Riluzole Prodrugs for Melanoma and ALS

我们已经发现了利鲁唑的新型IIb型前药，曲格鲁唑（FC-4157，BVH-4157），其具有 实质上改善治疗转移性黑色素瘤的破坏性病症的疗法的潜力 通过一种新的药物作用机制起作用。虽然利鲁唑在治疗糖尿病方面显示出有希望的疗效， 在C8161小鼠异种移植模型中，曲格鲁唑比利鲁唑本身的效力高> 20倍。 在MASS 20同种异体移植物模型中，与抗PD 1组合，曲格鲁唑是 旨在克服限制利鲁唑更广泛临床疗效的局限性。比如说， 利鲁唑片剂口服给药后的生物利用度为60%，归因于Cyp 1A 2介导的首过效应 这也会导致患者之间暴露的高度变异性。此外，利鲁唑是 与随餐服用时降低的水平相关（即，负面的食物影响），需要禁食三小时 (one餐前1小时和餐后2小时），患者依从性差。阿舒唑每天给药两次， 对肝功能试验的剂量依赖性影响，表现出在水中的低溶解度， 直接施用于口腔粘膜。曲格鲁唑解决了这些问题，因为它不受第一- 通过Cyp 1A 2代谢，可能适合每天给药一次，半衰期延长。曲格鲁唑是 由PepT 1转运蛋白从胃肠道主动摄取的三肽缀合物，而利鲁唑不是 主动转运，避免了禁食曲格鲁唑的需要。曲格鲁唑在胃肠道中稳定，但 吸收后裂开。口服给药后，在体循环中观察到高水平的利鲁唑 在小鼠、大鼠和食蟹猴中给予曲格鲁唑。我们已经实现了我们的目标， 第一和第二阶段SBIR赠款，以及进行了许多额外的研究，最初没有描述或 预期。我们与Biohaven Pharmaceuticals建立了共同开发合作伙伴关系，现在 寻求Bridge II期SBIR支持，通过昂贵的II期临床试验， 抗PD 1抗体nivolumab。我们的目标是开发曲格鲁唑作为一种口服抗癌剂， 至少在最初，可以与抗PD 1抗体组合，这可以显著增加抗PD 1抗体的功效。 PD 1单独治疗。未来也将考虑单药治疗，这取决于这些研究的结果。 问题研究在目标1中，我们将开展额外的临床前生物标志物和患者源性异种移植物（PDX）活动 支持将曲格鲁唑引入转移性黑色素瘤的人体临床试验，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，例如 关键途径中的信号转导（MAPK、Pi 3 K/AKT），VEGF、IL-8、CD 34、CCL 4表达的变化， 和MCSF，以及外周血中肿瘤源性外泌体的数量和含量的变化。在 目标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 与纳武单抗组合治疗转移性黑素瘤的人类临床试验。

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.