Riluzole Prodrugs for Melanoma and ALS

描述（由申请人提供）：我们已经鉴定了利鲁唑的新型IIb型前药FC-311，其具有通过新型神经递质作用机制起作用的革命性治疗转移性黑色素瘤的破坏性病症的疗法的潜力，并且还可用于治疗肌萎缩性侧索硬化症（ALS）和利鲁唑本身处于临床评价中的许多其他病症。FC-311不受利鲁唑的Cyp 1A 2代谢限制和较大的患者间暴露变异性的影响，口服给药后，FC-311的高寿命期约为利鲁唑的3倍，生物利用度更高，并以剂量依赖性方式在黑素瘤异种移植模型中显示出显著疗效。我们使用系统的体外和体内筛选策略，从约30种设计的候选药物中确定FC-311为最佳前药。我们已经最终证明FC-311不被Cyp 1A 2代谢，同时证实利鲁唑本身几乎完全被这种酶代谢，这种酶在一般人群中的表达水平不同。我们已经实现了I期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II期支持，以通过各种IND使能临床前开发活动来推进FC-311。我们的目标是将FC-311开发为口服抗癌药，以提供利鲁唑活性物质的患者间均匀给药。在目标1中，我们将开展通常被视为任何药物发现和开发计划一部分的原料药和化学相关活动。这些包括制备300 g非GMP活性药剂，选择合适的盐形式、载体和制剂，分析方法开发，原料药稳定性测试，评估额外的利鲁唑前药以增加专利保护，作为备份，并可能考虑额外的适应症，继续对所涉及的重要知识产权进行专利起诉，和制备5 kg FCC-311的cGMP。在目标2中，我们将继续开展所需的IND开发活动，包括完成代谢物ID研究（人、大鼠和犬），在另外两个种属中测定与药效学相关的完整PK参数，除了证明缺乏Cyp 1A 2外，还研究Cyp 450抑制作用，完成体外非GLP毒理学研究（hERG、艾姆斯、遗传毒性）、大鼠和犬28天安全性药理学试验以及FC-311的进一步辅助药理学试验。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价。我们已经成立了一个由八名临床医生、药理学家和经验丰富的药学专家组成的阿舒唑前药项目领导小组，以提供真实的时间指导和支持，确保该项目的成功。我们将为FC-311申请孤儿药资格，并寻求从风险投资和其他来源获得更多资金，或与大型制药公司合作，以推进FC-311通过临床开发的各个阶段。

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.