Riluzole Prodrugs for Melanoma and ALS

描述(申请人提供)：我们已经确定了一种新型的IIb型利鲁唑前药FC-311，它有可能通过一种新的谷氨酸能作用机制来革命性地治疗转移性黑色素瘤的破坏性疾病，还可以用于治疗肌萎缩侧索硬化症(ALS)和利鲁唑本身正在接受临床评估的许多其他疾病。FC-311不受利鲁唑限制的CYP1A2代谢和患者对患者暴露的大变异性的影响，具有约3倍的高寿命，口服时生物利用度更高，并以剂量依赖的方式在黑色素瘤异种移植模型中显示出显著的疗效。我们通过系统的体外和体内筛选策略，从设计的大约30个候选药物中确定FC-311为最佳前药。我们最终证明了FC-311不是由CYP1A2代谢的，同时证实了利鲁唑本身几乎完全由这种酶代谢，这种酶在普通人群中有不同的表达水平。我们已经实现了我们第一阶段研究计划的所有目标，并进行了许多最初没有描述或预期的额外研究。我们现在寻求第二阶段的支持，通过各种启用IND的临床前开发活动来推进FC-311。我们的目标是开发FC-311作为口服抗癌剂，以便为患者提供均匀的利鲁唑活性物质。在目标1中，我们将开展与药物物质和化学相关的活动，通常被认为是任何药物发现和开发计划的一部分。这包括制备300克非GMP活性药剂，选择合适的盐形式、载体和配方，分析方法开发，药物物质稳定性测试，评估额外的利鲁唑前体药物以增加专利保护，作为备份，并可能考虑更多的适应症，继续对所涉及的重要知识产权进行专利诉讼，以及制备5公斤FCC-311的cGMP。在目标2中，我们将继续必要的IND促进开发活动，包括完成代谢物ID研究(人、鼠和狗)、测定另外两种与药效学相关的PK参数、除了已证明缺乏CYP1A2之外还研究对CYP450的抑制作用、完成体外、非GLP毒理学研究(HERG、Ames、遗传毒性)、28天的大鼠和狗的安全药理试验，以及进一步的FC-311辅助药理试验。我们希望尽快向FDA提交IND，然后过渡到黑色素瘤患者的临床评估。我们已经建立了由8名临床医生、药理学家和经验丰富的药学专家组成的利鲁唑前体药物项目领导团队，为确保该项目的成功提供实时指导和支持。我们将为治疗黑色素瘤的FC-311申请孤儿药物指定，并寻求从风险投资和其他来源获得进一步资金，或与大型制药公司合作，在临床开发的各个阶段推动FC-311的发展。

DESCRIPTION (provided by applicant): We have identified a novel Type IIb prodrug of riluzole, FC-311, which has the potential to revolutionize therapy for the treatment of the devastating condition of metastatic melanoma acting via a novel glutamatergic mechanism of action, and also be useful to treat amyotrophic lateral sclerosis (ALS) and the many other conditions for which riluzole itself is under clinical evaluation. FC-311 is not subject to the limiting Cyp1A2 metabolism and large patient-to-patient variability of exposure that riluzole is, and has a ~3X longer high-life, higher bioavailability upon oral administration, and shows dramatic efficacy in a xenograft model of melanoma, in a dose dependent manner. We identified FC-311 as the optimal prodrug from among ~30 designed candidates using a systematic in vitro and in vivo screening strategy. We have demonstrated conclusively that FC-311 is not metabolized by Cyp1A2, while confirming that riluzole itself is metabolized nearly exclusively by this enzyme, which has variable levels of expression in the general population. We have achieved all of the aims of our Phase I program of study as well as conducted many additional studies that were not originally described or anticipated. We now seek Phase II support to advance FC-311 through various IND-enabling pre-clinical development activities. Our goal is to develop FC-311 as an oral anticancer agent in order to provide uniform, patient to patient delivery of riluzole active substance. In Aim 1, we will conduct drug substance and chemistry related activities normally considered as part of any drug discovery and development program. These include preparing 300 g of non-GMP active pharmaceutical agent, selection of suitable salt form, vehicle and formulation, analytical methods development, drug substance stability testing, evaluation of additional riluzole prodrugs for added patent protection, as back-ups, and for possible consideration for additional indications, continued patent prosecution of the important intellectual property involved, and preparation of 5 kg of cGMP of FCC-311. In Aim 2, we will continue the required IND-enabling development activities which include completion of metabolite ID studies (human, rat and dog), determination of full PK parameters in two additional species, correlated to pharmacodynamics, investigation of Cyp450 inhibition effect in addition to the demonstrated lack of Cyp1A2, completion of in vitro, non-GLP toxicology studies (hERG, Ames, genotoxicity), 28 day safety pharmacology testing in rats and dogs, and further ancillary pharmacology testing on FC-311. We wish to file an IND with the FDA as soon as possible, and then transition into clinical evaluation in melanoma patients. We have established a Riluzole Prodrug Project Leadership Team consisting of eight clinicians, pharmacologists and experienced pharmaceutical experts to provide real time guidance and support to ensure the success of this program. We will file for orphan drug designation for FC-311 for melanoma, and seek to obtain further funding from venture capital and other sources, or partner with a major pharmaceutical company, to advance FC-311 through the various phases of clinical development.