Over 250 million people worldwide are chronically infected with hepatitis B virus (HBV). Current therapies are life-long, using nucleotide and nucleoside analogs (Nucs) that only suppress viral replication; New antiviral agents that can reduce viral antigens, eliminate cccDNA and to effect viral clearance during a finite duration of therapy are urgently needed. SB 9200 is an orally bioavailable dinucleotide that causes hepato-selective activation of RIG-I, an innate immune receptor, resulting in the induction of IFNs and ISGs. SB 9200 was discovered by phenotypic approach involving synthesis and screening of nucleotide libraries in HepG2.2.15 cell lines. The compound was shown to bind to RIG-I with a Kd of 12 pM. In reporter assays. SB 9200 was also shown to induce IRF3, and IFN in a RIG-I-dependent manner. SB 9200 showed potent antiviral activity against wild type-, as well as, nucleoside and polymorphic capsid variants of HBV and was synergistic with Nucs. Orally administered SB 9200 showed potent, dose-dependent antiviral activity in the transgenic mouse and woodchuck models of HBV, with significant reductions in viral DNA, RNA, and antigens that was associated with induction of host immune response. The ACHIEVE Phase 2a clinical trial in treatment-naïve HBV patients evaluating safety and efficacy of ascending dose cohorts (25, 50 and 100 mg) of inarigivir monotherapy for 12 weeks, followed by switch to Tenofovir for 12 weeks, has been completed. Inarigivir monotherapy demonstrated a favorable safety profile with significant reductions in HBV DNA and RNA compared to placebo (ANOVA p &lt; 0.0001) with a clear dose response especially in HBeAg-ve patients. In addition, 13 of 47 (28%) patients also showed mean and median HBsAg reduction of 0.8 log10 (range 0.5 – 1.4 log10) with inarigivir alone or after Tenofovir switch. Inarigivir has been advanced to global Phase 2b clinical trials.

SB 9200 (inarigivir), a selective oral immuno-modulator for chronic hepatitis B

2019 Fall National Meeting

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