Scientific Approach

Despite a preventive vaccine and available therapies, there is currently no cure for chronic HBV infection

ATI-2173 – a descendent of clevudine

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 weeks1. Its mechanism of action uniquely demonstrated extended viral suppression following treatment discontinuation out to 24 weeks2. 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 3. 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 detected4. 

 

ASPIN vs Nucleoside analogue (NA)

NA – Traditional, chain-terminating nucleoside analogues inhibit some stages of DNA synthesis by competing for nucleotide positions in the HBV DNA chain, preventing priming and/or further elongation.

Active Site Polymerase Inhibitor Nucleotide (ASPIN) – active metabolite is the ONLY nucleotide that inhibits all stages of DNA synthesis by distorting its enzyme’s active site, non-competitively.

1 Shin, et al. Hepatol Int 2011; 5:644-670
2Lee, et al. Hepatol 2006; 43(5):982-988, Lim, et al. Aliment Pharmacol Ther 2008; 27:1282-1292, Yoo, et al. Hepatol 2007; 45:1172-1178, Yoo, et al. Hepatol 2007; 46:1041-1048
3Painter, et al. Chapter 24 – Clevudine: A novel 1-β-L nucleoside analogue in clinical development for the treatment of HBV infection. Frontiers in Viral Hepatitis, 281-300
4 Tak, et al. Hepatol Int 2014; 8:375-381

ATI-2173

ATI-2173 is a next generation ASPIN with improved pharmacokinetics relative to clevudine, and the same potent mechanism of action. In contrast to clevudine, ATI-2173 is ion-trapped in the liver as a monophosphate leading to high liver triphosphate (the active metabolite) levels and low systemic clevudine exposure. Liver targeting has been confirmed in rat and monkey PK studies. Monkey PK studies confirmed 82% first-pass uptake.