Development of 7HP349, an oral integrin activator to enhance therapeutic responses to immune checkpoint inhibitors

开发 7HP349，一种口服整合素激活剂，可增强对免疫检查点抑制剂的治疗反应

• 批准号: 10261525
• 负责人: LIONEL David LEWIS
• 金额: $ 101.56万
• 依托单位: 7 HILLS PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261525
• 关键词: Address; Adverse effects; Animal Model; Animals; Antigen Presentation; Antigens; Autoimmune; Biological; Biological Assay; Biological Availability; Blood specimen; CTLA4 gene; CYP3A4 gene; Calories; Cancer Patient; Canis familiaris; Cell Adhesion; Cell Adhesion Molecules; Cells; Clinical; Communicable Diseases; Cross-Over Studies; Crossover Design; Cyclic GMP; Development; Development Plans; Dose; Drug Kinetics; Effectiveness; Effector Cell; Evaluation; Fasting; Fatty acid glycerol esters; Food; Formulation; Foundations; Future; Generations; Grant; Guidelines; Hepatic; Human; Immune; Immune checkpoint inhibitor; Immune response; In Vitro; Infiltration; Instruction; Integrin alpha4beta1; Integrin-mediated Cell Adhesion Pathway; Integrins; Intercellular adhesion molecule 1; Investigational Drugs; Investigational New Drug Application; Left; Leukocytes; Ligands; Lipids; Metastatic Melanoma; Modeling; Monitor; Mus; National Comprehensive Cancer Network; Nivolumab; Normal tissue morphology; Oncology; Oral; Organ; Orphan Drugs; Patients; Pharmaceutical Preparations; Phase; Plasma; Price; Randomized; Rattus; Refractory; Regimen; Resistance; Safety; Schedule; Small Business Technology Transfer Research; Solid Neoplasm; Study Subject; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Thyroid Function Tests; Tissues; Toxic effect; Toxicology; Tumor Immunity; Tumor Tissue; United States Food and Drug Administration; Vaccines; Vascular Cell Adhesion Molecule-1; Work; absorption; anti-PD-1; anti-tumor immune response; bak protein; base; capsule; cell motility; checkpoint therapy; clinical development; cohort; commercialization; data modeling; drug efficacy; first-in-human; healthy volunteer; human study; immune checkpoint blockade; immunotoxicity; improved; ineffective therapies; inhibitor/antagonist; ipilimumab; meetings; melanoma; objective response rate; pembrolizumab; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 testing; pre-clinical; preclinical study; prevent; programmed cell death protein 1; response; risk minimization; side effect; small molecule; standard of care; trafficking; treatment response; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (CPIs), such aPD-1 agents (nivolumab, and pembrolizumab), are the current standard of care treatment for the frontline management of advanced melanoma and other solid tumors. However, ~70% of patients with approved FDA indications do not respond. Importantly, once patients progress, there are limited treatment options. Primary and acquired resistance to checkpoint inhibitors may be due to the lack of immune effector cell priming and trafficking into tumor tissue. 7HP349 is a first-in-concept, oral, small molecule, positive allosteric activator of specific integrin cell adhesion molecules, VLA-4 and LFA-1, which are essential for generation of a cellular immune response against solid tumors. These integrins are critical for T cell priming and tumor infiltration, and have been shown necessary for the effectiveness of immune checkpoint inhibitors, as well as for T cell vaccines. 7HP349, as systemic drug, has shown enhancement of spontaneous anti-tumor immunity alone or in combination with CPIs. Based on its favorable preclinical profile, US Food and Drug Administration, Division of Oncology Products 3, has approved the 7HP349 IND to conduct the proposed Phase 1 first-in-human study to lay the foundation for future studies in cancer patients. cGMP drug substance and drug product have been developed for first-in-human studies. In this Direct to Phase II grant, we plan to assess the safety and tolerability, and determine the 7HP349 optimal pharmacokinetic dose (OPD) and optimal biologic dose (OBD) for improving immune checkpoint blockade by performing the first-in-human study in healthy volunteers. This proposed Phase I study will not only guide the future evaluation of 7HP349 to augment antigen presentation in solid tumor patients that have failed PD-1- based therapies for potential approval in refractory melanoma, but also lay the foundation for the potential use in increasing the effectiveness of infectious disease vaccines.

项目摘要/摘要 免疫检查点抑制物(CPIs)，如APD1类药物(nivolumab和pembrolizumab)是目前最流行的 晚期黑色素瘤和其他实体肿瘤一线治疗的标准护理治疗。 然而，在FDA批准的适应症中，约70%的患者没有反应。重要的是，一旦患者 随着治疗的进展，治疗选择有限。对检查点抑制剂的初级和获得性耐药性可能是 由于缺乏免疫效应细胞的启动和运输进入肿瘤组织。7HP349是概念上的第一款， 口服小分子、特异性整合素细胞黏附分子变构阳性激活剂，VLA-4和LFA-1， 它们对于产生针对实体肿瘤的细胞免疫反应是必不可少的。这些整合素是 对于T细胞的启动和肿瘤的侵袭至关重要，并且已经被证明是有效的 免疫检查点抑制剂，以及T细胞疫苗。7HP349作为全身用药，已经显示出 单独或与CPIs联合增强自发抗肿瘤免疫。基于其有利的 临床前简介，美国食品和药物管理局，肿瘤学产品部门3，已批准 7HP349 IND将进行拟议的第一阶段首例人体研究，为未来的研究奠定基础 癌症患者。CGMP药物物质和药物制品已被开发用于首次人体研究。在……里面 这次直接到第二阶段的拨款，我们计划评估安全性和耐受性，并确定7HP349的最佳方案 改善免疫检查点阻断的药代动力学剂量(OPD)和最佳生物剂量(OBD) 在健康志愿者身上进行了第一次人类研究。这项拟议的第一阶段研究不仅将指导 7HP349在PD-1失败的实体瘤患者中增强抗原提呈的未来评估 基于治疗难治性黑色素瘤的潜在批准，但也为潜在的使用奠定了基础 在提高传染病疫苗的有效性方面。