Riluzole Prodrugs for Melanoma and ALS

我们发现了一种新型的IIb型利鲁唑前药--曲鲁唑(FC-4157，BVH-4157)，它具有 大幅改进转移性黑色素瘤治疗的潜力 通过一种新的谷氨酸能作用机制发挥作用。而利鲁唑已显示出良好的治疗效果。 在黑色素瘤患者中，在C8161小鼠移植瘤模型中，特里鲁唑的效力是利鲁唑的20倍 在MASS20同种异体移植模型中，与抗PD1联合使用，其效力增加了10倍。三里拉唑是 旨在克服利鲁唑限制其更广泛临床疗效的局限性。例如, 利鲁唑片口服后有60%的生物利用度，归因于CYP1A2介导的首次通过 肝脏中的新陈代谢，这也导致患者对患者暴露的高度可变性。此外，利鲁唑是 与进餐时摄入量减少有关(即对食物的负面影响)，需要禁食三个小时 (餐前一小时和餐后两小时)，患者依从性差。利鲁唑每天服用两次，有 对肝功能测试的剂量依赖性影响，在水中表现出低溶解度，如果出现强烈的口腔麻木 直接用在口腔粘膜上。Trigriluzole解决了这些问题，因为它不受第一个- 通过CYP1A2代谢，可能适合每天服用一次，半衰期延长。曲利路唑是一种 由PepT1转运体从胃肠道主动摄取的三肽结合物，而利鲁唑不是 积极运输，消除了对三聚氰胺禁食的需要。Trigriluzole在胃肠道中稳定，但 吸收后裂解。口服后体内循环中可观察到高水平的利鲁唑。 在小鼠、大鼠和食蟹猴体内给药。我们已经实现了我们的目标 第一阶段和第二阶段SBIR赠款，以及进行了许多最初没有描述或 已经预料到了。我们已经与生物港制药公司建立了共同开发伙伴关系，现在 寻求桥接二期SBIR支持，通过昂贵的二期联合临床试验推进特里鲁唑 使用抗PD1抗体nivolumab。我们的目标是开发三聚氰胺作为口服抗癌剂，用于 至少在最初阶段，与抗PD1抗体相结合，可以显著提高抗-PD1抗体的疗效 单用PD1治疗。未来也将考虑单一疗法，这取决于这些治疗的结果 学习。在目标1中，我们将进行额外的临床前生物标记物和患者来源的异种移植(Pdx)活动。 支持将三聚氰胺引入人类转移性黑色素瘤的临床试验，包括获得 所需的IND批准。在PDX模型中，我们将寻找可能的生物标志物，如 关键信号转导通路(MAPK、PI3K/AKT)、血管内皮生长因子、IL-8、CD34、CCL4、 外周血中肿瘤来源的外切体的数量和含量的变化。在……里面 AIM 2，我们在罗格斯大学新泽西癌症研究所的合作者将进行第二阶段 尼伏单抗联合治疗转移性黑色素瘤的人体临床试验。

We have discovered a novel Type IIb prodrug of riluzole, trigriluzole (FC-4157, BVH-4157), which has the potential to substantially improve therapy for the treatment of the devastating condition of metastatic melanoma acting via a novel glutamatergic mechanism of action. While riluzole has shown promising efficacy in treating melanoma in patients, trigrilluzole is >20X more potent than riluzole itself in a C8161 mouse xenograft model of melanoma, and >10X more potent in a MASS20 allograft model in combination with anti-PD1. Trigriluzole was designed to overcome the limitations of riluzole that have restricted its broader clinical efficacy. For example, riluzole tablets have 60% bioavailability upon oral administration, attributed to Cyp1A2-mediated first-pass metabolism in the liver, which also causes high patient-to-patient variability of exposure. In addition, riluzole is associated with reduced levels when taken with meals (i.e., a negative food effect), requiring a three hour fast (one hour before and two hours after a meal), with poor patient compliance. Riluzole is dosed twice a day, has dose-dependent effects on liver function tests, exhibits low solubility in water, and intense oral numbness if administered directly to the oral mucosa. Trigriluzole solves these problems because it is not subject to first- pass Cyp1A2 metabolism and may be suitable for once-daily dosing with an extended half life. Trigriluzole is a tripeptide conjugate that is actively taken up from the GI tract by the PepT1 transporter, whereas riluzole is not actively transported, obviating the need for fasting for trigriluzole. Trigriluzole is stable in the GI tract, but cleaves after absorption. High levels of riluzole are observed in the systemic circulation after oral administration of trigriluzole in mice, rats and cynomolgous monkeys. We have achieved the aims of our Phase I and II SBIR grants, as well as conducted many additional studies that were not originally described or anticipated. We have established a co-development partnership with Biohaven Pharmaceuticals, and now seek Bridge Phase II SBIR support to advance trigriluzole through costly Phase II clinical trials in combination with the anti-PD1 antibody nivolumab. Our goal is to develop trigriluzole as an oral anticancer agent used in combination, at least initially, with anti-PD1 antibodies, which could substantially increase the efficacy of anti- PD1 therapy alone. Monotherapy will also be considered in the future, depending on the results of these studies. In Aim 1, we will conduct additional preclinical biomarker and patient derived xenograft (PDX) activities to support the introduction of trigriluzole into human clinical trials for metastatic melanoma, including obtaining the required IND approval. In the PDX model, we will look for possible biomarkers such as differences in signal transduction in key pathways (MAPK, Pi3K/AKT), changes in expression of VEGF, IL-8, CD34, CCL4, and MCSF, and changes in the quantity and contents of tumor-derived exosomes in the peripheral blood. In Aim 2, our collaborators at the Cancer Institute of New Jersey at Rutgers University will conduct Phase II human clinical trials for the treatment of metastatic melanoma in combination with nivolumab.