Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: A randomized phase II study

Abstract

; for the MK-7009 Protocol 007 Study GroupVaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-a-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n 5 94) were randomized to receive open-label Peg-IFN-a-2a (180 lg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-a-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3log 10 IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. Conclusion: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration. (HEPATOLOGY 2012;56:884-893) S ince 2001, the combination of pegylated interferon alpha (Peg-IFN-a) plus ribavirin (RBV) has been the standard-of-care treatment for patients with hepatitis C virus (HCV) infection. 1-3 However, the recent approval of two novel HCV nonstructural protein (NS)3/4A protease inhibitors (boceprevir and telaprevir) heralds a new era in the treatment of chronic hepatitis C. [4][5][6][7][8] For treatment-naïve patients, the addition of these agents to a Peg-IFN plus RBV backbone increases rates of sustained virologic response (SVR) from 40%-50% to approximately 70%. 4,6 In addition, triple therapy with HCV protease inhibitors can be truncated to 24 or 28 weeks in 50%-60% of treatment-naïve patients who clear the virus early on treatment. 9 However, these firstAbbreviations: AEs, adverse events; APaT, all-patients-as-treated population; AUC, area under the plasma-concentration versus time curve; BID, twice-daily; bp, base pair; C 24h , concentration of drug in the plasma at 24 hours after

In Vitro Phenotypic Characterization of Hepatitis C Virus NS3 Protease Variants Observed in Clinical Studies of Telaprevir

“…The WT G1b replicon had EC 50 (ϮSD) values of 0.482 (Ϯ0.122) M and 0.269 (Ϯ0.096) M in the 48-h and 96-h assays, respectively, whereas the WT G1a replicon had an EC 50 (ϮSD) of Rarely observed in telaprevir studies G1b replicon (48-h assay) WT 0.482 Ϯ 0.122 0.961 (Ϯ0.132) M in the 96-h assay. The NS3 protease variants that were characterized included (i) variants most frequently observed (significantly enriched) in patients who did not achieve SVR in telaprevir-based regimens, including V36A/M, T54A/S, R155K/T, A156S/T, and V36MϩR155K (22); (ii) variants rarely observed (not significantly enriched) in patients who did not achieve SVR in telaprevir-based regimens, including V36C/G/I/L, I132V, V151A, R155G/I/M/S, A156F/N/V, V36AϩT54A, V36AϩR155K/T, V36LϩR155K, V36MϩR155T, V36A/MϩA156T, T54AϩA156S, T54SϩR155K, T54SϩA156S/T, R155TϩD168N, and V36Mϩ T54SϩR155K (22); and (iii) variants specifically observed for other HCV NS3 protease inhibitors, including Q41R, Q80R, and D168A/N/V, which are resistant to one or more macrocyclic inhibitors such as vaniprevir (36,44), ciluprevir (38), danoprevir (45), and simeprevir (46), and V55A, R109K, and V170A, which are resistant to linear NS3 protease inhibitors boceprevir (47,48) and SCH6 (49,50). The variants that were observed in clinical studies of telaprevir conferred different levels of resistance to telaprevir, with increases in EC 50 s ranging from 0.3-to Ͼ93-fold relative to the WT (Table 1).…”

Characterization of Resistance to the Protease Inhibitor GS-9451 in Hepatitis C Virus-Infected Patients

“…These results are in agreement with other previous in vitro resistance studies and clinical observations. For example, R155 in GT 1a virus and D168 in GT 1b virus, conferring cross-resistance to other macrocyclic PIs, are also commonly seen in patients treated with vaniprevir, danoprevir, BI 201335, and TMC-435 (7,12,15,26). Clinical studies with telaprevir identified V36A/M, T54A, R155T/K, and A156S/V/T mutations in NS3.…”

Mechanisms of Virologic Failure in Hepatitis C and Strategies for Treatment Failure

“…NS3/4A HCV PIs achieve high antiviral potency by blocking HCV poly-protein cleavage and may also neutralize HCV NS3 protease-mediated interference with the innate immune system. Through this mechanism, HCV NS3/4A PIs reverse the HCV NS3 protein's capacity to block intracellular signal-transduction pathways for endogenous IFN production in vitro and may also do so in vivo [19].…”