ATI-2173 is an orally-bioavailable, liver-targeted Active Site Polymerase Inhibitor Nucleotide (ASPIN). Its active metabolite is the ONLY nucleotide that inhibits all stages of DNA synthesis by distorting its enzyme’s active site, non-competitively.
ATI-2173 - a descendent of clevudine, a first generation ASPIN, was originally developed for the treatment of chronic HBV. In humans, monotherapy demonstrated equivalent antiviral efficacy to ETV after 48 weeks. Its mechanism of action uniquely demonstrated extended viral suppression following treatment discontinuation out to 24 weeks. However, clevudine was not liver targeted. It was voluntarily discontinued in Phase 3 by its developer, Pharmasset, due to reversible proximal skeletal muscle myopathy, which emerged after a minimum of 8 months of dosing (median exposure 16 months, 1% of patients at one year). This adverse event was also observed in a 12-month clevudine monkey toxicology program with a dose and duration relationship. Aside from this rare adverse event, clevudine demonstrated a well-defined safety profile and efficacy data from 1,500+ HBV-infected subjects. Further, combination treatment with adefovir demonstrated improved virological response with no viral resistance detected.
ATI-2173 is a next generation ASPIN with improved pharmacokinetics and the same potent mechanism of action. In contrast to clevudine, ATI-2173 is ion-trapped in the liver as monophosphate leading to high liver triphosphate (the active metabolite) levels and low systemic clevudine exposure. Liver targeting has been confirmed in rat (below) and monkey PK studies. Monkey PK studies confirmed 82% first-pass uptake.