Stanley Wang

Glecaprevir and Pibrentasvir Yield High response Rates in Patients with HCV Genotype 1-6 without Cirrhosis

BACKGROUND & AIMS Hepatitis C virus (HCV) therapy that is highly efficacious, pangenotypic, with a high barrier to resistance and short treatment duration is desirable. The efficacy and safety of 8- and 12-week treatments with glecaprevir (ABT-493; NS3/4A protease inhibitor) and pibrentasvir (ABT-530; NS5A inhibitor) were evaluated in non-cirrhotic patients with chronic HCV genotype 1-6 infection. METHODS SURVEYOR-I and SURVEYOR-II were phase II, open-label, multicenter, dose-ranging trials including patients with chronic HCV genotype 1-6 infection who were either previously untreated or treated with pegylated interferon plus ribavirin. Patients received once-daily glecaprevir plus pibrentasvir at varying doses with or without ribavirin for 8 or 12weeks. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at post-treatment week 12 (SVR12). RESULTS Of the 449 patients who received varying doses of glecaprevir plus pibrentasvir, 25%, 29%, 39%, and 8% had HCV genotype 1, 2, 3, and 4-6 infection, respectively. Twelve-week treatment achieved SVR12 in 97-100%, 96-100%, 83-94%, and 100% in genotypes 1, 2, 3, and 4-6, respectively. Eight-week treatment with 300mg glecaprevir plus 120mg pibrentasvir in genotype 1-, 2-, or 3-infected patients yielded 97-98% SVR12 with no virologic failures. Three (0.7%) patients discontinued treatment due to adverse events; most events were mild (grade 1) in severity. No post-nadir alanine aminotransferase elevations were observed. CONCLUSIONS Glecaprevir plus pibrentasvir was well tolerated and achieved high sustained virologic response rates in HCV genotypes 1-6-infected patients without cirrhosis following 8- or 12-week treatment durations. LAY SUMMARY The combination of direct-acting antivirals glecaprevir and pibrentasvir comprise a once-daily, all-oral, pangenotypic treatment for HCV genotype 1-6 infection. This article describes results from two phase II trials investigating a range of doses at treatment durations of 8 or 12weeks in 449 patients without cirrhosis. Efficacy of the optimal dose, as determined by rates of sustained virologic response at post-treatment week 12, ranged from 92%-100%; treatment was well tolerated and significant laboratory abnormalities were rare. CLINICAL TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT02243280 and NCT02243293. http://www.clinicaltrials.gov/show/NCT02243280, http://www.clinicaltrials.gov/show/NCT01939197.

Glecaprevir–Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection

BACKGROUND Glecaprevir and pibrentasvir are direct‐acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8‐week and 12‐week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS We conducted two phase 3, randomized, open‐label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once‐daily glecaprevir–pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir–pibrentasvir or sofosbuvir–daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir–pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1–infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8‐week group and 99.7% (95% CI, 99 to 100) in the 12‐week group. Genotype 3–infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir–pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir–daclatasvir; 8 weeks of treatment with glecaprevir–pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS Once‐daily treatment with glecaprevir–pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE‐1 and ENDURANCE‐3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157.)

Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis

Background & Aims Hepatitis C virus (HCV) has high genotypic diversity and global distribution. Agents that are effective against all major HCV genotypes, with shorter treatment duration, are needed to reduce disease burden. Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) have a high barrier to resistance and synergistic antiviral activity. We evaluated the safety and efficacy of 8 and 12 weeks’ treatment with glecaprevir/pibrentasvir in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis in 3 separate phase 3 trials. Methods We performed 2 open label, single‐arm studies (SURVEYOR‐II, Part 4 and ENDURANCE‐4) and a randomized, double‐blind, placebo‐controlled study (ENDURANCE‐2). In the ENDURANCE‐2 study, adult patients with untreated or previously treated HCV genotype 2 infection without cirrhosis were randomly assigned (2:1) to groups given once‐daily oral glecaprevir/pibrentasvir (n = 202; 300 mg/120 mg) or placebo (n = 100) for 12 weeks. In the SURVEYOR‐II, Part 4 and ENDURANCE‐4 studies, adult patients with untreated or previously treated patients with HCV genotype 2, genotype 4, genotype 5, or genotype 6 infection, without cirrhosis, were given once‐daily oral glecaprevir/pibrentasvir (n = 121 in ENDURANCE‐4 and n = 145 in SURVEYOR‐II) for 12 or 8 weeks, respectively. In all studies the primary endpoint was sustained virologic response at 12 weeks after treatment (SVR12) in the intention‐to‐treat population. Results Among patients receiving glecaprevir/pibrentasvir for 8 weeks, rates of SVR12 were 98% (95% CI, 94.1–99.3) in those infected with HCV genotype 2 and 93% (95% CI, 83.6–97.3) in those infected with HCV genotypes 4, 5, or 6. Among patients receiving glecaprevir/pibrentasvir for 12 weeks, rates of SVR12 were 99.5% (95% CI, 98.5–100) in those infected with HCV genotype 2 and 99% (95% CI, 97.6–100) in those infected with HCV genotype 4, 5, or 6. No virologic failures occurred in patients with HCV genotype 4, 5, or 6 infections. The frequency and severity of adverse events in patients receiving glecaprevir/pibrentasvir were similar to those of patients who received placebo. Conclusion In 3 Phase 3 studies, 8 weeks’ treatment with glecaprevir/pibrentasivr produced an SVR12 in at least 93% of patients with chronic HCV genotype 2, 4, 5, or 6 infection without cirrhosis, with virologic failure in less than 1%. The drug combination had a safety profile comparable to 12 week’s treatment with glecaprevir/pibrentasvir. ClinicalTrials.gov numbers: NCT02640482 (ENDURANCE‐2), NCT02636595 (ENDURANCE‐4), and NCT02243293 (SURVEYOR‐II).

Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial

This study assessed the efficacy and safety of ribavirin‐free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. SURVEYOR‐II, Part 3 was a partially randomized, open‐label, multicenter, phase 3 study. Treatment‐experienced (prior interferon or pegylated interferon ± ribavirin or sofosbuvir plus ribavirin ± pegylated interferon therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment‐naive or treatment‐experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at posttreatment week 12 (SVR12). Safety was evaluated throughout the study. There were 131 patients enrolled and treated. Among treatment‐experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; 95% confidence interval [CI], 72‐97) and 95% (21/22; 95% CI, 78‐99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; 95% CI, 87‐99) of treatment‐naive patients treated for 12 weeks and 96% (45/47; 95% CI, 86‐99) of patients with prior treatment experience treated for 16 weeks. No adverse events led to discontinuation of study drug, and no serious adverse events were related to study drug. Conclusion: Patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. (Hepatology 2018;67:514‐523).

Glecaprevir/Pibrentasvir for HCV Genotype 3 Patients with Cirrhosis and/or Prior Treatment Experience: A Partially Randomized Phase III Clinical Trial

This study assessed the efficacy and safety of ribavirin‐free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. SURVEYOR‐II, Part 3 was a partially randomized, open‐label, multicenter, phase 3 study. Treatment‐experienced (prior interferon or pegylated interferon ± ribavirin or sofosbuvir plus ribavirin ± pegylated interferon therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment‐naive or treatment‐experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at posttreatment week 12 (SVR12). Safety was evaluated throughout the study. There were 131 patients enrolled and treated. Among treatment‐experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; 95% confidence interval [CI], 72‐97) and 95% (21/22; 95% CI, 78‐99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; 95% CI, 87‐99) of treatment‐naive patients treated for 12 weeks and 96% (45/47; 95% CI, 86‐99) of patients with prior treatment experience treated for 16 weeks. No adverse events led to discontinuation of study drug, and no serious adverse events were related to study drug. Conclusion: Patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. (Hepatology 2018;67:514‐523).

High Svr Rates with ABT-493 + ABT-530 Co-Administered for 8 Weeks in Non-Cirrhotic Patients with HCV Genotype 3 Infection

PS098 Partially randomised, open-label, multicentre phase 2 trial evaluating the dose combination of ABT-493 and ABT-530 identified in the dose-ranging part 1 of this study SURVEYOR-II Part 2 Study Design *RBV dosed once-daily ABT-493 300 mg ABT-530 120 mg ABT-493 300 mg ABT-530 120 mg ABT-493 300 mg ABT-530 120 mg ABT-493 300 mg ABT-530 120 mg ABT-493 300 mg ABT-530 120 mg RBV* 800 mg GT3 N=29 GT2 N=54

High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: An integrated analysis of HCV genotype 1–6 patients without cirrhosis

BACKGROUND & AIMS Glecaprevir plus pibrentasvir (G/P) is a pangenotypic, once-daily, ribavirin-free direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection. In nine phase II or III clinical trials, G/P therapy achieved rates of sustained virologic response 12 weeks after treatment (SVR12) of 93-100% across all six major HCV genotypes (GTs). An integrated efficacy analysis of 8- and 12-week G/P therapy in patients without cirrhosis with HCV GT 1-6 infection was performed. METHODS Data were pooled from nine phase II and III trials including patients with chronic HCV GT 1-6 infection without cirrhosis who received G/P (300 mg/120 mg) for either 8 or 12 weeks. Patients were treatment naïve or treatment experienced with peginterferon, ribavirin, and/or sofosbuvir; all patients infected with HCV GT 3 were treatment naïve. Efficacy was evaluated as the SVR12 rate. RESULTS The analysis included 2,041 patients without cirrhosis. In the intent-to-treat population, 943/965 patients (98%) achieved SVR12 when treated for eight weeks, and 1,060/1,076 patients (99%) achieved SVR12 when treated for 12 weeks; the difference in rates was not significant (p = 0.2). A subgroup analysis demonstrated SVR12 rates > 95% across baseline factors traditionally associated with lower efficacy. G/P was well tolerated, with one DAA-related serious adverse event (<0.1%); grade 3 laboratory abnormalities were rare. CONCLUSIONS G/P therapy for eight weeks in patients with chronic HCV GT 1-6 infection without cirrhosis achieved an overall SVR12 rate of 98% irrespective of baseline patient or viral characteristics; four additional weeks of treatment did not significantly increase the SVR12 rate, demonstrating that the optimal treatment duration in this population is eight weeks. LAY SUMMARY In this integrated analysis of nine clinical trials, patients with chronic HCV genotype 1-6 infection without cirrhosis were treated for either 8 or 12 weeks with the direct-acting antiviral regimen glecaprevir/pibrentasvir (G/P). The cure rate was 98% and 99% following 8 and 12 weeks of treatment, respectively; the difference in rates was not significant (p = 0.2), nor was there a significant difference in the cure rates across the two treatment durations on the basis of baseline patient or viral characteristics. These results, along with a favourable safety profile, indicate that G/P is a highly efficacious and well-tolerated pangenotypic eight-week therapy for most patients with chronic HCV infection.