Advancing a novel potent double anti-HCV nucleoside analog combination treatment for the OUD population to the clinic

我们的目标是开发一种治疗OUD患者丙型肝炎病毒(HCV)感染的超短期治疗方案。 丙型肝炎病毒是许多OUD患者的主要共病。治疗他们的丙型肝炎病毒减少了他们随后静脉注射药物的使用。 虽然目前可用的方案可以在8-12周内治愈大多数患者的丙型肝炎病毒，但在患有丙型肝炎的患者中治愈时间更长 晚期肝病或耐药突变在OUD患者中更常见，当这些相同 方案只使用了4周，大多数患者失败了，他们产生了抗药性突变。超短 目前还不能实现高治愈率的治疗方案，也不能预期有任何 市场上或正在开发中的药物。我们现在寻求利用我们激动人心的“SBIR第一阶段等价物” 一种新型双核苷类药物治疗慢性丙型肝炎的研究结果。我们的整体 假设RiBoscience的独特和高度协同的双核苷(NUC)方案(RBS1154，a 单磷酸尿苷前药，比吉列德的索莫布韦+RBS1502更有效，同样优越 单磷酸胞苷前体药物)将在4周或更短的时间内只需一张处方就能治愈患者(大多数 可能在1-2周内，但那些没有治愈的人可以简单地接受更长时间的治疗-因为他们没有风险 全核苷方案耐药)。这样的双重NUC组合将对以下方面产生重大影响 对很大一部分人的支持性关怀--加快治愈频繁的重大疾病的时间 共病，降低丙型肝炎病毒传播到其他OUD患者的风险，并减少静脉注射药物的使用。为了测试 我们的假设，并使我们的双核苷组合在OUD患者中的临床研究成为可能，我们试图 完成以下具体目标：1)完成关键化学和制造(CMC)和病毒学 活动：a)完成RBS1502‘S过程化学，合成每个NUC 1公斤非GMP用于非 GLP毒素研究；b)完成初级药理包(病毒学)；2)使GLP毒性能够支持IND 研究：a)合成每个核苷的15公斤GMP原料药，以支持GLP tox和第一阶段研究；b) 开发分析方法以支持ADME和毒性研究；3)进行体外和体内实验 能够进行GLP毒性研究的特征：a)完成初级和次级药理学 符合FDA指南的U和C类似物的表征，包括PK和体内外 ADME研究；b)对U和C类似物进行剂量范围寻找非GLP毒性研究；4)完成 支持IND备案的数据包执行：a)8周的U和C GLP毒性研究以及4周的U+C毒性研究 联合毒性研究；b)GLP安全药理(呼吸、心血管、中枢神经系统)和遗传毒性研究。 我们目标的成功实现将对OUD患者的支持性护理产生重大影响。 我们新的双核苷方法可以产生最方便、最安全、最短时间的治疗方案 丙型肝炎病毒感染者。这将是一个对患者非常有吸引力的商业解决方案，并使 为进一步的临床开发和商业成功获得后续私营部门的额外资金。

Our goal is to develop an ultra short curative regimen for hepatitis C virus (HCV) infection in OUD patients. HCV is a major co-morbidity of many OUD patients. Treating their HCV reduces their subsequent IV drug use. While currently available regimens can cure HCV in most patients in 8-12 weeks, longer in patients with advanced liver disease or drug resistance mutations that are more frequent in OUD patients, when these same regimens are used for just 4 weeks, most patients fail and they develop drug resistance mutations. Ultra short treatment regimens with high cure rates are not currently achievable, nor can they be anticipated with any of the drugs on the market or in development. We now seek to leverage our exciting “SBIR Phase 1 equivalent” research results into a novel double nucleoside-based treatment for HCV in OUD patients. Our overall hypothesis is that Riboscience’s unique and highly synergistic double nucleoside (nuc) regimen (RBS1154, a uridine monophosphate prodrug that is more potent than Gilead’s sofosbuvir + RBS1502, an equally superior cytidine mono-phosphate prodrug) will cure patients with just one prescription in 4 weeks or less (most probably in 1-2 weeks, but those who don’t get cured can simply be treated a bit longer—as their is no risk of resistance with an all nucleoside regimen). Such a double nuc combo will have a major impact with respect to the supportive care of a large segment of the OUD population--accelerating time to cure of a frequent major comorbidity, reducing the risk of HCV spread to other OUD patients, and decreasing IV drug use. To test our hypothesis, and enable clinical studies of our double nucleoside combo in OUD patients, we seek to accomplish the following specific aims: 1) complete critical chemistry and manufacturing (CMC) and virology activities by: a) finishing RBS1502’s process chemistry and synthesize 1 Kg non-GMP of each nuc for non- GLP tox studies; b) complete primary pharmacology package (virology); 2) enable IND-enabling GLP toxicity studies by: a) synthesizing 15 Kg of GMP API of each nucleoside to support GLP tox and Phase 1 studies; b) develop analytical methods to support ADME and toxicity studies; 3) Perform in vitro and in vivo characterizations to enable GLP toxicity studies by: a) completing primary and secondary pharmacology characterizations for the U and C analogs in line with FDA guidances, including PK and in vitro and in vivo ADME studies; b) performing dose-range finding non-GLP toxicity studies for the U and C analogs; 4) complete data package to support IND filing by performing: a) 8-wk GLP toxicity studies for U and C and 4-wk U+C combination toxicity study; b) GLP safety pharmacology (respiratory, CV, CNS) and genotoxicity studies. Successful accomplishment of our aims will have a major impact on the supportive care of OUD patients. Our novel double nucleoside approach can yield the most convenient, safest, ultra short treatment option for HCV-infected OUD patients. This will be a very attractive commercial solution for OUD patients and enable securing subsequent additional private sector funding for further clinical development and commercial success.