Development of a first-in-class antiviral to address CMV drug resistance in immunocompromised patients

摘要 人类巨细胞病毒(CMV)感染了世界上大多数人，是#年主要的致病原因。 移植患者和新生儿，占先天出生缺陷比唐氏综合征，脊柱 或称胎儿酒精综合征。目前还没有批准的CMV疫苗和所有现有的抗病毒疗法 预防或治疗存在毒性和抗药性进化的低障碍。因此，在那里 是对有效的CMV抗病毒药物的迫切的医学需求，这种药物对药物的发展具有很高的障碍 抵抗。VxBiosciences的使命是开发防逃逸或抗药性的疗法。这个 这项工作的长期目标是开发并临床翻译一种一流的抗病毒药物，有效地克服 CMV抗病毒力。这项建议的具体目标是：(1)建立体内疗效和剂量 一种一流的以病毒转录电路为靶点的抗逃逸核酸脂质纳米粒(LNP) 通过使用动物特有的类似物(即，替代物)；以及(Ii)开发GMP级药物配方 支持IND-Enabling GLP-毒理学数据收集的产品。建议的抗病毒药物建立在我们的研究基础上 在CMV中定位一个重要的转录反馈电路(Teng等人。2012年；Vardi等人。2018；Chaturvedi et 艾尔2020)，我们的工作是分离抑制CMV的反馈干扰物(FD)分子(Chaturvedi等人)。2022)，以及 最近的数据显示，药物产品的全身给药抑制了小鼠多个器官中的CMV，并停止了 全身性疾病可显著提高受感染的免疫受损小鼠的存活率。这些广泛的 初步数据证实，FD药物物质在 体外和体内都有很高的遗传屏障，对抗性的进化产生了影响。LNP的理由是- FD药物产品方法依赖于FDA批准的LNP纳米药物(例如Onpattro)的安全性概况 并成功开发了基于LNP的针对其他病毒的药物产品。基于我们广泛的 初步数据，我们的中心假设是LNP-FDs将构成一种安全、有效的抗病毒策略，具有 抗性进化的高障碍。这项提议的严谨性取决于我们发表的研究，我们的GMP- 生产专业知识，以及我们通过FDA将一流抗病毒药物带入临床试验的经验。 第一阶段的特定目标将使用替代分子在体内评估有效性和安全性(基于现有的 FDA使用代用品的先例)，预期结果是减少CMV疾病并提高存活率 在这个与生理相关的模型中。第二阶段的具体目标将建立GMP级的生产 抗病毒和收集支持IND的数据。这些研究的回报将是建立第一个- 类纳米药物靶向转录电路并证明这种治疗策略有很高的疗效 抵抗力进化的障碍。基于显示低毒的试点研究，该药物产品可能 最终成为治疗先天性CMV感染的一种可行的干预措施。最终，治疗靶向的批准 病毒转录电路可以使一类新的抗病毒药物具有高抗药性。

ABSTRACT Human cytomegalovirus (CMV) infects a majority of the world’s population and is a leading cause of disease in transplant patients and newborns, accounting for more congenital birth defects than Down’s syndrome, spina bifida, or fetal alcohol syndrome. There is no approved vaccine and all current antiviral therapies for CMV prevention or treatment suffer from toxicity and a low barrier to the evolution of resistance. Consequently, there is an urgent unmet medical need for effective CMV antivirals that have a high barrier to the evolution of drug resistance. The mission of VxBiosciences is to develop escape-resistant or resistance-proof therapeutics. The long-term goal of this work is to develop and clinically translate a first-in-class antiviral that effectively overcomes CMV antiviral resistance. The specific objectives of this proposal are: (i) to establish in vivo efficacy and dosing of a first-in-class ‘escape-resistant’ nucleic-acid lipid nanoparticle (LNP) that targets viral transcriptional circuitry via use of an animal-specific analog (i.e., ‘surrogate’); and (ii) to develop a GMP-grade formulation of the drug product to enable collection of IND-enabling GLP-toxicology data. The proposed antiviral builds off our studies mapping an essential transcriptional feedback circuit in CMV (Teng et al. 2012; Vardi et al. 2018; Chaturvedi et al. 2020), our work isolating feedback disruptors (FD) molecules that inhibit CMV (Chaturvedi et al. 2022), and recent data showing the systemic delivery of the drug product inhibits CMV in multiple organs in mice, and halts systemic disease to dramatically increase survival of infected immunocompromised mice. These extensive preliminary data establish proof-of-concept that the FD drug substance displays strong CMV antiviral efficacy in vitro and in vivo and have a very high genetic barrier to the evolution of resistance. The rationale for the LNP- FD drug product approach rests upon FDA-approval and safety profiles of LNP nanomedicines (e.g., Onpattro) and our successful development of LNP-based drug products for other viruses. Based on our extensive preliminary data, our central hypothesis is that LNP-FDs will constitute a safe, effective antiviral strategy with a high barrier to the evolution of resistance. The proposal’s rigor rests upon our published studies, our GMP- production expertise, and our experience shepherding first-in-class antivirals through the FDA to clinical trials. The Phase-I specific aims will evaluate efficacy and safety in vivo using a surrogate molecule (based on existing FDA precedent for use of surrogates) and the expected outcome is reduced CMV disease and improved survival in this physiologically-relevant model. Phase-II specific aims will establish of GMP-grade production of the antiviral and collect IND-enabling data. The payoff of these studies will be to establish feasibility of a first-in- class nanomedicine targeting transcriptional circuitry and demonstrate that such therapeutic strategies have high barriers to the evolution of resistance. Based on pilot studies showing low toxicity, the drug product may ultimately be a viable intervention for congenital CMV infections. Ultimately, approval of a therapeutic targeting viral transcriptional circuitry could enable a new class of antivirals with high barriers to resistance.