Selection and preclinical development of a bacteria-targeting, non-antibiotic lead candidate to improve cancer chemotherapy outcomes

选择和临床前开发一种针对细菌的非抗生素主要候选药物，以改善癌症化疗结果

• 批准号: 10006516
• 负责人: Ward Peterson
• 金额: $ 99.95万
• 依托单位: SYMBERIX, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006516
• 关键词: Acute; Antibiotics; Antineoplastic Agents; Back; Bacteria; Beta-glucuronidase; Binding Proteins; Camptothecin; Cancer Patient; Canis familiaris; Caring; Chemistry; Chemotherapy-Oncologic Procedure; Clinical Trials; Collaborations; Colorectal Cancer; Data; Development; Diarrhea; Dose; Drug Kinetics; Drug usage; Effectiveness; Enterobacteriaceae; Enterocytes; Enzyme Inhibitor Drugs; Enzymes; Evaluation; Event; Genetic; Glucuronides; Goals; Hospitalization; In Vitro; Incidence; Investigational Drugs; Investigational New Drug Application; Lead; Liver; Lower Gastrointestinal Tract; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measures; Medical; Medicine; Metabolism; Methods; Modification; Molecular; Mus; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacology Study; Phase; Plasma; Plasma Proteins; Population; Preparation; Prevention; Quality of life; Reporting; Risk; Rodent; Safety; Small Business Innovation Research Grant; System; Therapeutic; Topoisomerase-I Inhibitor; Toxicity Tests; Toxicokinetics; Toxicology; Treatment outcome; Work; analog; analytical method; base; chemotherapeutic agent; chemotherapy; cytotoxicity; drug discovery; experience; first-in-human; gut bacteria; gut microbiome; improved; in vitro testing; in vivo; irinotecan; lead candidate; meetings; microbiome; novel; palliative; pancreatic cancer patients; phase 2 study; phase 2 testing; plasma lead level; pre-clinical; preclinical development; preclinical safety; preclinical study; preclinical toxicity; prevent; small molecule inhibitor; sugar; survival outcome; targeted treatment; therapeutic effectiveness

The long-term objective of this project is a therapeutic adjunct to prevent chemotherapy-induced diarrhea (CID) based on a completely new mechanism of action targeting enteric bacteria. This Fast-Track SBIR proposal outlines the strategy for selecting a lead development candidate to be evaluated in investigational new drug (IND)-enabling studies to support a first-in-human trial. The focus of this project is prevention of diarrhea associated with irinotecan (IRI), an important drug used to treat advanced colorectal and pancreatic cancer patients. Intense, delayed diarrhea is the major reason for reducing, postponing or stopping IRI chemotherapy. The cancer-killing, active agent of IRI is SN38, a potent topoisomerase I inhibitor. As part of its elimination from the body, SN38 is detoxified primarily by the liver to an inactive glucuronide (SN38-G) that is subsequently shuttled to the lower gastrointestinal tract. The β-glucuronidase enzyme (GUS) expressed in a subset of gut bacteria metabolizes SN38-G back into SN38, which is highly toxic to enterocytes. This reactivation of SN38 by bacterial GUS in the gut microbiome is a key triggering event leading ultimately to serious, delayed diarrhea. A selective, non-proprietary bacterial GUS inhibitor (SBX-1) was previously shown to alleviate IRI-induced diarrhea in rodents. Phase 1 of this project discloses five proprietary analogs of SBX-1 and outlines the efficacy/tolerability studies to enable selection of the two most promising analogs to advance into Phase 2 SBIR studies. The lead candidate will be selected in the first aim of Phase 2. The remaining Phase 2 activities include chemistry/manufacturing/control (CMC)-related work and regulatory/safety preclinical studies that will transition this project from drug discovery to preclinical development. Aim 1 (Phase 1): Profile novel SBX-1 analogs in vitro for their off-target pharmacology, cytotoxicity, metabolism liability and stability in plasma. Aim 2 (Phase 1): Identify the two most promising SBX-1 analogs based on their therapeutic window and candidacy for formal preclinical studies. Aim 3 (Phase 2): Select lead candidate. Generate CMC and additional non-GLP preclinical data to support a pre-IND meeting with the FDA. Aim 4 (Phase 2): Conduct CMC-related activities to enable formal evaluations of the formulated lead candidate in GLP toxicology and safety pharmacology studies. A key deliverable in the proposed Phase 2 work is a preclinical data package that will adequately qualify the lead candidate for further evaluation in an acute-administration, first-in-human clinical trial in advanced colorectal and/or pancreatic cancer patients undergoing irinotecan-containing chemotherapy.

该项目的长期目标是预防化疗引起的腹泻（CID）的治疗辅助 基于针对肠道细菌的全新作用机制。 概述了选择在研究性新药中进行评估的先导开发候选药物的策略 支持首次人体试验的（IND）研究该项目的重点是预防腹泻。 与伊立替康 (IRI) 相关，伊立替康是一种用于治疗晚期结直肠癌和胰腺癌的重要药物 严重、迟发性腹泻是减少、推迟或停止 IRI 化疗的主要原因。 IRI 的抗癌活性剂是 SN38，它是一种有效的拓扑异构酶 I 抑制剂，也是其从体内消除的一部分。 在体内，SN38 主要通过肝脏解毒成无活性的葡萄糖醛酸苷 (SN38-G)，随后 穿梭至下胃肠道 β-葡萄糖醛酸酶 (GUS) 在肠道的一部分中表达。 细菌将 SN38-G 代谢回 SN38，这对肠细胞具有剧毒。 肠道微生物组中的细菌 GUS 是最终导致严重迟发性腹泻的关键触发事件。 一种选择性的、非专有的细菌 GUS 抑制剂 (SBX-1) 先前已被证明可以减轻 IRI 诱导的症状 该项目的第一阶段公开了 SBX-1 的五种专有类似物，并概述了 功效/耐受性研究，以选择两种最有希望的类似物进入第二阶段 SBIR 研究将在第 2 阶段的第一个目标中选出。第 2 阶段的其余活动 包括化学/制造/控制 (CMC) 相关工作和监管/安全临床前研究，这些研究将 将该项目从药物发现过渡到临床前开发。 目标 1（第 1 阶段）：在体外分析新型 SBX-1 类似物的脱靶药理学、细胞毒性、 目标 2（第 1 阶段）：确定两种最有前途的 SBX-1 类似物。 根据他们的治疗窗口和正式临床前研究的候选资格目标 3（第 2 阶段）：选择先导药物。 生成 CMC 和其他非 GLP 临床前数据，以支持与 FDA 举行的 IND 前会议。 目标 4（第 2 阶段）：开展 CMC 相关活动，以便对制定的先导化合物进行正式评估 GLP 毒理学和安全药理学研究的候选者是拟议的第二阶段工作的关键成果。 是一个临床前数据包，将充分证明主要候选人的资格，以便在急性给药中进行进一步评估， 在晚期结直肠癌和/或胰腺癌患者中进行的首次人体临床试验 含伊立替康的化疗。