Development of an LXR agonist as first in class therapy for treatment of metastatic melanoma

开发 LXR 激动剂作为治疗转移性黑色素瘤的同类首创疗法

基本信息

批准号：
9201922
负责人：
Isabel Kurth
金额：
$ 111.8万
依托单位：
RGENIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9201922
关键词：
Address Adjuvant Adjuvant Therapy Agonist Apolipoprotein E Biological Markers Biopsy Biotechnology Blood Blood specimen Cancer Etiology Canis familiaris Cardiac Cardiovascular Physiology Cardiovascular system Cell Line Cells Chronic Clinic Clinical Clinical Research Clinical Trials Cytotoxic T-Lymphocyte-Associated Protein 4 Data Development Development Plans Diagnosis Disease Dose Drug Kinetics Drug resistance E protein Glioblastoma Goals Grant Growth Health Housing Human Immune Immunohistochemistry Immunotherapy In Vitro Incidence Infiltration Lead Leukocytes Liver X Receptor Malignant neoplasm of ovary Marketing Measurable Measurement Measures Medical Metastasis Suppression Metastatic Melanoma Metastatic to Methods Monkeys Mus Myelogenous Neoplasm Metastasis Neuraxis Operative Surgical Procedures Orphan Orphan Drugs Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Primary Neoplasm Property Protocols documentation Rattus Reading Recurrence Regulation Reporter Research Infrastructure Resistance Respiratory physiology Route S Phase Safety Sampling Small Business Innovation Research Grant Staging Suppressor-Effector T-Lymphocytes Surrogate Endpoint Survival Rate System Telemetry Testing Therapeutic Time Training Treatment outcome Tumor Immunity Tumor Suppressor Genes Validation abstracting analytical method angiogenesis cancer cell cancer type cohort commercial application commercialization drug candidate improved in vivo innovation melanoma metastasis prevention method development molecular marker mortality mouse model novel novel therapeutics outcome forecast patient population pharmacodynamic biomarker phase I trial pre-clinical prevent respiratory response scale up stability testing success targeted treatment tumor tumor growth tumorigenic

项目摘要

Abstract Metastatic melanoma remains incurable for the majority of patients. Of the ~39,000 patients diagnosed with Stage IIB-IV melanoma annually, ~50% do not respond to existing treatments and for those that do, resistance is a major concern. Furthermore, survival rates for patients with stage (IIA-IIIB) primary tumors steadily decrease with increasing stage. Prevention of metastasis itself would offer the best chance at cure. Currently, there is no adjuvant therapy that is effective in preventing metastatic spread. To address this need, Rgenix is developing RGX-104 as a first-in-class orally available therapeutic for the treatment of metastatic melanoma. RGX-104 is a Liver X receptor (LXR) agonist, which activates expression of Apolipoprotein E (ApoE), a recently identified tumor suppressor gene. ApoE activates the anti-tumor immunity by suppressing myeloid derived suppressor cells (MDSCs), inhibits cancer cell invasion and angiogenesis. This intricate mechanism, which is fundamentally different from that of existing treatments, results in robust tumor growth suppression and inhibition of metastatic growth in mouse models of melanoma. Strong activity was also observed using cell lines that are resistant to approved therapies (vemurafenib and decarbazine). Furthermore, combining RGX- 104 with approved therapeutics (vemurafenib, anti-CTLA-4 or anti-PD-1) results in additive tumor suppressive efficacy. In depth ADME, pharmacodynamic and pharmacokinetic studies have demonstrated RGX-104 to be an excellent drug candidate. Rgenix has also identified ApoE as a molecular biomarker, which can be measured in the blood as a read-out of response, in mice and monkeys. Here, Rgenix aims to complete pre- clinical development of RGX-104 by developing analytical methods for ApoE PD biomarker measurements of clinical samples, completing GMP scale up synthesis for Phase I clinical trial, and performing safety pharmacology studies. The long-term goal is to develop a safe and efficient therapy for both treating metastatic melanoma and preventing metastasis formation. To this end, Rgenix will perform bioanalytical method development for ApoE measurement in white blood cells by quantitative real-time PCR and for ApoE protein and MDSC content in patient biopsies by immunohistochemistry, using a training cohort of commercially available blood and tumor samples. Success in this in vitro system will set the stage for testing correlation of ApoE expression with treatment outcome during Phase I. This will establish ApoE expression as a surrogate endpoint during clinical development. In addition, routes for GMP scale up synthesis will be refined and a 10- 12kg batch of RGX-104 for human clinical trials produced. Finally, to test potentially harmful effects of the drug during chronic dosing, safety pharmacology studies for cardiovascular function, central nervous system effects and respiratory function will be conducted. Successful completion of these studies will move RGX-104 into the clinic and allow development in both the metastatic and adjuvant settings. Additionally, an easily measurable molecular biomarker reflecting target engagement would accelerate clinical development of RGX-104.

抽象的对于大多数患者来说，转移性黑色素瘤仍然无法治愈。在约 39,000 名确诊患有此病的患者中每年，约 50% 的 IIB-IV 期黑色素瘤对现有治疗没有反应，而那些有反应的人则出现耐药性是一个主要问题。此外，原发性肿瘤 (IIA-IIIB) 期患者的生存率稳定随着阶段的增加而减少。预防转移本身将提供最好的治愈机会。现在，没有任何辅助疗法可以有效预防转移扩散。为了满足这一需求，Rgenix 是开发 RGX-104 作为治疗转移性黑色素瘤的一流口服疗法。 RGX-104 是一种肝脏 X 受体 (LXR) 激动剂，可激活载脂蛋白 E (ApoE) 的表达，载脂蛋白 E (ApoE) 是一种最近发现了抑癌基因。 ApoE 通过抑制骨髓细胞激活抗肿瘤免疫衍生抑制细胞（MDSC），抑制癌细胞侵袭和血管生成。这个复杂的机制，与现有治疗方法根本不同，可有效抑制肿瘤生长并抑制小鼠黑色素瘤模型中的转移生长。使用细胞也观察到强烈的活性对已批准的疗法（维莫非尼和迪卡巴嗪）具有耐药性的品系。此外，结合 RGX- 104 使用已批准的治疗药物（维罗非尼、抗 CTLA-4 或抗 PD-1）可产生附加肿瘤抑制作用功效。深入的 ADME、药效学和药代动力学研究表明 RGX-104 一个优秀的候选药物。 Rgenix 还确定了 ApoE 作为一种分子生物标志物，可以在小鼠和猴子的血液中进行测量，作为反应读数。在这里，Rgenix 的目标是完成预通过开发 ApoE PD 生物标志物测量的分析方法来进行 RGX-104 的临床开发临床样品，完成I期临床试验的GMP放大合成，并执行安全性药理学研究。长期目标是开发一种安全有效的疗法来治疗转移性癌症黑色素瘤并预防转移形成。为此，Rgenix将进行生物分析方法开发通过定量实时 PCR 测量白细胞中的 ApoE 和 ApoE 蛋白使用商业化的训练队列，通过免疫组织化学分析患者活检中的 MDSC 含量可用的血液和肿瘤样本。该体外系统的成功将为测试相关性奠定基础 ApoE 表达与 I 期治疗结果。这将建立 ApoE 表达作为替代临床开发期间的终点。此外，还将完善 GMP 放大合成路线，并制定 10- 生产出12公斤批次用于人体临床试验的RGX-104。最后，测试药物的潜在有害作用长期给药期间，心血管功能、中枢神经系统影响的安全药理学研究并进行呼吸功能检查。这些研究的成功完成将使 RGX-104 进入临床并允许在转移和辅助环境中发展。此外，一个易于测量的反映靶点参与的分子生物标志物将加速 RGX-104 的临床开发。