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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R42AI174554-01A1
Agency Tracking Number: R42AI174554
Amount: $300,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA22-178
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-09-12
Award End Date (Contract End Date): 2024-08-31
Small Business Information
537 24th Street
Oakland, CA 94612
United States
DUNS: 117517470
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 (510) 545-6669
Business Contact
Phone: (510) 545-6669
Research Institution
SAN FRANCISCO, CA 94158-2261
United States

 Domestic Nonprofit Research Organization

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.

* Information listed above is at the time of submission. *

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