Advancing a novel potent Zika virus specific nucleoside analog to the clinic

Period of Performance: 08/18/2017 - 07/31/2018


Phase 2 SBIR

Recipient Firm

Riboscience, LLC
Principal Investigator


Our goal is to leverage our exciting ?SBIR Phase 1 equivalent? research results into a novel nucleoside based treatment for Zika virus (ZIKV) that can be used for prevention or treatment of ZIKV infection. Our lead molecule, RBS1069, is the first potent and specific inhibitor of ZIKV replication (EC50 0.48 micromolar; CC50 > 100 micromolar) and that is suitable for the development of both oral and intravenous dosage forms. RBS1069 is a prodrug that improves delivery of the nucleoside 4AU to infected cells. 4AU has already shown safety in chronic toxicity studies in rats and monkeys and in a Phase 1 clinical study performed in healthy volunteers and HCV patients at doses up to 2000mg and up to 2 week treatment duration. We now seek to develop RBS1069 as an improved prodrug of 4AU into a clinical stage drug by: 1) optimizing the process chemistry route to synthesize larger quantities of RBS1069, and synthesizing scale up batches to support in vitro and in vivo characterization (30g and 300g); 2) completing the antiviral characterization of RBS1069 in vitro and in vivo in ZIKV mouse models and in vitro resistance characterization including the testing against available ZIKV strains in cell culture including multiple primary human cells, determining efficacy in protecting mice from systemic spread of infection, infection of pregnant mice and impact of timing of treatment start, passaging RBS1069 in Huh-7 cells at increasing drug concentrations to select resistant ZIKV variants and generating recombinant ZIKV polymerase to confirm resistance mutations; 3) determining key in vitro pharmacology and preclinical safety parameters of RBS1069, including permeability in Caco-2 cells and cytotoxicity in primary human cells and formation and half-life of 4AU triphosphate in human target cells, and in animal cells (mouse, rat, dog); 4) determining the in vivo pharmacokinetics and initial toxicity profile of RBS1069 in single dose PK studies in two species (rats and dogs), in in vitro safety, genotoxicity and ADME studies (including CYP and transporter inhibition assays, hERG inhibition, AMES, MNT, chromosomal aberration testing, metabolic stability), and safety (CV, respiratory, and CNS) profiling and 7-day non-GLP toxicity studies; 5) synthesizing a 4kg GMP grade batch of RBS1069 and perform 2 week GLP toxicity studies and safety pharmacology studies to enable IND. Our team is highly experienced in successful drug discovery and development. In addition, this team is expert in the synthesis and characterization of selective, efficacious and safe nucleoside analogs for viral diseases. This team is therefore well positioned to deliver a highly innovative potent, selective, well tolerated, easy to use inhibitor of ZIKV replication, targeting the ZIKV polymerase with high barrier to resistance capable of providing prophylactic and therapeutic protection against this serious pathogen.