Gastroenterology

Gastroenterology

Volume 146, Issue 2, February 2014, Pages 420-429
Gastroenterology

Original Research
Full Report: Clinical-Liver
Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection

Parts of this study were presented at The Liver Meeting: The 63rd Annual Meeting of the AASLD, Boston, MA, November 9-13, 2012, Oral LB-3; and The International Liver Congress 2013: The 48th Annual Meeting of the European Association for the Study of the Liver, Amsterdam, The Netherlands, April 24-28, 2013.
https://doi.org/10.1053/j.gastro.2013.10.057Get rights and content
Under a Creative Commons license
open access

Background & Aims

The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection.

Methods

We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]).

Results

In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms.

Conclusions

In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.

Keywords

Liver Disease
Therapy
DAA
Drug Combination

Abbreviations used in this paper

EC50
median effective concentration
GT
genotype
HCV
hepatitis C virus
IL
interleukin
SVR
sustained virologic response
SVR24
sustained virologic response at 12 weeks

Cited by (0)

Conflicts of interest These authors disclose the following: Gregory Everson has been on advisory committees or review panels for Roche/Genentech, Merck, and HepC Connection; has been a board member of HepQuant, LLC, and PSC Partners; has performed consulting for Roche/Genentech and Abbott; has received grant/research support from Roche/Genentech, Pharmassett, Vertex, GSK, Schering-Plough, Bristol-Myers Squibb, Tibotec, GlobeImmune, Pfizer, Abbott, Conatus, ZymoGenetics, and PSC Partners; has held a management position for HepQuant, LLC; and has a patent held/filed with the University of Colorado; Maribel Rodriguez-Torres has been a consultant for Akros Pharmaceutical, Bristol-Myers Squibb, Genentech, Hoffman-La Roche, Inhibitex, Janssen R&D Ireland, Merck Sharp & Dohme, Corp, Pharmasset, Santaris Pharma, and Vertex Pharmaceutical, Inc; has received grant/research support from Inhibitex, Johnson & Johnson, Merck Sharp & Dohme, Corp, Mochida Pharmaceutical, Novartis, Pfizer, Pharmasset, Santaris Pharma, A/S, Scynexis, Inc, Siemens Healthcare Diagnostics, Vertex Pharmaceutical, Inc, ZymoGenetics, Abbott Laboratories, Akros Pharmaceutical, Anadys Pharmaceutical, Beckman Coulter, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Pharmaceuticals, Glaxo Smith Kline, Hoffman-La Roche, Human Genome Sciences, Idenix Pharmaceutical, and Idera Pharmaceutical; Christophe Hézode has been compensated for speaking and teaching by Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Corp, Janssen, Abbvie, and Gilead; Eric Lawitz had performed consulting for Theravance; has received grant/research support from Abbott Laboratories, Anadys Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Glaxo-SmithKline, GlobeImmune, Medtronic, Idenix Pharmaceuticals, Idera Pharmaceuticals, Medarex, Merck & Co, Novartis, Roche, Schering-Plough, Pfizer, Vertex Pharmaceuticals, ZymoGenetics, Tibotec/Johnson and Johnson, Pharmasset, Biolex, Achillion Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Inhibitex Pharmaceuticals, Pharmasset, Santaris, and Scynexis Pharmaceuticals; Marc Bourlière has been a member of advisory committees or review panels for Merck; has been a board member of Gilead and Tibotec; has performed consulting for Boehringer Ingelheim, Roche, Schering-Plough, Novartis, Bristol-Myers Squibb, Abbott, and Janssen; Veronique Loustaud-Ratti has been compensated for speaking and teaching by Roche, Schering-Plough, Merck Sharp & Dohme, Corp, Janssen, Bristol-Myers Squibb, and Gilead; and has received grant/research support from Roche and Bristol-Myers Squibb; and has been a board member of Gilead and Roche; Vinod Rustgi has received grant/research support from Gilead, Bristol Myers Squibb, Abbot, Anadys, and Boehringer-Ingelheim; has been compensated for speaking and teaching by Merck, Genentech, and Vertex; Patrick Marcellin has performed consulting for Roche, Gilead, Bristol-Myers Squibb, Vertex, Novartis, Janssen-Tibotec, Merck Sharp & Dohme, Corp, Boehringer, Abbott, and Pfizer; has received grant/research support from Roche, Gilead, Janssen-Tibotec, and Merck Sharp & Dohme, Corp; has been compensated for speaking and teaching by Roche, Gilead, Bristol-Myers Squibb, Vertex, Janssen-Tibotec, Merck Sharp & Dohme, Corp, and Abbott; and is a stock shareholder in Novartis; Stanislas Pol has served as a board member of Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Vertex, Gilead, Roche, Merck Sharp & Dohme, Corp, Novartis, and Abbvie; and has been compensated for speaking and teaching by Glaxo Smith Kline; Paul Thuluvath has been a member of advisory committees or review panels for Bayer; has received grant/research support from Bayer, Bristol-Myers Squibb, Boehringer, and Novartis; and has been compensated for speaking and teaching by Bayer/Onyx, Roche, Vertex, and Gilead; Karen Sims, Timothy Eley, Xiaodong Wang, Shu-Pang Huang, Fiona McPhee, Megan Wind-Rotolo, Ellen Chung, Claudio Pasquinelli, Dennis Grasela, and David Gardiner are employees and may be shareholders of Bristol-Myers Squibb. The remaining authors have nothing to disclose.

This study is registered with ClinicalTrials.gov, number NCT01455090, and also is known as study AI443-014.

Funding This study was sponsored by Bristol-Myers Squibb. The study was designed and conducted by the sponsor in collaboration with the principal investigators. The sponsor collected the data, monitored the study conduct, and performed the statistical analyses.

Professional medical writing and editorial assistance was provided by Carolyn Carroll, PhD, an employee of Bristol-Myers Squibb.

Author names in bold designate shared co-first authorship.