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; 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）是一种罕见的侵略性癌症。大多数情况是转移或本地的 诊断为较低的五年生存率<15％的诊断。唯一经FDA批准的化学治疗性 Mitotane代理具有剧毒，难以服用，并且只有适度的有效。替代化疗方案 免疫切除点抑制剂可提供有限的好处。迫切需要新疗法。 我们建议基于第一类小分子拮抗剂开发针对ACC的靶向疗法 类固醇生成因子-1（SF-1或NR5A1），孤儿核接收器和转录因子，对 肾上腺的生长和发育。多个发现表明SF-1在 ACC的发病机理：（i）较高水平的肿瘤内SF-1表达与成人的预后不良相关 ACC，（ii）SF-1是转移性ACC的诊断标记； （iii）SF-1是染色体扩增的，SF-1蛋白 在小儿ACC中，相对于正常的肾上腺组织，相对于正常的肾上腺组织升高。此外，FDA与NCI协商 在其儿科分子靶点范围内包括SF-1。 Orphagen已经确定了高度选择性的SF-1拮抗剂OR-449，该拮抗剂以每天30 mg/kg的口服给药 抑制了SJ-ACC3的生长，SJ-ACC3是最初分离在圣裘德儿童的儿科ACC肿瘤特征 研究医院。 OR-449还阻断了分解的SJ-ACC3肿瘤细胞培养物中的DNA合成。这 SJ-ACC3 Xenographtics中的剂量响应mRNA签名支持OR-449的SF1的直接参与。 此外，OR-449在小鼠，大鼠和狗中表现出出色的口服抽象和药代动力学（PK）特性 在口服两周的每日给药鼠安全研究中，以100 mg/kg的耐受性良好。 拟议的SBIR直接进入II期项目的基础是基于对ACC肿瘤生长的高效抑制和 OR-449的有希望的初步安全性。我们的项目目标是完成所有临床前安全研究 需要为ACC中SF-1拮抗剂的首次临床试验提交研究新药申请。 目的是：1）进行探索性（非GLP），剂量范围调查毒性研究OR-449在小鼠AT 剂量高达400 mg/kg，以识别任何严重的安全信号，并提供关键的剂量数据以设计1- 月监管（GLP）毒理学研究； 2）优化合成化学过程，发展分析 方法，并完成OR-449的1公里扩大规模合成以提供进一步的非临床安全研究 并准备GMP制造； 3）对狗进行高剂量PK研究，然后进行非GLP 7天 通过组织学和心血管监测的耐受性和14天的剂量调查安全性研究； 4） 与FDA指导一致的小鼠和狗的1个月重复剂量GLP一般毒理学研究。 成功完成项目将提供必要的数据，以选择阶段1的起始剂量 OR-449在ACC中的临床试验。最终，OR-449的商业化可以提供安全有效的 有针对性的治疗可显着提高ACC患者的生存率。