Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

doi:10.1016/j.jhep.2010.08.040

Journal of Hepatology

Volume 54, Issue 6, June 2011, Pages 1114-1122

https://doi.org/10.1016/j.jhep.2010.08.040 Get rights and content

Background & Aims

BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.

Methods

Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20–240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48–240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan.

Results

In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were −3.0, −3.6, −3.7, and −4.2 log₁₀ for the 20, 48, 120, and 240 mg groups. VL breakthroughs (⩾1 log₁₀ from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15–28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL <25 IU/ml at Day 28 in 3/6, 4/7, and 5/6 patients in the 48, 120, and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing.

Conclusions

BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.

Introduction

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and liver cancer worldwide. Genotype-1 (GT-1) represents the most prevalent and also most difficult-to-treat HCV subtype. Treatment with the current standard-of-care (SOC) i.e. 48 weeks of pegylated interferon alfa (PegIFN) and ribavirin (RBV), leads to a sustained virologic response (SVR) in 40–50% of patients, indicative of the resolution of the infection [1], [2], [3], [4], [5]. However, more than 50% of those treated do not respond or relapse. In addition, many patients cannot tolerate interferon and/or RBV-based therapies. Furthermore, SVR rates are much lower for so-called difficult-to-treat populations like patients with decompensated liver cirrhosis, human immunodeficiency virus (HIV)-HCV co-infected patients, post-transplant HCV infection, hemodialysis patients, and others [3].

The HCV protease inhibitor BILN 2061 was the first agent in man to specifically target HCV replication and thus provided the proof-of-concept for directly inhibiting HCV NS3/NS4A protease as a means of suppressing viral replication [6]. This agent showed 3–4 log₁₀ reductions in HCV RNA within 48 h of treatment in HCV GT-1 patients [7], as well as a smaller but significant activity against GT-2/3 infection [8]. However, the development of BILN 2061 was halted due to ultrastructural cardiotoxic changes observed in animals treated with supratherapeutic doses. The encouraging viral response to this first protease inhibitor, however, has led to the development of several follow-up agents, many of which are now in different stages of drug development. Two developmental protease inhibitors, telaprevir and boceprevir, are now being tested in phase III trials, after successful completion of phase II studies [9], [10], [11]. In these trials, telaprevir is given for 8 or 12 weeks on a background of 24 or 48 weeks of PegIFN/RBV, while boceprevir is given for 24 or 44 weeks in combination with 28 to 48 weeks of PegIFN/RBV. However, both drugs are being given every 8 h or three times per day and have significant side effects including skin rash, anemia, and gastrointestinal symptoms. Therefore, HCV protease inhibitors with improved pharmacokinetics, safety, and tolerability are needed.

Protease inhibitors given as monotherapy also show rapid selection of drug-resistant variants. These variants result from the poor replication fidelity of the virus and are selected due to the pressure placed on the virus. Consequently, combination of a HCV protease inhibitor with PegIFN/RBV is currently required in order to minimize the risk of virologic breakthrough due to resistance [9], [10], [11].

BI201335 is a peptidomimetic HCV-specific protease inhibitor with high in vitro activity against GT-1a and -1b subtypes, with EC₅₀ values of 6.5 and 3.1 nM, respectively. Preclinical and preliminary human pharmacokinetic studies suggested that BI201335 maintains sufficient plasma concentrations at steady-state to allow once-daily (qd) dosing (Boehringer Ingelheim, unpublished data). A multiple rising dose study in volunteers indicated that BI201335 was safe and well tolerated at doses of 20–240 mg qd for 21–28 days (Boehringer Ingelheim, unpublished data). These observations allowed progression to the phase Ib trial (1220.2) reported here.

Section snippets

Study design

This was a randomized, multi-center, multiple rising-dose trial, performed between December 2007 and June 2008 at 16 sites in France, Germany, Spain, and USA. The trial was double-blind and placebo-controlled for groups with treatment-naïve (TN) patients. The trial was conducted in full compliance with the Guidelines of Good Clinical Practice and the Declaration of Helsinki and approved by all competent institutional review boards, ethical committees, and national authorities. All patients gave

Patient disposition and baseline characteristics

In 2007 and 2008, a total of 171 patients were screened: 53 patients were randomized to treatment in this study; 75 patients did not meet the inclusion criteria, 43 patients were entered into later cohorts that will be reported in a separate manuscript. The rate of study completion was high; 52 out of 53 patients randomized to treatment completed the study. The reason for the discontinuation of one subject was the diagnosis of an unexpected pregnancy of his partner representing an exclusion

Discussion

This trial investigated the antiviral activity, safety and pharmacokinetics of BI201335 in 53 patients with HCV GT-1 infection treated with BI201335 ± PegIFN and RBV for 28 days.

When given qd as monotherapy in TN patients for 14 days, 48–240 mg BI201335 qd induced a rapid, dose-dependent decrease in plasma HCV RNA by ⩾2 log₁₀ from baseline in all patients. Maximal VL declines from baseline occurred within 2–3 days of first administration. At the 240 mg qd dose, the median maximal decline from baseline

Financial disclosures

Michael Manns has received grant support, contributed to clinical trials, and is a member of a speaker bureau and/or consulted for Schering Plough, Roche, Merck, Bristol-Myers Squibb, Vertex, Tibotec, Astra/Arrows, Novartis, Human Genome Sciences, Boehringer Ingelheim, and Valeant. Peter W. White, Jerry Stern, Gerhard Steinmann, Chan-Loi Yong, George Kukolj, Joe Scherer and Wulf O. Boecher are employees of Boehringer Ingelheim.

ClinicalTrials.gov identifier: NCT00793793.

Acknowledgments

Editorial assistance was provided by StemScientific, supported by Boehringer Ingelheim.

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Cited by (105)

Interferon-free regimen: Equally effective in treatment naive and experienced HCV patients
2019, Annals of Hepatology
Introduction and aim. Interferon-free regimen has been reported to be highly efficient in treatment of HCV infection, including patients with compensated cirrhosis. We compared the efficacy of Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir and Ribavirin (OBT/PTV/r, with DSV and RBV) therapy in patients with chronic HCV genotype 1b infection and compensated cirrhosis with and without prior treatment experience with pegylated interferon and ribavirin (IFN/RBV).
Material and methods. A prospective two-center study was conducted in Mures County Hospital and Brasov County Hospital, Romania in period November 2015-July 2016. Both treatment naïve and PegIFN/RBV experienced patients with chronic HCV genotype 1b infection received 12 weeks of OBT/PTV/r, with DSV and RBV. Sustained virologic response 12 weeks after the treatment and eventual discontinuation of therapy due to adverse events were assessed in order to estimate safety and efficiency of therapeutic regimen.
Results. Fifty nine patients were included in study, 35 (59.3%) of them were previously treated with IFN/RBV. Forty four (74.5%) patients were previously diag-nosed with cirrhosis Child Pugh score 5, while 15 (25.4%) with Child Pugh score 6. All 59 patients achieved a SVR12 of 100% and one patient from treatment naïve cohort discontinued the therapy due to hyperbilirubinemia and encephalopathy. However viral load assessed at 12 weeks after discontinuation of therapy in this patient was undetectable.
Conclusion An all-oral regimen of co-for-mulated OBT/PTV/r with DSV and RBV results in high rate of sustained virologic response at post-treatment week 12 among HCV GT1b infected patients associated with compensated cirrhosis, regardless of previous treatment experience with PegIFN/RBV.
Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3
2018, Clinical Therapeutics
Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3.
These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3.
Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log₁₀ IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log₁₀ IU/mL for GT1- and GT3-infected participants.
The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose–response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).
Faldaprevir, pegylated interferon, and ribavirin for treatment-naïve HCV genotype-1: Pooled analysis of two phase 3 trials
2016, Annals of Hepatology
Introduction & aim. Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor. The STARTVerso1 and STARTVerso2 phase 3 studies evaluated faldaprevir plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic HCV genotype-1 infection.
Material and methods. Patients were randomized 1:2:2 to receive placebo, faldaprevir 120 mg q.d. (12 or 24 weeks) or faldaprevir 240 mg q.d. (12 weeks) all with PegIFN/RBV (24-48 weeks). Faldaprevir 120 mg for 12 weeks only (STARTVerso1 only) required early treatment success (ETS, HCV RNA < 25 IU/mL at week 4 and undetected at week 8). All faldaprevir-treated patients with ETS stopped PegIFN/RBV at week 24. Primary endpoint: sustained virologic response 12 weeks post-treatment (SVR12).
Results. SVR12 rates were significantly higher for patients treated with faldaprevir 120 or 240 mg (72% and 73%, respectively) compared with placebo (50%); estimated differences (adjusted for trial, race, and genotype-1 subtype) faldaprevir 120 mg 24% (95% CI: 17-31%, P < 0.0001), faldaprevir 240 mg 23% (95% CI: 16-30%, P < 0.0001). Subgroup analyses consistently showed higher SVR12 rates for patients receiving faldaprevir compared with placebo. The incidence of adverse events (AEs) was similar in faldaprevir 120-mg and placebo groups and slightly higher in the faldaprevir 240-mg group. Serious AEs were reported in 6%, 7%, and 8% of patients in placebo, faldaprevir 120-mg, and faldaprevir 240-mg groups, respectively.
Conclusion. Addition of faldaprevir to PegIFN/RBV increased SVR12 in patients with HCV genotype-1, and was well tolerated. Faldaprevir 120 mg is effective in the treatment of HCV genotype-1. ClinicalTrials.gov: NCT01343888 and NCT01297270.
Ombitasvir, paritaprevir, and ritonavir plus ribavirin for chronic hepatitis C virus genotype 4 infection in Egyptian patients with or without compensated cirrhosis (AGATE-II): a multicentre, phase 3, partly randomised open-label trial
2016, The Lancet Gastroenterology and Hepatology
In Egypt, chronic hepatitis C virus (HCV) infection occurs in around 10% of the population (about 8 million individuals), and is a leading cause of liver cirrhosis, hepatocellular carcinoma, and mortality. Although HCV genotype 4 constitutes about 20% of HCV infections worldwide, the prevalence in Egypt is more than 90%. We assessed the efficacy and safety of the two direct-acting antiviral drugs ombitasvir, an NS5A inhibitor, and paritaprevir, an NS3/4A protease inhibitor dosed with ritonavir, plus ribavirin in treatment of chronic HCV infection in Egypt.
AGATE-II was a phase 3, open-label, partly randomised trial in patients with chronic HCV genotype 4 infection recruited from five academic and hepatology centres in Egypt. Patients were HCV treatment-naive or treatment-experienced with interferon-based regimens. Eligible patients were aged 18 years or older, and had been chronically infected with HCV genotype 4 for at least 6 months with a plasma HCV RNA concentration of more than 1000 IU/mL at screening. Patients without cirrhosis were assigned to receive 12 weeks of 25 mg ombitasvir, 150 mg paritaprevir, and 100 mg ritonavir orally once daily plus weight-based ribavirin. Patients with compensated cirrhosis were randomly assigned (1:1) to receive the same treatment for either 12 weeks or 24 weeks. Randomisation was stratified by previous pegylated interferon and ribavirin treatment experience using a web-based interactive response technology system and computer-generated schedules prepared by personnel from the funder's statistics department. Investigators were masked to randomisation schedules and were informed of each patient's assigned treatment by the interactive response technology system immediately after allocation. The primary endpoint was the proportion of patients with a sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the last dose of study drug (SVR12). All patients who received at least one dose of study drugs were included in the primary and safety analysis. This study is registered with ClinicalTrials.gov, number NCT02247401.
Between Nov 4, 2014, and March 16, 2015, we screened 182 patients with HCV infection, of whom 160 were eligible for inclusion; 100 patients were assessed as not having cirrhosis and were given 12 weeks of treatment, and 60 patients assessed as having cirrhosis were randomly assigned to the 12-week treatment group (n=31) or the 24-week treatment group (n=29). 94 (94%; 95% CI 88–97) of 100 patients in the without cirrhosis group, 30 (97%; 84–99) of 31 patients in the cirrhosis 12-week treatment group, and 27 (93%; 78–98) of 29 patients in the cirrhosis 24-week treatment group achieved SVR12. The most common adverse events in patients without cirrhosis were headache (41 [41%]) and fatigue (35 [35%]). Fatigue occurred in nine (29%) patients in the cirrhosis 12-week treatment group and 11 (38%) patients in the cirrhosis 24-week treatment group, and headache occurred in nine (29%) patients in the cirrhosis 12-week treatment group and in 10 (35%) patients in the cirrhosis 24-week treatment group. Adverse events were predominantly mild or moderate in severity, and laboratory abnormalities were not clinically meaningful. No patients discontinued treatment because of an adverse event. One serious adverse event in the group without cirrhosis was attributed to study drugs by the investigators; the patient had deep venous thrombosis.
Ombitasvir, paritaprevir, and ritonavir plus ribavirin for 12 weeks achieved SVR12 in a high proportion of patients and was well tolerated in Egyptian patients with HCV genotype 4 infection with or without compensated cirrhosis. Extension of treatment to 24 weeks in patients with cirrhosis did not improve the proportion of patients achieving SVR12. A shorter duration regimen could be useful to address the significant burden of HCV genotype 4 infection in patients with compensated cirrhosis.
AbbVie.
Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in genotype 1 HCV patients: The MALACHITE-I/II trials
2016, Journal of Hepatology
Citation Excerpt :
The high SVR12 rates among patients who reduced RBV are consistent with previous reports indicating RBV reduction does not impact efficacy of either regimen [9–11,13,29]. The most common laboratory abnormality with OBV/PTV/r + DSV ± RBV was a transient elevation in bilirubin (predominantly indirect bilirubin), consistent with the known roles of PTV as an inhibitor of the OATP1B1 and OATP1B3 transporters and RBV-induced hemolysis [18,30]. Alanine aminotransferase and bilirubin elevations observed with OBV/PTV/r + DSV ± RBV were infrequent and generally isolated abnormalities that recovered without drug discontinuation, consistent with previous studies [10–12].
Telaprevir plus pegylated interferon/ribavirin (TPV + PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin (OBV/PTV/r + DSV ± RBV) and TPV + PegIFN/RBV.
Treatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r + DSV + weight-based RBV, OBV/PTV/r + DSV (treatment-naïve, GT1b-infected patients only), or 12 weeks of TPV + PegIFN + weight-based RBV and 12–36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR₁₂). Patient-reported outcome questionnaires evaluated mental and physical health during the studies.
Three hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR₁₂ rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r + DSV + RBV and TPV + PegIFN/RBV-treated GT1a-infected patients; SVR₁₂ rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r + DSV + RBV, OBV/PTV/r + DSV, and TPV + PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR₁₂ rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r + DSV + RBV and TPV + PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r + DSV ± RBV than TPV + PegIFN/RBV. Rates of discontinuation due to adverse events (0–1% and 8–11%, respectively, p <0.05) and rates of hemoglobin decline to <10 g/dl (0–4% and 34–47%, respectively, p <0.05) were lower for OBV/PTV/r + DSV ± RBV than TPV + PegIFN/RBV.
Among non-cirrhotic, HCV GT1-infected patients, SVR₁₂ rates were 97–99% with 12 week, multi-targeted OBV/PTV/r + DSV ± RBV regimens and 66–82% with 24–48 total weeks of TPV + PegIFN/RBV. OBV/PTV/r + DSV ± RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.
Development and application of a fast, reproducible assay to measure HCV NS3 protease activity using Escherichia coli lysate
2015, Journal of Virological Methods
The hepatitis C virus (HCV) NS3/4A protease is a key target of efforts to develop direct-acting antiviral inhibitors for treatment of chronic HCV infection. In vitro analyses of the effects of NS3/4A mutations and polymorphisms on protease inhibitor (PI) susceptibility are essential to nonclinical and clinical compound characterization, but can be hampered by time and technical limitations of current in vitro methods using replicon or purified protein systems. We have developed a fast and simple method utilizing full-length NS3/4A protease inducibly expressed in Escherichia coli cells. Minimally processed E. coli whole cell lysate was used for analyzing NS3/4A protease activity and inhibition by antiviral compounds. Assay conditions were optimized to develop a reproducible assay that can be used for efficient analysis of NS3 protease mutants with poor replication capacity in the replicon system. IC₅₀ fold-changes for NS3 mutants relative to their wild-types generated by this NS3 assay are comparable to those observed in the replicon system, with an R² of 0.82 for the values obtained by the two methods. In addition, we demonstrate that this assay can be successfully used for population and clonal phenotyping of patient samples and characterization of PIs against the NS3/4A protease from HCV genotypes 1–6.

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Research ArticlePotency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

Background & Aims

Methods

Results

Conclusions

Introduction

Section snippets

Study design

Patient disposition and baseline characteristics

Discussion

Financial disclosures

Acknowledgments

Lancet

J Hepatol

Gastroenterology

J Hepatol

Gastroenterology

Gastroenterology

J Biol Chem

J Hepatol

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection

N Engl J Med

The way forward in HCV treatment – finding the right path

Nat Rev Drug Discov

Diagnosis, management, and treatment of hepatitis C: an update

Hepatology

Research Article
Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection