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.

项目总结/摘要 免疫检查点抑制剂（CPI），如aPD-1药物（纳武单抗和派姆单抗），是目前的治疗药物。 晚期黑色素瘤和其他实体瘤一线治疗的标准治疗。 然而，约70%具有FDA批准适应症的患者没有反应。重要的是，一旦患者 进展，治疗选择有限。对检查点抑制剂的原发性和获得性耐药性可能是 这是由于缺乏免疫效应细胞引发和运输到肿瘤组织中。7 HP 349是第一个概念， 口服，小分子，特异性整联蛋白细胞粘附分子的正变构激活剂，VLA-4和LFA-1， 其对于产生针对实体瘤的细胞免疫应答是必需的。这些整合素是 对于T细胞引发和肿瘤浸润至关重要，并且已经显示对于 免疫检查点抑制剂，以及T细胞疫苗。7 HP 349作为全身用药， 单独或与CPI组合增强自发抗肿瘤免疫。基于其良好的 临床前概况，美国食品药品监督管理局肿瘤产品3部已批准 7 HP 349 IND进行拟议的I期首次人体研究，为未来的研究奠定基础。 癌症患者。cGMP原料药和制剂已开发用于首次人体研究。在 我们计划评估7 HP 349的安全性和耐受性，并确定7 HP 349的最佳治疗方案。 用于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） 在健康志愿者中进行首次人体研究。这项拟议的第一阶段研究不仅将指导 未来评估7 HP 349在PD-1失败的实体瘤患者中增强抗原呈递的作用- 为潜在的难治性黑色素瘤批准的基础疗法，也奠定了潜在的使用基础 提高传染病疫苗的有效性。