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