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用于OUD患者丙型肝炎病毒（HCV）感染的超短治愈方案。 HCV是许多OUD患者的主要合并症。治疗他们的HCV减少了他们随后的IV药物使用。 虽然目前可用的治疗方案可以在8-12周内治愈大多数患者的HCV，但对于患有HCV感染的患者， 晚期肝病或耐药突变在OUD患者中更常见，当这些相同时， 虽然这些方案仅使用4周，但大多数患者失败，并产生耐药性突变。超短 高治愈率的治疗方案目前无法实现，也不能预期任何 市场上的药物或正在开发的药物。我们现在寻求利用我们令人兴奋的“SBIR第1阶段同等产品” 研究结果为一种新的双核苷为基础的治疗丙型肝炎病毒在OUD患者。我们的整体 假设是Riboscience独特和高度协同的双核苷（nuc）方案（RBS 1154， 比吉利德的索非布韦+RBS 1502更有效的尿苷一磷酸前药，同样是一种上级药物。 胞苷一磷酸前药）将在4周或更短的时间内用一个处方治愈患者（大多数 可能在1-2周内，但那些没有治愈的人可以简单地治疗更长时间-因为他们没有风险 全核苷方案的抗性）。这样的双nuc组合将产生重大影响， OUD人群中很大一部分人的支持性护理--加快了治愈频繁发生的重大疾病的时间， 合并症，降低HCV传播到其他OUD患者的风险，并减少IV药物使用。测试 我们的假设，并使我们的双核苷组合在OUD患者的临床研究，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RBS 1502的工艺化学，并合成1 Kg非GMP的每种nuc， GLP毒性研究; B）完整的主要药理学包（病毒学）; 2）实现IND使能GLP毒性 研究：a）合成15 Kg每种核苷的GMP API，以支持GLP毒性和1期研究; B） 开发支持ADME和毒性研究的分析方法; 3）进行体外和体内研究 通过以下方式进行GLP毒性研究：a）完成主要和次要药理学研究 U和C类似物的表征符合FDA指南，包括PK以及体外和体内 ADME研究; B）进行U和C类似物的剂量范围探索非GLP毒性研究; 4）完成 数据包，通过执行：a）U和C的8周GLP毒性研究和4周U+C 联合毒性研究; B）GLP安全药理学（呼吸系统、CV、CNS）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。 我们的新型双核苷方法可以产生最方便，最安全，超短的治疗选择， HCV感染的OUD患者。这对于OUD患者来说将是一个非常有吸引力的商业解决方案， 确保后续额外的私营部门资金用于进一步的临床开发和商业成功。

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.