Although there is a vaccine to prevent HBV infection, for people already infected there are treatments that control the disease but there is no cure for chronic HBV infection. Current therapies, including chain-terminating nucleoside analogues (“NAs”) such as tenofovir and entecavir, control viral replication, but viral load quickly rebounds to pre-treatment levels upon discontinuation of therapy in the majority (>90%) of patients. It is believed that resistance to cure is driven by the persistence of the viral genomic reservoir, covalently closed circular DNA (cccDNA), in the host cell.
Traditional, chain-terminating NAs inhibit some stages of DNA synthesis by competing for nucleotide positions in the HBV DNA chain, preventing further elongation. However, if treatment is stopped there is nothing to prevent HBV DNA synthesis and viral replication starts a new.
ATI-2173’s active metabolite is the ONLY nucleotide that inhibits all stages of DNA synthesis by distorting its enzyme’s active site, non-competitively. Unlike traditional NA’s, which inhibit viral replication one new genome at a time, ATI-2173/ASPINs inhibit replication one polymerase at a time, leading to a more efficient mechanism of inhibition.
ATI-2173 is an Active Site Polymerase Inhibitor Nucleotide (ASPIN) that is in development as the backbone of an oral, once-daily potential curative therapy for HBV. It is a liver-targeted (low systemic exposure) phosphoramidate pro-drug of clevudine, in which the active metabolite inhibits all stages of DNA synthesis by distorting its enzyme’s active site, non-competitively.ATI-2173’s liver targeting has been confirmed in rat and monkey PK studies, with monkey PK studies confirming 82% first-pass uptake. Unlike currently available therapies, which require lifelong treatment to provide ongoing viral suppression, the combination of ATI-2173 with a chain-terminating NA could completely shut down the HBV polymerase and all viral replication.