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1194 SYNERGISTIC COMBINATIONS OF ENTRY INHIBITORS WITH DACLATASVIR OR SOFOSBUVIR FOR PREVENTION AND TREATMENT OF CHRONIC HEPATITIS C
POSTERS 1194 SYNERGISTIC COMBINATIONS OF ENTRY INHIBITORS WITH DACLATASVIR OR SOFOSBUVIR FOR PREVENTION AND TREATMENT OF CHRONIC HEPATITIS C I. Fofana1,2 , F. Xiao1,2 , C. Thumann1,2 , R. Alles1,2 , F. Habersetzer1,2,3 , M. Doffoel ¨ 1,2,3 , P. Leyssen4 , J. Neyts4 , M.B. Zeisel1,2 , T.F. Baumert1,2,3 . 1 Inserm U 748, 2 Universit´e de Strasbourg, 3 Hˆ opitaux Universitaires de Strasbourg, Strasbourg, France; 4 Katholieke Universiteit Leuven, Leuven, Belgium E-mail: [email protected] Background and Aims: Although the clinical development of direct-acting antivirals (DAAs) improves the virological response of standard-of-care of chronic hepatitis C virus (HCV) infection, adverse effects and resistance remain major challenges. Furthermore, strategies for prevention of liver graft infection are absent and options for difficult-to-treat patients remain unsatisfactory. Thus, there is an unmet medical need for novel antiviral approaches with improved efficacy and safety. Viral entry is required for initiation and maintenance of infection and a promising target for antiviral therapy. Indeed, we have shown that compounds targeting HCV cell entry factors efficiently inhibit infection of all major HCV genotypes and resistant strains (Fofana et al. Gastroenterology 2010, Lupberger et al. Nat. Med. 2011, Zahid et al. Hepatology 2012). Methods: To explore the potential of entry inhibitors as antivirals for prevention and treatment of HCV infection, we investigated the antiviral efficacy and toxicity of entry inhibitors (receptor-specific monoclonal antibodies, kinase inhibitors erlotinib and dasatinib) in combination with DAAs, including polymerase (sofosbuvir) and NS5A (daclatasvir) inhibitors, in cell culture models. Synergy was assessed by two independent methods comprising the combination index and the method of Prichard and Shipman. Results: Combinations of entry inhibitors with daclatasvir or sofosbuvir resulted in a marked and synergistic inhibition of persistent HCV infection over a broad range of concentrations with undetectable toxicity. Combinations of receptor-specific monoclonal antibodies or erlotinib with daclatasvir or sofosbuvir decreased the IC50 of the compounds up to 100-fold. Furthermore, entry inhibitors efficiently inhibited HCV infection of DAA-resistant viruses. Conclusion: Our results provide the rationale for the development of antiviral strategies combining entry inhibitors with daclatasvir or sofosbuvir by taking advantage of synergy and marked efficacy against resistant viruses. The uncovered combinations open novel perspectives for IFN-a free regimens in multiresistant patients and provide efficient strategies to prevent liver graft infection. 1195 HEALTHY VOLUNTEER FIRST-IN-HUMAN EVALUATION OF GS-5816, A NOVEL SECOND GENERATION BROAD-GENOTYPIC NS5A INHIBITOR WITH POTENTIAL FOR ONCE-DAILY DOSING P. German, P. Pang, C. Yang, L. Han, J.O. Link, B.P. Kearney, A. Mathias. Gilead Sciences, Inc., Foster City, CA, USA E-mail: [email protected] Background: GS-5816, a novel second generation NS5A broadgenotypic inhibitor, is in development for the treatment of chronic HCV infection. GS-5816 demonstrates 7–59 picomolar antiviral potency against GT1–6 replicons and is not cross-resistant with mutants resistant to other classes of HCV inhibitors. In nonclinical studies, GS-5816 exhibits modest bioavailability (25–30%), high metabolic stability, low systemic clearance and low potential for metabolic drug–drug interactions. This Phase 1 first-in-human study evaluated the pharmacokinetics (PK), safety and tolerability of GS-5816 in healthy volunteers. Methods: This was a randomized, double-blind, placebo-controlled study with 4 staggered dose-escalation and 2 food effect (FE: low calorie and high-calorie/high fat) cohorts. Within each doseS486
escalation cohort, unique healthy subjects were randomized to receive single (SD) and multiple (MD) daily doses (7 days) of GS5816 (N = 12) or matching placebo (N = 3) of 5 mg, 50 mg, 150 mg or 450 mg in the fasted state, with a 5-day washout between SD and MD. In FE cohorts, subjects (N = 12/cohort) received SD GS-5816 100 mg in the fasted and fed states with a 5-day washout inbetween. GS-5816 PK parameters were estimated and summarized by dose; dose proportionality of GS-5816 was examined across evaluated doses. FE was assessed. Safety was examined throughout the study. Results: All enrolled subjects completed the study. GS-5816 was well-tolerated at all doses; no subjects discontinued therapy early, and no clinically significant laboratory or ECGs abnormalities were observed. GS-5816 was absorbed quickly following single and multiple fasted oral doses with the maximum plasma concentrations (Cmax ) occurring between 1.50 and 3.25 hours (median Tmax ). GS-5816 exhibited nonlinear PK from 5 mg to 50 mg and from 100 mg to 450 mg. Median t1/2 ranged from 13–17 hours, supporting QD dosing. The mean plasma concentrations 24 hours post-dose were >70-fold above the protein-adjusted EC50 for all genotypes at all doses ≥50 mg. FE cohorts are under evaluation. Conclusion: GS-5816 was well tolerated as a single or multiple daily doses in healthy subjects. The in-vitro antiviral potency, safety and PK profile of GS-5816 supports further evaluation of its antiviral activity in HCV-infected subjects. 1196 ANALYSIS OF THE KINETICS OF VIRAL DECLINE DURING 14 DAYS OF ADMINISTRATION OF SOFOSBUVIR AND GS-0938 J. Guedj1 , P.S. Pang2 , E. Lawitz3 , M. Rodriguez-Torres4 , B. Symonds2 , A.S. Perelson5 . 1 INSERM U 738, Paris, France; 2 Gilead Sciences, Inc., Foster City, CA, 3 Alamo Medical Research, San Antonio, TX, 4 Fundaci´ on de Investigaci´ on de Diego, Santurce, PR, 5 Los Alamos National Laboratory, Los Alamos, NM, USA E-mail: [email protected] Background and Aim: Sofosbuvir (GS-7977) and GS-0938 are complementary nucleotide analogs with activity against hepatitis C virus (HCV). Here we evaluated the antiviral activity of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 treatment naïve patients treated for a total of 14 days (NUCLEAR study). Methods: We characterized the kinetics of HCV RNA decay using a mathematical model. Results: With either drug or a combination of the two viral load declined rapidly in a biphasic manner. The kinetics could be well fitted by a model that assumed the drug effectiveness increased over time. The mean time needed to reach maximum level of effectiveness GS-0938 and sofosbuvir was approximately 1 and 2 days, respectively. Both drugs had a similar mean antiviral effectiveness, e = 0.9996 and the combination had a mean e = 0.9998. Thus, on average, adding a second drug produced no increase in viral decay. However, in 8 subjects one drug had lower effectiveness than the other and a slight enhancement in viral decay was noticed when the second drug was added. Both drugs led to a rapid second phase of viral decline with a mean rate of 0.35 d−1 . Because both drugs were nucleotides, an Emax model assuming the concentrations of the drugs normalized by their respective EC50 ’s added provide a good description for the effectiveness of combination therapy. No effect of IL28B-polymorphism was found on viral kinetic parameters. Conclusion: We characterized viral kinetics during nucleotide analogue therapy. Both sofosbuvir and GS-0938 reached a high final effectiveness in blocking viral production. Sofosbuvir and GS-0938 led to slower initial viral declines than protease inhibitors or NS5A inhibitors, and likely represents the time needed to accumulate intracellular triphosphates. Both drugs led to a rapid and consistent
Journal of Hepatology 2013 vol. 58 | S409–S566
escalation cohort, unique healthy subjects were randomized to receive single (SD) and multiple (MD) daily doses (7 days) of GS5816 (N = 12) or matching placebo (N = 3) of 5 mg, 50 mg, 150 mg or 450 mg in the fasted state, with a 5-day washout between SD and MD. In FE cohorts, subjects (N = 12/cohort) received SD GS-5816 100 mg in the fasted and fed states with a 5-day washout inbetween. GS-5816 PK parameters were estimated and summarized by dose; dose proportionality of GS-5816 was examined across evaluated doses. FE was assessed. Safety was examined throughout the study. Results: All enrolled subjects completed the study. GS-5816 was well-tolerated at all doses; no subjects discontinued therapy early, and no clinically significant laboratory or ECGs abnormalities were observed. GS-5816 was absorbed quickly following single and multiple fasted oral doses with the maximum plasma concentrations (Cmax ) occurring between 1.50 and 3.25 hours (median Tmax ). GS-5816 exhibited nonlinear PK from 5 mg to 50 mg and from 100 mg to 450 mg. Median t1/2 ranged from 13–17 hours, supporting QD dosing. The mean plasma concentrations 24 hours post-dose were >70-fold above the protein-adjusted EC50 for all genotypes at all doses ≥50 mg. FE cohorts are under evaluation. Conclusion: GS-5816 was well tolerated as a single or multiple daily doses in healthy subjects. The in-vitro antiviral potency, safety and PK profile of GS-5816 supports further evaluation of its antiviral activity in HCV-infected subjects. 1196 ANALYSIS OF THE KINETICS OF VIRAL DECLINE DURING 14 DAYS OF ADMINISTRATION OF SOFOSBUVIR AND GS-0938 J. Guedj1 , P.S. Pang2 , E. Lawitz3 , M. Rodriguez-Torres4 , B. Symonds2 , A.S. Perelson5 . 1 INSERM U 738, Paris, France; 2 Gilead Sciences, Inc., Foster City, CA, 3 Alamo Medical Research, San Antonio, TX, 4 Fundaci´ on de Investigaci´ on de Diego, Santurce, PR, 5 Los Alamos National Laboratory, Los Alamos, NM, USA E-mail: [email protected] Background and Aim: Sofosbuvir (GS-7977) and GS-0938 are complementary nucleotide analogs with activity against hepatitis C virus (HCV). Here we evaluated the antiviral activity of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 treatment naïve patients treated for a total of 14 days (NUCLEAR study). Methods: We characterized the kinetics of HCV RNA decay using a mathematical model. Results: With either drug or a combination of the two viral load declined rapidly in a biphasic manner. The kinetics could be well fitted by a model that assumed the drug effectiveness increased over time. The mean time needed to reach maximum level of effectiveness GS-0938 and sofosbuvir was approximately 1 and 2 days, respectively. Both drugs had a similar mean antiviral effectiveness, e = 0.9996 and the combination had a mean e = 0.9998. Thus, on average, adding a second drug produced no increase in viral decay. However, in 8 subjects one drug had lower effectiveness than the other and a slight enhancement in viral decay was noticed when the second drug was added. Both drugs led to a rapid second phase of viral decline with a mean rate of 0.35 d−1 . Because both drugs were nucleotides, an Emax model assuming the concentrations of the drugs normalized by their respective EC50 ’s added provide a good description for the effectiveness of combination therapy. No effect of IL28B-polymorphism was found on viral kinetic parameters. Conclusion: We characterized viral kinetics during nucleotide analogue therapy. Both sofosbuvir and GS-0938 reached a high final effectiveness in blocking viral production. Sofosbuvir and GS-0938 led to slower initial viral declines than protease inhibitors or NS5A inhibitors, and likely represents the time needed to accumulate intracellular triphosphates. Both drugs led to a rapid and consistent
Journal of Hepatology 2013 vol. 58 | S409–S566