Riluzole Prodrugs for Melanoma and ALS

治疗黑色素瘤和 ALS 的利鲁唑前药

基本信息

批准号：
9525036
负责人：
Allen Bernard Reitz
金额：
$ 100万
依托单位：
FOX CHASE CHEMICAL DIVERSITY CENTER, INC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-27 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9525036
关键词：
Active Biological Transport Aftercare Allografting Amines Amino Acid Transporter Amyotrophic Lateral Sclerosis Antibodies Antineoplastic Agents Autologous Biological Availability Biological Markers Blood Blood Circulation C57BL/6 Mouse CCL2 gene CCL4 gene CD34 gene CSF1 gene Cancer Institute of New Jersey Cell Line Cell Transplants Cells Chemicals Cleaved cell Clinical Clinical Treatment Clinical Trials Development Dose Excitatory Amino Acids Exhibits Exposure to FDA approved Fasting Food Foxes Funding Future GRM1 gene Gastrointestinal tract structure Generations Glutamates Glutamic Acid Goals Grant Growth Half-Life Hour Human IL8 gene Immune Immune checkpoint inhibitor Immunocompetent Immunotherapy Investigational New Drug Application Investments Life Liver Liver Function Tests Luciferases MAP Kinase Gene Mediating Melanoma Cell Metabolic Metabolism Metastatic Melanoma Modeling Monkeys Mus N hydroxylation Newly Diagnosed Numbness Oral Oral Administration Oral mucous membrane structure Outcome PDCD1LG1 gene PI3K/AKT PIK3CG gene Pathway interactions Patients Peptide Transport Pharmaceutical Preparations Pharmacologic Substance Phase Phase II Clinical Trials Problem Solving Prodrugs Program Development Proto-Oncogene Proteins c-akt Rattus Recurrence Relapse Research Design Resistance Riluzole Rodent Model SLEB2 gene Sampling Signal Transduction Small Business Innovation Research Grant Solubility Tablets Testing Therapeutic Trials Toxic effect Tumor-Derived Universities Vascular Endothelial Growth Factors Water Work Xenograft Model Xenograft procedure absorption anti-PD-1 anti-PD1 antibodies anti-PD1 therapy biomarker identification chemotherapy clinical efficacy clinical practice combinatorial compliance behavior cost design efficacy study exosome experimental study glycylsarcosine immune reconstitution improved in vivo evaluation liver function melanoma mouse model neoplastic cell novel outcome forecast patient population patient variability peripheral blood phase II trial pre-clinical primary endpoint programs research clinical testing response secondary endpoint treatment effect tumor tumor growth tumor progression

项目摘要

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.

我们已经发现了一种新颖的IIB型Riluzole，Trigriluzole（FC-4157，BVH-4157），其中具有有可能改善治疗转移性黑色素瘤毁灭性状况的治疗的潜力通过一种新型的谷氨酸能作用机理作用。 riluzole在治疗方面表现出了有希望的功效在患者中，在C8161小鼠异种移植模型中，Trigilluzole比Riluzole本身高20倍> 20倍黑色素瘤，在Mass20同种异体移植模型中效果更高，结合使用抗PD1。 Trigriluzole是旨在克服限制其更广泛的临床功效的Riluzole的局限性。例如， riluzole片剂在口服时具有60％的生物利用度，归因于CYP1A2介导的第一通道肝脏中的代谢，这也会导致暴露的患者到患者的差异。此外，riluzole是与餐食服用时的水平降低相关（即食物效应），需要快速三个小时（一小时前和进餐后两个小时），患者依从性差。 Riluzole每天服用两次，有剂量依赖性对肝功能测试的影响，水的溶解度较低，并且口服麻木直接施用到口腔粘膜。 Trigriluzole解决了这些问题，因为它不受首先的影响通过CYP1A2代谢，可能适用于每天一次的剂量，延长半衰期。 Trigriluzole是一个 pept1转运蛋白从胃肠道中积极地从胃肠道中占用的三肽结合物，而riluzole不是积极运输，消除了对三格鲁唑的禁食需求。 Trigriluzole在胃肠道中稳定，但吸收后切割。口服后在全身循环中观察到高水平的riluzole 在小鼠，大鼠和愤世嫉俗的猴子中给药。我们已经实现了我们的目标第一阶段和II SBIR赠款，并进行了许多其他最初没有描述或预期。我们已经与Biohaven Pharmaceuticals建立了共同开发合作伙伴关系，现在寻求桥梁II阶段SBIR支持，以通过昂贵的II期临床试验促进三级学士学位抗PD1抗体nivolumab。我们的目标是开发Trigiluzole作为使用的口服抗癌剂至少最初与抗PD1抗体的组合可以大大提高抗抗体的功效仅PD1治疗。将来还将考虑单一疗法，具体取决于这些结果研究。在AIM 1中，我们将进行其他临床前生物标志物和患者衍生的异种移植（PDX）活动支持将Trigiluzole引入人类的转移性黑色素瘤临床试验中，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（MAPK，PI3K/AKT）中的信号转导，VEGF，IL-8，CD34，CCL4的表达变化和MCSF，以及外周血中肿瘤衍生外泌体的数量和含量的变化。在 AIM 2，我们在罗格斯大学新泽西州癌症研究所的合作者将进行II阶段人类的临床试验，用于治疗转移性黑色素瘤与Nivolumab结合使用。