Elsevier

Journal of Hepatology

Volume 67, Issue 2, August 2017, Pages 263-271
Journal of Hepatology

Research Article
Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1–6 without cirrhosis

https://doi.org/10.1016/j.jhep.2017.03.039Get rights and content

Highlights

  • An all oral, once-daily, RBV-free, pangenotypic HCV treatment option is described.

  • 8- or 12-week treatment with glecaprevir + pibrentasvir yielded high rates of SVR12.

  • Treatment was well-tolerated with a favorable safety profile.

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; NS3/4 A 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 12 weeks. 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 300 mg glecaprevir plus 120 mg 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 12 weeks 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.

Introduction

Hepatitis C virus (HCV) infection is a global disease burden, with 350,000 deaths attributed to HCV-related complications annually.[1], [2] Geographic distributions of HCV genotypes vary widely.[2], [3] Of the six major HCV genotypes, genotype 3 infection accounts for approximately 30% of global HCV infections and is now considered the most difficult to cure with interferon (IFN)-free direct-acting antiviral (DAA) therapy.[3], [4] Highly effective and safe IFN-free DAA HCV treatments are available, and some may provide broad coverage for all six major genotypes with 12 weeks of treatment.[5], [6], [7], [8] However, a regimen involving other DAA classes with a shorter treatment duration and high barrier to viral resistance that preserves efficacy would further enhance HCV therapeutic management. Indeed, regimens with shorter treatment durations are associated with enhanced patient convenience, adherence and tolerability, and can thereby improve access to care.[1], [9]

Glecaprevir (formerly ABT-493; GLE) is an HCV non-structural (NS) protein 3/4A protease inhibitor identified by AbbVie and Enanta, and pibrentasvir (formerly ABT-530; PIB) is an HCV NS5A inhibitor. Both DAA compounds have potent antiviral activity in vitro against all six major HCV genotypes with a high barrier to the selection of common variants with resistance-associated substitutions. The in vitro half maximal effective concentration (EC50) of GLE is 0.85–2.8 nM across HCV genotypes 1–6, and PIB has EC50 values of 1–5 pM across genotypes 1–6. Following 3-day monotherapy in treatment-naïve patients with HCV genotype 1 infection, GLE and PIB each displayed approximately 4 log10 IU/ml declines in HCV genotype 1 RNA from baseline across a range of doses.[10], [11]

Here, we present results from two phase II studies (SURVEYOR-I and SURVEYOR-II, parts 1 and 2) designed to evaluate the efficacy and safety of various doses of GLE in combination with PIB with or without ribavirin (RBV) for the treatment of non-cirrhotic patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who were previously untreated or pegylated interferon (PegIFN) plus RBV (PegIFN/RBV) treatment-experienced patients. The impact of RBV, treatment duration, and baseline polymorphisms in NS3 and NS5A on SVR12 rates, as well as treatment-emergent substitutions in NS3 and NS5A in patients who experienced virologic failure, were also assessed.

Section snippets

Patients

Patients were screened at 80 sites in the United States, Canada, Europe, Australia, New Zealand, and Puerto Rico. Patients 18–70 years of age were eligible if they had chronic HCV genotypes 1, 2, 3, 4, 5, or 6 infection with an HCV RNA level greater than 10,000 IU/ml at screening. HCV genotype was determined using the Versant® HCV Genotype Inno Line Probe Assay (LiPA), version 2.0 or higher (Siemens, Malvern, PA). Absence of cirrhosis was documented by means of a liver biopsy (METAVIR score <3,

Baseline demographic and clinical characteristics

In total, 449 patients were enrolled and received at least one dose of study drug. Of these, 113 had genotype 1 infection, 128 had genotype 2, 174 had genotype 3, 22 had genotype 4, one had genotype 5, and 11 patients had genotype 6 infection (Table 1A). The majority of patients were white (89%) and male (57%) with a mean HCV RNA level of 6.5 log10 IU/ml.

Efficacy outcomes of dose-ranging arms (part 1)

For genotype 1 infection, the SVR12 rate was 97% (38/39; 95% CI, 87–100%) in patients who received 200 mg GLE with the lower 40 mg PIB dose, and

Discussion

The Part 1, dose-ranging studies demonstrated that the once-daily regimen of 300 mg GLE and 120 mg PIB had high efficacy across genotypes 1, 2, and 3, regardless of prior treatment experience. Additionally, in genotype 3-infected patients, the higher-dose combination of GLE 300 mg plus PIB 120 mg demonstrated higher efficacy than the lower-dose combination of GLE 200 mg plus PIB 40 mg. This is consistent with previous data showing a lower decline in HCV RNA (4.1 log10 vs. 4.5 log10) in genotype

Financial support

This trial was funded by AbbVie Inc. In collaboration with the principal investigator (P.K.) and the study-designated physicians (A.A and S.W.), the sponsor designed and conducted the studies, contributed to the collection of data, statistical analyses, and interpretation of data, and participated in writing, review and approval of the manuscript. This manuscript contains information of the investigational use of glecaprevir and pibrentasvir.

Conflict of interest

P.Y. Kwo: Grant support AbbVie, Bristol-Myers Squibb, Conatus, Eisai, Gilead, Janssen, Merck. Advisor Abbott, AbbVie, BMS, Gilead, Janssen, Merck, Quest, Alnylam, Durect, DSMB Inovio. F. Poordad: Grant/research support: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer-Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex,

Authors’ contributions

Dr. Kwo had full access to all of the data in the studies and takes responsibility for the integrity of the data and the accuracy of the data analysis. Design and conduct of the study: Kwo, Poordad, Asatryan, Wang, Lin, Liu, Lovell, Ng, Kort, Mensa. Collection, management, analysis, and interpretation of the data: Poordad, Kwo, Wyles, Asatryan, Wang, Hassanein, Lalezari, Felizarta, Sulkowski, Gane, Maliakkal, Overcash, Gordon, Lin, Liu, Lovell, Ng, Kort, Mensa. Data analysis: Asatryan, Wang,

Acknowledgements

We thank AbbVie employees Wei Liu, PhD, Tami Pilot-Matias, PhD, Christine Collins, PhD, Rakesh Tripathi, MS, Gretja Schnell, PhD, Preethi Krishnan, PhD, Jill M. Beyer, Thomas J. Reisch, MS, Tanya Dekhtyar, MS, and Michelle L. Irvin, MS, for assistance provided in the preparation and operation of the SURVEYOR studies. Medical writing support was provided by Douglas E. Dylla, PhD, and Zoë N. Hunter, PhD, of AbbVie.

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