A single antiviral to treat multiple opportunistic infections

PROJECT SUMMARY/ABSTRACT Immunosuppressed transplant patients have heightened susceptibility to environmental pathogens as well as adventitious agents traveling with donor tissues or resident in the recipient. Traditional therapies target the virus and are thereby limited in effectiveness to the specific virus targeted. Evrys Bio is developing orally administered, broad-spectrum antivirals that target the host-cell sirtuin-2 protein (SIRT2). In vitro feasibility was demonstrated in SBIR Phase I for an early lead, FLS-359, showing broad effectiveness against four families of viruses posing problems for immunosuppressed transplant patients: herpesviruses, polyomaviruses, hepatitis viruses, and respiratory viruses. Additionally, SIRT2-targeting with FLS-359 blocked acquisition of viral drug resistance in an influenza model and was additive in antiviral activity with traditional direct-acting antivirals. A prototype was developed in SBIR Phase II, allowing selection of a Drug Candidate (DC) for Investigational New Drug (IND)-enablement that satisfied the in vitro Target Compound Profile with respect to antiviral potency and ADME, and in vivo oral bioavailability, target engagement, and tolerability. The DC is designated EV-100. In this SBIR Phase IIB application, we request funding to advance EV-100 toward an IND filing. The clinical trial will be designed to test the utility of EV-100 for prophylaxis of human cytomegalovirus (HCMV) infection and disease in adult HCMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant. To advance to the IND filing, we will establish relationships between EV-100 dose, pharmacokinetic parameters, efficacy, and toxicity. We will conduct non-GLP dose range finding safety studies in rats and dogs, and efficacy studies in murine HCMV viral challenge models to provide guidance and minimize risk with dosing regimen selection for costly GLP and clinical studies. In addition, we will perform studies to address published FDA in vitro virology study recommendations that will support an IND filing. These studies will include the assessment of EV-100 antiviral activity versus multiple laboratory and clinical HCMV isolates, including the analysis of EV-100 inhibitory activity toward HCMV variants that are resistant to currently approved drugs; testing for the evolution of viral drug resistance during serial passage of HCMV in increasing concentrations of EV-100 in cell culture; evaluation of EV-100 efficiency in combination with currently approved anti-HCMV drugs; delineation of EV- 100 as a function of HCMV dose; and additional parameters that help to predict the efficacy of EV-100 in transplant recipients. Finally, although HCMV prophylaxis is the intended initial indication, the broad-spectrum antiviral profile against human viruses is a potential breakthrough feature of EV-100. The drug has already been shown to inhibit both RNA and DNA viruses in addition to HCMV that can threaten both the organ and the survival of the patient following a transplant. In vitro studies in human cells and in vivo studies in humanized in mice will be performed to further evaluate this potentially unique broad-spectrum utility of EV-100.