Preclinical development of OR-449, a novel targeted therapy for adrenocortical cancer

肾上腺皮质癌新型靶向疗法 OR-449 的临床前开发

• 批准号: 10445073
• 负责人: Scott McNear Thacher
• 金额: $ 69.32万
• 依托单位: ORPHAGEN PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445073
• 关键词: 4 year old; Address; Adrenal Gland Cancer; Adrenal Glands; Adrenergic Antagonists; Adrenocortical carcinoma; Adult; Behavioral; Binding Proteins; Biological Assay; Canis familiaris; Cardiovascular Physiology; Cardiovascular system; Chemistry; Chemotherapy-Oncologic Procedure; Childhood; Chromosomal Duplication; Clinical; Clinical Trials; Consultations; Cultured Tumor Cells; DNA biosynthesis; Data; Development; Development Plans; Diagnosis; Disease; Dose; Drug Kinetics; Ensure; Europe; Exhibits; FDA approved; Formulation; Future; Genetic Transcription; Goals; Growth; Growth and Development function; Histology; Human; Immune checkpoint inhibitor; Immunocompromised Host; Insecticides; Investigational New Drug Application; Kilogram; Localized Malignant Neoplasm; Malignant Neoplasms; Malignant neoplasm of adrenal cortex; Maximum Tolerated Dose; Messenger RNA; Molecular Target; Monitor; Mus; Nuclear Orphan Receptor; Nuclear Receptors; Oncology; Operative Surgical Procedures; Oral; Orphan; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Plasma Proteins; Polymorph; Procedures; Process; Prognosis; Property; Proteins; Rattus; Recovery; Residual state; Respiratory physiology; Role; SF1; Safety; Saint Jude Children' s Research Hospital; Signal Transduction; Small Business Innovation Research Grant; Survival Rate; Synthesis Chemistry; Testing; Therapeutic; Tissues; Toxic effect; Toxicokinetics; Toxicology; Xenograft procedure; absorption; analytical method; antagonist; base; chemotherapeutic agent; chemotherapy; clinical candidate; clinical development; commercialization; crystallinity; design; diagnostic biomarker; dosage; improved; meetings; neoplastic cell; new therapeutic target; novel therapeutics; patient derived xenograft model; preclinical development; preclinical safety; rare cancer; safety study; scale up; side effect; small molecule; targeted treatment; transcription factor; tumor; tumor growth; tumor xenograft; virtual

ABSTRACT Adrenocortical carcinoma (ACC) is a rare, aggressive cancer. The majority of cases are metastatic or locally advanced at diagnosis with a dismal five-year survival of <15%. The only FDA-approved chemotherapeutic agent, mitotane, is highly toxic, difficult to dose, and only modestly effective. Alternative chemotherapy regimens and immune checkpoint inhibitors provide limited benefit. There is an urgent need for new therapies. We propose to develop a targeted therapy for ACC based on first-in-class small molecule antagonists to steroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor and transcription factor that is essential for the growth and development of the adrenal gland. Multiple findings indicate that SF-1 has a crucial role in the pathogenesis of ACC: (i) Higher levels of intra-tumoral SF-1 expression correlate with poor prognosis in adult ACC, (ii) SF-1 is a diagnostic marker of metastatic ACC; (iii) SF-1 is chromosomally amplified and SF-1 protein is elevated, relative to normal adrenal tissue, in pediatric ACC. Further, the FDA, in consultation with NCI, has included SF-1 on its Pediatric Molecular Target List for oncology. Orphagen has identified a highly selective SF-1 antagonist, OR-449, that at 30 mg/kg daily oral dosing completely inhibited the growth of SJ-ACC3, a pediatric ACC tumor xenograft originally isolated at St. Jude Children’s Research Hospital. OR-449 also blocked DNA synthesis in cultures of dissociated SJ-ACC3 tumor cells. The dose-responsive mRNA signature in the SJ-ACC3 xenografts supports direct engagement of SF1 by OR-449. Further, OR-449 showed excellent oral absorption and pharmacokinetic (PK) properties in mouse, rat, and dog and was well-tolerated at 100 mg/kg in an oral, two-week daily dosing murine safety study. The proposed SBIR Direct to Phase II Project builds on the highly effective inhibition of ACC tumor growth and promising preliminary safety profile of OR-449. Our Project goal is to complete all preclinical safety studies required to file an Investigational New Drug application for the first clinical trial of an SF-1 antagonist in ACC. The Aims are: 1) Conduct an exploratory (non-GLP), dose range-finding toxicity study of OR-449 in mice at doses up to 400 mg/kg to identify any serious safety signals and to provide key dosing data for designing a 1- month regulatory (GLP) toxicology study; 2) Optimize synthetic chemistry processes, develop analytical methods, and complete a 1-kilogram scale-up synthesis of OR-449 to supply further nonclinical safety studies and prepare for GMP manufacturing; 3) Conduct high-dose PK studies in dogs followed by non-GLP 7-day toleration and 14-day dose range-finding safety studies with histology and cardiovascular monitoring; 4) Complete 1-month repeat dose GLP general toxicology studies in mouse and dog consistent with FDA guidance. Successful completion of the Project will provide the necessary data to select a starting dose for a Phase 1 clinical trial of OR-449 in ACC. Ultimately, commercialization of OR-449 could provide a safe and effective targeted therapy to significantly improve survival for ACC patients.

抽象的 肾上腺皮质癌（ACC）是一种罕见的侵袭性癌症。大多数病例是转移性或局部性的 诊断时处于晚期，五年生存率<15%。唯一获得 FDA 批准的化疗药物 米托坦（mitotane）具有剧毒，难以剂量，且效果有限。替代化疗方案 免疫检查点抑制剂的作用有限。迫切需要新疗法。 我们建议开发基于一流小分子拮抗剂的 ACC 靶向治疗 类固醇生成因子-1（SF-1 或 NR5A1），一种孤儿核受体和转录因子，对于 肾上腺的生长和发育。多项研究结果表明 SF-1 在 ACC 的发病机制：(i) 肿瘤内较高水平的 SF-1 表达与成人不良预后相关 ACC，(ii) SF-1 是转移性 ACC 的诊断标志物； (iii) SF-1 被染色体扩增并且 SF-1 蛋白 在儿科 ACC 中，相对于正常肾上腺组织，该值升高。此外，FDA 与 NCI 协商后， 将 SF-1 列入其儿科肿瘤学分子靶标列表。 Orphagen 已鉴定出一种高度选择性的 SF-1 拮抗剂 OR-449，每天口服 30 mg/kg 剂量即可完全 抑制 SJ-ACC3 的生长，SJ-ACC3 是一种最初在 St. Jude Children's 分离的儿科 ACC 肿瘤异种移植物 研究医院。 OR-449 还阻断了分离的 SJ-ACC3 肿瘤细胞培养物中的 DNA 合成。这 SJ-ACC3 异种移植物中的剂量响应 mRNA 特征支持 OR-449 直接参与 SF1。 此外，OR-449 在小鼠、大鼠和狗中表现出优异的口服吸收和药代动力学 (PK) 特性 在一项为期两周、每日一次的小鼠口服安全性研究中，100 mg/kg 的耐受性良好。 拟议的 SBIR Direct to Phase II 项目建立在高效抑制 ACC 肿瘤生长和 OR-449 的初步安全性有希望。我们的项目目标是完成所有临床前安全研究 需要提交 ACC 中 SF-1 拮抗剂首次临床试验的研究性新药申请。 目标是： 1) 在小鼠体内进行 OR-449 的探索性（非 GLP）剂量范围探索毒性研究 剂量高达 400 mg/kg，以识别任何严重的安全信号，并为设计 1- 月监管（GLP）毒理学研究； 2) 优化合成化学工艺，开发分析 方法，并完成OR-449的1公斤放大合成，以提供进一步的非临床安全性研究 并为GMP生产做好准备； 3) 在狗中进行高剂量 PK 研究，然后进行 7 天的非 GLP 研究 通过组织学和心血管监测进行耐受性和 14 天剂量范围寻找安全性研究； 4） 根据 FDA 指导，完成小鼠和狗的 1 个月重复剂量 GLP 一般毒理学研究。 该项目的成功完成将为选择第一阶段的起始剂量提供必要的数据 OR-449在ACC的临床试验。最终，OR-449 的商业化可以提供安全有效的 靶向治疗可显着提高 ACC 患者的生存率。