SB 9200, a Novel Agonist of Innate Immunity, Shows Potent Antiviral Activity against Resistant HCV Variants

POSTER PRESENTATIONS THU-233 SB 9200, A NOVEL AGONIST OF INNATE IMMUNITY, SHOWS POTENT ANTIVIRAL ACTIVITY AGAINST RESISTANT HCV VARIANTS M. Jones1, M. Cunningham1, P. Wing1, S. DeSilva1, A. Sheri2, S. Padmanabhan2, R. Iyer2, N. Afdhal2, G. Foster1. 1The Liver Unit, QMUL, London, United Kingdom; 2Spring Bank Pharmaceuticals, Milford, United States E-mail: [email protected] Background and Aims: New direct-acting antiviral (DAA’s) agents for chronic HCV infection have substantially increased the rates of sustained virological response (SVR). Relapse after antiviral therapy remains a significant problem, especially in patients with cirrhosis and salvage therapy with new therapeutic agents remains the only viable option. SB 9200 is a novel, first-in-class oral modulator of innate immunity via its activation of RIG-I and NOD2 pathways. Being a host-targeted antiviral agent, SB 9200 is agnostic to the viral genotype as demonstrated by its pan-genotypic ant-HCV activity in the “capture fusion assay”. (Foster AASLD 2013). In Phase I clinical trials, SB 9200 has been shown to maximally reduce HCV RNA by 1.9 log10 in HCV patients (Thompson EASL 2015). We evaluated the activity of SB 9200 against HCV positive serum from patients who failed to respond to current treatment regimens and viruses with known variants associated with poor response to current NS5A inhibitors. Methods: Patient sera (n = 35) from treatment naïve, responders or previously failed either DAA (Sofosbuvir and Ledipasvir) or pegIFN/ RBV ± DAAs were tested in a capture fusion assay. THP-1 cells were exposed to donor serum, fused with Huh7 derivative cells and treated with SB 9200 before qPCR assessment of HCV replication. Dose response curves were used to calculate the IC50 values. Results: Replication of all HCV genotypes from patient sera was inhibited by SB 9200 in a dose-dependent manner. No difference in the HCV sensitivity to SB 9200 was found between the treatment naïve and treatment experienced patient sera (for g3, naïve mean IC50 0.026 ± 0.007 μM, experienced mean IC50 0.022 ± 0.012 μM). No difference in HCV sensitivity to SB 9200 was observed in pre- and post pegIFN/RBV treatment samples ( pre IC50 0.45 μM, post IC50 0.455 μM). SB9200 showed potent activity against sera from g1a patients who failed sofosbuvir/ledipasvir treatment (n = 13) including samples with NS5a variants (M28, Q30 and L31). Furthermore, a g3 DAA relapse sample which showed reduced sensitivity to both sofosbuvir and RBV with the accumulation of Y93H mutations in the capture fusion assay, retained SB 9200 sensitivity. Conclusions: Activity of SB 9200 is pan-genotypic and not influenced by previous treatment exposure. Given the potent activity of SB 9200 against HCV resistant variants resulting from previous pegIFN/RBV or DAA treatment, its clinical evaluation in combination with DAAs for patients requiring salvage therapy is warranted. THU-234 HIGH SUSTAINED VIROLOGIC RESPONSE RATES IN PATIENTS INFECTED WITH GENOTYPE 2 WITH BASELINE NS5A POLYMORPHISMS TREATED WITH DACLATASVIR-BASED REGIMENS N. Zhou1, Z. Han1, S.H. Neumann1, B. DeGray1, J. Ueland1, V. Vellucci1, D. Hernandez1, F. McPhee1. 1Bristol-Myers Squibb, Wallingford, United States E-mail: [email protected] Background and Aims: The in vitro resistance barrier to daclatasvir ( pangenotypic HCV NS5A inhibitor; DCV), against genotype 2 (GT-2) sequences has previously been reported to be lower compared with other genotypes. We assessed the heterogeneity of GT-2 NS5A sequences, the prevalence of DCV-resistant polymorphisms, and the impact of these polymorphisms on patient-derived NS5A sequences and their association with virologic response to DCV-based regimens. Methods: Phylogeny and baseline NS5A polymorphisms associated with DCV resistance (at 28-32, 58, 62, 92, or 93) were examined in 283 patient-derived NS5A sequences from phase 2/3 clinical trials

and 143 NS5A sequences from the European Union (EU) HCV database. Analyses of susceptibility of a diverse range of GT-2 NS5A sequences to DCV were performed, and the impact of baseline NS5A polymorphisms on sustained virologic response rate was assessed. Results: NS5A-L31M was the most prevalent DCV-resistant baseline polymorphism, observed in 60% of NS5A sequences globally and in approximately 40% in the EU database. DCV EC50 values for patientderived NS5A sequences representing GT-2a/b/c, and -2 (subtype not assigned) ranged from 0.005 to 60 nM. EC50 values for patientderived NS5A sequences with only the L31M polymorphism ranged from 15 to 20 nM compared with 0.3 nM for one patient with NS5AL31M + N62G. In GT-2 patients receiving DCV-based regimens, the sustained virologic response rate was minimally impacted by baseline NS5A-L31M (Table). The single patient who did not achieve sustained virologic response (relapse) after receiving 12 weeks of DCV + sofosbuvir (an NS5B nucleotide polymerase inhibitor) + ribavirin had Child-Pugh class C cirrhosis and no emergent DCV-resistant variants in ≥1% of the virus population.

Conclusions: High sustained virologic response rates were achieved in GT-2 patients irrespective of the absence or presence of the highly prevalent NS5A-L31M resistance-associated polymorphism. THU-235 PRE-TREATMENT REDUCTION IN SENSITIVITY TO SOFOSBUVIR AND RIBAVIRIN IN PATIENTS WITH GENOTYPE 3 HEPATITIS C VIRUS WHO RELAPSE FOLLOWING ALL ORAL ANTIVIRAL THERAPY P. Wing1, A. Filipe2, M.E. Cunningham1, S. De Silva1, M. Cheung1, M. Jones1, W. Irving3, J. McLauchlan2, G.R. Foster1. 1The Liver Unit, Queen Mary University of London, London; 2Center for Virus Research, University of Glasgow, Glasgow; 3Queen’s Medical Centre, University of Nottingham, Nottingham, United Kingdom E-mail: [email protected] Background and Aims: Despite recent advances in direct acting antiviral (DAA) therapy for hepatitis C virus (HCV), a variation in response remains between the different genotypes (G) with G3 being least responsive. Future HCV treatment is likely to include Sofosbuvir (SOF) and next wave NS5A inhibitors (such as Valpatasvir) but in patients with cirrhosis response rates are reduced and ribavirin (RBV) may still be required. Previous work from our laboratory, using a novel capture-fusion assay to study patient-derived HCV, suggests that pre-treatment RBV sensitivity influences pegylated interferon/ RBV response. Here we expand upon this observation by assessing RBV and SOF sensitivity in G3 patient-derived HCV. Results: 10 patients were studied, all had advanced cirrhosis and were treated in the English Early Access Programme with sofosbuvir + ledipasvir (N = 5) or daclatasvir (N = 5). A reduced RBV and SOF sensitivity was observed in pre-treatment G3 isolates from patients who relapsed compared to patients with SVR (RBV IC50 = 0.48 ± 0.12 μM, SOF IC50 = 0.016 ± 0.0037 μM for SVR samples, RBV IC50 = 1.053 ± 0.16 μM, SOF IC50 0.18 ± 0.048 μM for relapse samples). Comparison of RBV and SOF sensitivity pre- and post- relapse from a G3 non-responder revealed a pre-treatment sensitivity to RBV and SOF (RBV IC50 = 0.43 μM, SOF IC50 = 0.028 μM), which was reduced post relapse (RBV IC50 > 1.25 μM, SOF IC50 > 0.25 μM). Analysis of viral sequencing data showed selection of NS5A RAVs Y93H and S62L in

Journal of Hepatology 2016 vol. 64 | S213–S424

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