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

摘要 转移性黑色素瘤对于大多数患者来说仍然是不可治愈的。在约39，000名被诊断为 每年的IIB-IV期黑色素瘤，约50%对现有治疗无反应，而对现有治疗有反应的患者，则出现耐药性 是一个主要问题。此外，IIA-IIIB期原发性肿瘤患者的生存率稳定 随着阶段的增加而减少。预防转移本身将提供治愈的最佳机会。目前， 没有有效预防转移扩散的辅助治疗。为了满足这一需求，Rgenix 开发RGX-104作为治疗转移性黑色素瘤的一流口服治疗药物。 RGX-104是一种肝X受体（LXR）激动剂，可激活载脂蛋白E（ApoE）的表达， 最近发现的肿瘤抑制基因。ApoE通过抑制骨髓细胞激活抗肿瘤免疫 衍生的抑制细胞（MDSC）抑制癌细胞侵袭和血管生成。这种复杂的机制， 这与现有的治疗方法有着根本的不同， 和抑制黑素瘤小鼠模型中的转移生长。使用细胞也观察到强活性 对批准的治疗（维罗非尼和达卡巴嗪）耐药的品系。此外，结合RGX- 104与批准的治疗剂（维罗非尼、抗CTLA-4或抗PD-1）联合使用导致额外的肿瘤抑制作用。 功效深入的ADME、药效学和药代动力学研究已证明RGX-104是 一种很好的候选药物Rgenix还将ApoE确定为分子生物标志物， 在小鼠和猴子的血液中测量，作为反应的读数。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，并进行安全性 药理学研究。长期目标是开发一种安全有效的治疗方法， 黑色素瘤和防止转移形成。为此，Rgenix将进行生物分析方法 通过定量实时PCR测量白色血细胞中的ApoE和ApoE蛋白的开发 和MDSC含量的患者活检组织的免疫组化，使用一个训练队列的商业 血液和肿瘤样本这种体外系统的成功将为测试 I期研究期间ApoE表达与治疗结局。这将建立ApoE表达作为替代 临床开发期间的终点。此外，GMP放大合成的路线将得到改进， 生产了用于人体临床试验的12 kg RGX-104批次。最后，为了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性药理学研究 并进行呼吸功能检查。这些研究的成功完成将使RGX-104进入 临床上，并允许在转移和辅助设置的发展。此外，一个易于测量的 反映靶点结合的分子生物标志物将加速RGX-104的临床开发。

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.