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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.

摘要