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

开发一流的抗病毒药物来解决免疫功能低下患者的 CMV 耐药性问题

基本信息

批准号：
10766598
负责人：
Robert Rodick
金额：
$ 30万
依托单位：
VXBIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-12 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10766598
关键词：
Accounting Address Animals Antiviral Agents Antiviral Therapy Antiviral resistance Benefits and Risks Biological Assay Biological Availability Blindness Bone Marrow Transplantation Cause of Death Cessation of life Clinical Clinical Trials Collection Congenital Abnormality Cytomegalovirus Data Development Disease Dose Dose Limiting Down Syndrome Drug Delivery Systems Drug Formulations Drug Kinetics Drug Targeting Drug resistance Enzyme-Linked Immunosorbent Assay Evolution Failure Feedback Fetal Alcohol Syndrome Formulation Frequencies Ganciclovir Genetic Genetic Transcription Genetic Variation Goals Herpesviridae Human Human Herpesvirus 5 Immediate-Early Genes Immunocompromised Host Immunologic Deficiency Syndromes In Vitro Intervention Liver Maps Medical Mental Retardation Mission Modeling Molecular Morbidity - disease rate Murid herpesvirus 1 Mus Nature Neutropenia Newborn Infant Nucleic Acids Organ Outcome Pathogenesis Patients Persons Pharmaceutical Preparations Phase Physiological Pilot Projects Population Pregnant Women Prevention Probability Production Proteins Publications Publishing Regulator Genes Resistance Rest SCID Mice Safety Salivary Glands Solid Spinal Dysraphism Spleen Survival Analysis Systemic disease Therapeutic Toxic effect Toxicology Translating Transplant Recipients Vaccines Viral Viral Load result Virus Work analog anti-viral efficacy congenital cytomegalovirus cytotoxic deafness design drug efficacy efficacy evaluation experience improved in vivo lipid nanoparticle mortality nanomedicine nanoparticle drug neonatal mice organ transplant recipient pharmacokinetics and pharmacodynamics phase 2 study phase III trial response standard of care therapeutic target transplant model viral resistance virology

项目摘要

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.

抽象的人类巨细胞病毒 (CMV) 感染世界上大多数人口，是导致疾病的主要原因移植患者和新生儿，导致先天性出生缺陷的比例高于唐氏综合症、脊柱裂，或酒精胎儿综合症目前还没有批准的 CMV 疫苗和所有抗病毒疗法。预防或治疗遭受毒性和耐药性进化的低障碍测试，有。有效的 CMV 抗病毒药物是一项未得到满足的迫切医疗需求，这些药物对药物的发展具有很高的障碍 VxBiosciences 的使命是开发抗逃逸或抗耐药性的疗法。这项工作的长期目标是开发并临床转化一种一流的抗病毒药物，有效克服 CMV 抗病毒耐药性该提案的具体目标是：(i) 确定体内疗效和剂量。首创的针对病毒转录回路的“抗逃逸”核酸脂质纳米颗粒（LNP）通过使用动物特异性类似物（即“替代物”）；以及 (ii) 开发 GMP 级药物制剂该产品能够收集支持 IND 的 GLP 毒理学数据。拟议的抗病毒药物是我们研究的基础。绘制 CMV 中重要的转录反馈回路（Teng 等人，2012 年；Vardi 等人，2018 年；Chaturvedi 等人，2018 年） al. 2020），我们的工作分离了抑制 CMV 的反馈干扰（FD）分子（Chaturvedi et al. 2022），以及最近的数据显示，该药物的全身递送可抑制小鼠多个器官中的 CMV，并停止全身性疾病可显着提高受感染的免疫功能低下小鼠的存活率。初步数据证实 FD 原料药在以下疾病中表现出强大的 CMV 抗病毒功效体外和体内都具有非常高的遗传屏障来进化耐药性。 FD 药品方法取决于 LNP 纳米药物的 FDA 批准和安全性概况（例如 Onpattro）基于我们广泛的研究，我们成功开发了针对其他病毒的 LNP 药物产品。根据初步数据，我们的中心假设是 LNP-FD 将构成一种安全、有效的抗病毒策略，该提案的严格性取决于我们已发表的研究、我们的 GMP- 生产专业知识，以及我们引导一流抗病毒药物通过 FDA 进入临床试验的经验。第一阶段的具体目标将使用替代分子（基于现有的 FDA 使用替代物的先例），预期结果是减少 CMV 疾病并提高生存率在这个生理相关模型中，第二阶段的具体目标将是建立 GMP 级生产。这些研究的回报将是确定首创的可行性。类纳米药物靶向转录电路并证明这种治疗策略具有很高的根据显示低毒性的初步研究，该药品可能会阻碍耐药性的发展。最终成为先天性巨细胞病毒感染的可行干预措施，最终批准治疗目标。病毒转录回路可以使一类具有高耐药性的新型抗病毒药物成为可能。