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Original Article Randomized Study of Asunaprevir Plus Pegylated Interferon-Α and Ribavirin for Previously Untreated Genotype 1 Chronic Hepatitis C

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Original Article Randomized Study of Asunaprevir Plus Pegylated Interferon-Α and Ribavirin for Previously Untreated Genotype 1 Chronic Hepatitis C Antiviral Therapy 2013; 18:885–893 (doi: 10.3851/IMP2660) Original article Randomized study of asunaprevir plus pegylated interferon-α and ribavirin for previously untreated genotype 1 chronic hepatitis C Jean-Pierre Bronowicki1*, Stanislas Pol2, Paul J Thuluvath3, Dominique Larrey4, Claudia T Martorell5, Vinod K Rustgi6, David W Morris7, Ziad Younes8, Michael W Fried9, Marc Bourlière10, Christophe Hézode11, K Rajender Reddy12, Omar Massoud13, Gary A Abrams14, Vlad Ratziu15, Bing He16, Timothy Eley16, Alaa Ahmad17, David Cohen18, Robert Hindes19, Fiona McPhee18, Bridget Reilly16, Patricia Mendez16, Eric Hughes16 1INSERM 954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy, France 2Université Paris Descartes, INSERM U1610 and Liver Unit, Hôpital Cochin, Paris, France 3Mercy Medical Center, Baltimore, MD, USA 4Hôpital Saint Eloi, Service d’Hépato-Gastroentérologie et Transplantation, INSERM 1040-IRB, Montpellier, France 5The Research Institute, Springfield, MA, USA 6Metropolitan Research, Fairfax, VA, USA 7Healthcare Research Consultants, Tulsa, OK, USA 8Gastro One, Germantown, TN, USA 9Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA 10Hôpital Saint Joseph, Service d’Hépato-Gastroentérologie, Marseille, France 11CHU Henri Mondor, Service d’Hépato-Gastroentérologie, Créteil, France 12Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA 13Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL, USA 14Alabama Liver & Digestive Specialists, Montgomery, AL, USA 15Groupe Hospitalier Pitié Salpêtrière, Service d’Hépato-Gastroentérologie, Paris, France 16Bristol–Myers Squibb, Princeton, NJ, USA 17Hoffmann–La Roche, Nutley, NJ, USA 18Bristol–Myers Squibb, Wallingford, CT, USA 19BeyondWest Pharmaceuticals, Skillman, NJ, USA *Corresponding author e-mail: [email protected] Background: Asunaprevir is a selective NS3 protease inhib- twice-daily, 600 mg twice-daily and 600 mg once-daily itor with in vitro activity against HCV genotypes 1 and 4. groups, respectively, versus 0% (0/11) in the placebo Methods: In this Phase IIa double-blind study, treatment- group. Corresponding SVR24 rates were 83% (10/12), naive HCV genotype-1-infected patients in the United 83% (10/12) and 92% (11/12) in the asunaprevir groups States and France were randomly assigned 1:1:1:1 to pla- and 46% (5/11) in the placebo group. There was no viro- cebo or asunaprevir 200 mg twice daily, 600 mg twice logical breakthrough in any asunaprevir group. Following daily or 600 mg once daily in combination with pegylated the 12-week analysis, the 600 mg doses were reduced interferon (PEG-IFN)-α2a and ribavirin for 48 weeks. The to 200 mg twice daily because of a greater frequency of primary efficacy end point was undetectable HCV RNA transaminase elevations at the 600 mg dose. The most at weeks 4 and 12 (extended rapid virological response common grade 3–4 laboratory abnormalities were con- [eRVR]). Other end points included safety and undetect- sistent with those reported for PEG-IFN and ribavirin. able HCV RNA at 24 weeks post-treatment (24-week sus- Conclusions: Asunaprevir plus PEG-IFN and ribavirin tained virological response [SVR24]). achieved higher response rates than placebo plus PEG- Results: A total of 47 patients were randomized and IFN and ribavirin, with a tolerable adverse event profile at treated. eRVR was achieved by 75% (9/12), 75% (9/12) the 200 mg twice-daily dose. This dose is being evaluated and 92% (11/12) of patients in the asunaprevir 200 mg in the Phase IIb and Phase III studies. ©2013 International Medical Press 1359-6535 (print) 2040-2058 (online) 885 J-P Bronowicki et al. Introduction IU/ml. Patients had no prior treatment with any anti- HCV agent or <4 weeks of total exposure to ribavirin Chronic infection with HCV affects up to 170 million or PEG-IFN-based therapy. Patients had to be non- individuals worldwide, including up to 5.2 million in the cirrhotic, documented by liver biopsy obtained within United States [1–3]. Chronic HCV infection is a common 24 months before randomization. Exclusion criteria cause of chronic liver disease, cirrhosis and hepatocellu- included advanced liver disease, coinfection with HBV lar carcinoma [2,4]. Among the seven main HCV geno- or HIV, hepatocellular carcinoma, and other clinically types, genotype 1 is one of the most difficult to treat and relevant comorbidities. Patients were excluded if they the most prevalent globally [1,5]. The genotype 1a sub- had alanine aminotransferase (ALT)≥5× the upper limit type predominates in the United States whereas subtype of normal (ULN), total bilirubin ≥2 mg/dl, albumin ≤3.5 1b predominates in Europe and Japan [1,5–7]. g/dl, international normalized ratio (INR)≥1.7, platelets Current treatment options for patients with chronic ≤90×109 cells/l, or haemoglobin ≤12 g/dl (women) or HCV genotype 1 infection are evolving and include dual ≤13 g/dl (men). therapy with pegylated interferon (PEG-IFN)-a2a or -2b and ribavirin, and triple-therapy regimens including an Study design HCV protease inhibitor. A 24-week sustained virological This Phase IIa double-blind parallel-group study (clini- response (SVR24; undetectable HCV RNA at 24 weeks caltrials.gov identifier NCT01030432) randomized post-treatment) is achieved in only 40–50% of patients patients 1:1:1:1 to placebo plus PEG-IFN-a2a (Pegasys®, treated with dual therapy and 68–75% of patients Roche, Basel, Switzerland) and ribavirin (Copegus®, treated with triple therapy [8–11]. However, these Roche) or oral asunaprevir 200 mg twice daily, 600 mg regimens are limited by adverse events, difficult dosing twice daily or 600 mg once daily plus PEG-IFN and schedules and the potential for viral resistance. A need ribavirin for 48 weeks. PEG-IFN was administered sub- remains for other direct-acting antivirals with improved cutaneously at 180 mg/week, and ribavirin was admin- tolerability and more convenient dosing schedules. New istered orally twice daily and dosed according to body agents will also likely be used in combination with other weight (1,000 mg/day if <75 kg and 1,200 mg/day if classes of direct-acting antivirals, with or without PEG- ≥75 kg). Patients meeting futility criteria – a decrease IFN or ribavirin, to optimize treatment regimens. from baseline in HCV RNA of <2 logs and HCV RNA Asunaprevir is a selective HCV NS3 protease inhibitor ≥ the lower limit of quantitation (LLOQ; 25 IU/ml) at with activity against HCV genotypes 1 and 4 in vitro [12]. week 12; or HCV RNA detectable at week 12 and >50 In single- and multiple-ascending dose studies in patients IU/ml at week 24; or virological breakthrough (defined with HCV genotype 1 infection, asunaprevir produced below) – were required to discontinue treatment. rapid and substantial declines in HCV RNA, with a toler- The asunaprevir dose range was selected based on the able adverse event profile [13]. In HCV genotype 1a- or results of monotherapy studies [13]. After the week 12 1b-infected null responders, asunaprevir plus the NS5A analysis, the asunaprevir 600 mg once daily and twice inhibitor daclatasvir and PEG-IFN/ribavirin achieved daily doses were changed to 200 mg twice daily due to SVR in ≥90% of patients [14,15]. The all-oral regimen elevations in ALT and aspartate aminotransferase (AST). of asunaprevir plus daclatasvir achieved SVR in 91% of The elevations were greater and more frequent at the genotype-1b-infected null responders, and in 64% of gen- 600 mg than the 200 mg dose, and only patients receiv- otype-1b-infected patients intolerant to, or ineligible for, ing the 600 mg doses discontinued due to transaminase PEG-IFN/ribavirin therapy [16]. abnormalities. The 48-week treatment duration was This study is the first Phase IIa clinical trial conducted based on health authorities’ recommendation to add to evaluate the safety and efficacy profile of asunaprevir asunaprevir to the previous standard-of-care for geno- at different doses in combination with PEG-IFN/ribavi- type 1 HCV, and allowed data collection on the safety of rin in previously untreated patients with HCV genotype extended asunaprevir treatment. Shorter durations will 1 infection. Based on the results of this exploratory study, be explored in the Phase IIb study. an asunaprevir dose was selected for further evaluation Patients were enrolled at 15 sites in the United States in combination with PEG-IFN/ribavirin in an ongoing and France between 9 February and 29 April 2010; Phase IIb study, and in combination with daclatasvir with follow-up was complete on 9 September 2011. Eligi- or without PEG-IFN/ribavirin in large Phase III studies. ble patients were randomly assigned to a treatment by an interactive voice response system using a computer- Methods generated random allocation sequence. Investigators and patients were blinded to treatment assignment Patients throughout the study. The sponsor was blinded to Eligible patients were adults aged 18–70 years with treatment assignment until the primary end point anal- chronic HCV genotype 1 infection and HCV RNA≥105 ysis. Written informed consent was obtained from all 886 ©2013 International Medical Press Asunaprevir plus PEG-IFN/ribavirin for chronic hepatitis C patients. The study was approved by the institutional a validated pharmacokinetic programme (Kinetica®; review board at each participating site and was con- Letchworth, UK) and included observed maximum ducted in compliance with the Declaration of Helsinki, (Cmax) and minimum (Cmin) plasma concentrations and Good Clinical Practice guidelines, and local regulatory area under the concentration–time curve in one dosing requirements. interval (AUCTAU). End points Statistical analyses The primary efficacy end point was the proportion of It was determined that a target sample size of 12 patients with undetectable HCV RNA at weeks 4 and patients per arm would detect, with 80% probability, a 12 (extended rapid virological response [eRVR]). Safety safety event occurring at an incident rate of 13%.
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