行性多灶性白质脑病 (PML) 的重大安全性问题阻碍了其在该领域的使用 开发有效的双重 α4β1 和 α4β7 拮抗剂，其本质上不是生物制剂，而是一种药物。 每天一次口服小分子药物，且不存在 PML 的安全问题， 这就是本文提出的第一阶段 STTR 计划的目标。 I 期研究已确定了一种潜在的主要候选整合素 α4β7 和 α4β1 拮抗剂，可有效 结肠炎的 T 细胞转移模型，但不诱导造血干细胞动员或 B 细胞淋巴细胞增多，这 与那他珠单抗治疗引起的 PML 相关。先导类化合物可口服。 指示每日一次给药的药代动力学参数在这个第二阶段提案中，我们将执行 IND 启用。 研究，包括安全药理学、ADME、毒理学/毒代动力学和生物标志物开发，这些将导致 最终临床候选者选择并提交 IND 以在 IBD 患者中进行测试。