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

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

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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）感染了世界大多数人口，是疾病的主要原因移植患者和新生儿，占先天性先天缺陷的占比唐氏综合症的先天缺陷多扁平菌或胎儿酒精综合征。 CMV没有批准的疫苗和所有当前的抗病毒疗法预防或治疗遭受毒性的障碍和耐药性进化的低障碍。因此，那里是对有效CMV抗病毒药的紧急医疗需求，该抗病毒药具有很高的障碍反抗。 VXBiosciences的任务是开发抗逃生或防抗性治疗。这项工作的长期目标是开发和临床翻译一种有效克服的一类抗病毒 CMV抗病毒抗性。该提案的具体目标是：（i）建立体内效率和给药靶向病毒转录电路的第一类“抗逃避”核酸脂质纳米颗粒（LNP）通过使用动物特异性类似物（即“替代”）；（ii）开发药物的GMP级公式可以收集辅助GLP毒理学数据的产品。拟议的抗病毒是在我们的研究中建立的在CMV中绘制必需的转录反馈电路（Teng等人，2012; Vardi等人，2018; Chaturvedi et al。 2020年），我们的工作隔离反馈破坏者（FD）分子，该分子抑制CMV（Chaturvedi等人2022），并且最新数据显示药物的全身传递会抑制小鼠多个器官中的CMV，并停止全身性疾病可显着增加感染免疫功能低下的小鼠的存活。这些广泛初步数据确定了FD药物在表现出强的CMV抗病毒效率的概念证明体内和体内，具有很高的遗传障碍，可以抗球的进化。 LNP-的理由 FD药物产品方法取决于LNP纳米医学的FDA批准和安全概况（例如，Onpattro）以及我们成功开发基于LNP的药品为其他病毒开发。基于我们的广泛初步数据，我们的核心假设是LNP-FD将构成安全，有效的抗病毒药策略抗药性演变的高障碍。该提案的严谨基于我们已发表的研究，我们的GMP- 生产专业知识，以及我们通过FDA到临床试验的一流抗病毒药的经验。 I阶段特定的目的将使用替代分子在体内评估效率和安全性（基于现有 FDA使用替代物的先例），预期的结果是CMV疾病降低并提高了生存率在这个与物理相关的模型中。第三阶段的特定目的将建立GMP级生产抗病毒和收集辅助数据。这些研究的回报将是确定第一届类纳米医学靶向转录电路，并证明这种治疗策略具有很高的阻力演变的障碍。基于显示低毒性的试点研究，药物可能最终，对先天性CMV感染是可行的干预措施。最终，批准治疗靶向病毒转录电路可以使新的抗病毒药具有较高的阻力障碍。