ABSTRACT
A challenge to the treatment of chronic hepatitis C with direct-acting antivirals is the emergence of drug-resistant hepatitis C virus (HCV) variants. HCV with preexisting polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b and 437 genotype 1a sequences). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (<1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naive patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response 24 weeks after the end of treatment (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b, and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies, there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment experienced (17% compared to 26%; P = 0.47) or treatment naive (62% compared to 66%; P = 0.72).
Subject(s)
Antiviral Agents/therapeutic use , Drug Resistance, Viral/genetics , Hepacivirus/genetics , Oligopeptides/therapeutic use , Polymorphism, Genetic , Protease Inhibitors/therapeutic use , Thiazoles/therapeutic use , Viral Nonstructural Proteins/genetics , Amino Acid Substitution , Aminoisobutyric Acids , Clinical Trials as Topic , Drug Monitoring , Drug Resistance, Viral/drug effects , Gene Expression , Genotype , Hepacivirus/drug effects , Hepacivirus/enzymology , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Humans , Leucine/analogs & derivatives , Mutation , Proline/analogs & derivatives , Quinolines , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolismABSTRACT
Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143-2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).
Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C/drug therapy , Interferon-alpha/therapeutic use , Oligopeptides/therapeutic use , Polyethylene Glycols/therapeutic use , Ribavirin/therapeutic use , Thiazoles/therapeutic use , Adolescent , Adult , Aged , Aminoisobutyric Acids , Antiviral Agents/administration & dosage , Carrier Proteins/antagonists & inhibitors , Drug Therapy, Combination , Female , Genotype , Humans , Interferon-alpha/administration & dosage , Intracellular Signaling Peptides and Proteins , Leucine/analogs & derivatives , Male , Middle Aged , Oligopeptides/administration & dosage , Polyethylene Glycols/administration & dosage , Proline/analogs & derivatives , Quinolines , RNA, Viral/genetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Ribavirin/administration & dosage , Thiazoles/administration & dosage , Viral Nonstructural Proteins/antagonists & inhibitors , Young AdultABSTRACT
Faldaprevir, an investigational agent for hepatitis C virus treatment, is well tolerated but associated with rapidly reversible, dose-dependent, clinically benign, unconjugated hyperbilirubinemia. Multidisciplinary preclinical and clinical studies were used to characterize mechanisms underlying this hyperbilirubinemia. In vitro, faldaprevir inhibited key processes involved in bilirubin clearance: UDP glucuronosyltransferase (UGT) 1A1 (UGT1A1) (IC50 0.45 µM), which conjugates bilirubin, and hepatic uptake and efflux transporters, organic anion-transporting polypeptide (OATP) 1B1 (IC50 0.57 µM), OATP1B3 (IC50 0.18 µM), and multidrug resistance-associated protein (MRP) 2 (IC50 6.2 µM), which transport bilirubin and its conjugates. In rat and human hepatocytes, uptake and biliary excretion of [(3)H]bilirubin and/or its glucuronides decreased on coincubation with faldaprevir. In monkeys, faldaprevir (≥20 mg/kg per day) caused reversible unconjugated hyperbilirubinemia, without hemolysis or hepatotoxicity. In clinical studies, faldaprevir-mediated hyperbilirubinemia was predominantly unconjugated, and levels of unconjugated bilirubin correlated with the UGT1A1*28 genotype. The reversible and dose-dependent nature of the clinical hyperbilirubinemia was consistent with competitive inhibition of bilirubin clearance by faldaprevir, and was not associated with liver toxicity or other adverse events. Overall, the reversible, unconjugated hyperbilirubinemia associated with faldaprevir may predominantly result from inhibition of bilirubin conjugation by UGT1A1, with inhibition of hepatic uptake of bilirubin also potentially playing a role. Since OATP1B1/1B3 are known to be involved in hepatic uptake of circulating bilirubin glucuronides, inhibition of OATP1B1/1B3 and MRP2 may underlie isolated increases in conjugated bilirubin. As such, faldaprevir-mediated hyperbilirubinemia is not associated with any liver injury or toxicity, and is considered to result from decreased bilirubin elimination due to a drug-bilirubin interaction.
Subject(s)
Hepacivirus/drug effects , Hepatitis C/drug therapy , Hyperbilirubinemia/chemically induced , Oligopeptides/adverse effects , Oligopeptides/therapeutic use , Thiazoles/adverse effects , Thiazoles/therapeutic use , Aminoisobutyric Acids , Animals , Bilirubin/metabolism , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Double-Blind Method , Glucuronosyltransferase/genetics , Hepatitis C/genetics , Hepatitis C/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/virology , Humans , Hyperbilirubinemia/genetics , Hyperbilirubinemia/metabolism , Leucine/analogs & derivatives , Liver/drug effects , Liver/virology , Macaca mulatta , Multicenter Studies as Topic , Multidrug Resistance-Associated Protein 2 , Oligopeptides/pharmacology , Proline/analogs & derivatives , Quinolines , Randomized Controlled Trials as Topic , Rats , Thiazoles/pharmacologyABSTRACT
UNLABELLED: Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. CONCLUSION: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. (HEPATOLOGY 2013;57:2143-2154).
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Oligopeptides/therapeutic use , Polyethylene Glycols/therapeutic use , Ribavirin/therapeutic use , Thiazoles/therapeutic use , Adult , Aminoisobutyric Acids , Carrier Proteins/antagonists & inhibitors , Double-Blind Method , Drug Therapy, Combination , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/virology , Humans , Intracellular Signaling Peptides and Proteins , Leucine/analogs & derivatives , Male , Middle Aged , Oligopeptides/pharmacology , Proline/analogs & derivatives , Quinolines , Recombinant Proteins/therapeutic use , Thiazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitorsABSTRACT
UNLABELLED: Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (<1 log10 viral load [VL] drop at any time on treatment) or partial response (≥1 log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI. Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL <25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. In the 240 mg QD/LI group, a significantly higher proportion of mRVR patients rerandomized to 48 weeks' treatment achieved SVR compared with those assigned to 24 weeks treatment (72% versus 43%; P = 0.035). Rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were increased at 240 mg BID compared with the 240 mg QD dose. Faldaprevir discontinuations owing to adverse events occurred in 6%, 4%, and 23% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. CONCLUSION: Faldaprevir 240 mg QD with PegIFN/RBV was safe and tolerable and produced substantial SVR rates in prior null and partial responders. The 240 mg QD dose is currently undergoing phase 3 evaluation.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Polyethylene Glycols/therapeutic use , Ribavirin/therapeutic use , Adult , Carrier Proteins/antagonists & inhibitors , Double-Blind Method , Drug Therapy, Combination , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/virology , Humans , Intracellular Signaling Peptides and Proteins , Male , Middle Aged , Recombinant Proteins/therapeutic use , Treatment Failure , Viral Nonstructural Proteins/antagonists & inhibitorsABSTRACT
BACKGROUND & AIMS: Faldaprevir (BI 201335) is a potent once-daily (QD) NS3/4A protease inhibitor for the treatment of patients with genotype-1 (GT-1) hepatitis C virus (HCV). The aim of this study was to evaluate the safety, pharmacokinetics and efficacy of faldaprevir plus pegylated interferon alfa-2a (PegIFN) and ribavirin (RBV) in Japanese patients infected with chronic GT-1 HCV. METHODS: Part 1 of this phase II study was a randomized, double-blind, placebo-controlled, dose-ascending study. Treatment-naïve patients received faldaprevir 120 or 240 mg QD, or placebo, plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. In Part 2 (open label), treatment-experienced patients received faldaprevir 240 mg QD plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. Efficacy was assessed using sustained virological response (SVR) 24 weeks after treatment completion. The pharmacokinetics, safety and tolerability of faldaprevir were also assessed. RESULTS: SVR was achieved by 4/6 (67%) treatment-naïve patients treated with faldaprevir 120 mg QD, 5/6 (83%) patients treated with faldaprevir 240 mg QD and 2/4 (50%) patients who received placebo. Of the treatment-experienced patients, 3/6 (50%) achieved SVR. Faldaprevir was well tolerated. There was one serious adverse event, which was not considered to be treatment related. Rash and hyperbilirubinaemia were more frequently reported with faldaprevir than with placebo in treatment-naïve patients, but no cases were severe or serious and none led to discontinuation. Steady-state plasma concentrations of faldaprevir were reached within 7 days of QD dosing. CONCLUSIONS: Faldaprevir with PegIFN/RBV was efficacious and well tolerated, supporting further evaluation of this combination in Japanese patients.
Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Oligopeptides/therapeutic use , Polyethylene Glycols/therapeutic use , Ribavirin/therapeutic use , Thiazoles/therapeutic use , Adult , Aminoisobutyric Acids , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Asian People , Double-Blind Method , Drug Therapy, Combination , Female , Genotype , Hepacivirus/genetics , Hepacivirus/growth & development , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/ethnology , Humans , Interferon-alpha/adverse effects , Japan , Leucine/analogs & derivatives , Male , Middle Aged , Oligopeptides/adverse effects , Oligopeptides/pharmacokinetics , Polyethylene Glycols/adverse effects , Proline/analogs & derivatives , Quinolines , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Ribavirin/adverse effects , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Time Factors , Treatment OutcomeABSTRACT
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 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) 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.
Subject(s)
Antiviral Agents/pharmacology , Hepatitis C/drug therapy , Oligopeptides/pharmacology , Protease Inhibitors/pharmacology , Thiazoles/pharmacology , Adult , Aminoisobutyric Acids , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Carrier Proteins/antagonists & inhibitors , Double-Blind Method , Drug Resistance, Viral/genetics , Female , Hepacivirus/drug effects , Hepacivirus/enzymology , Hepacivirus/genetics , Hepatitis C/blood , Hepatitis C/virology , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Intracellular Signaling Peptides and Proteins , Leucine/analogs & derivatives , Male , Middle Aged , Oligopeptides/administration & dosage , Oligopeptides/adverse effects , Oligopeptides/pharmacokinetics , Polyethylene Glycols/administration & dosage , Proline/analogs & derivatives , Protease Inhibitors/administration & dosage , Protease Inhibitors/adverse effects , Protease Inhibitors/pharmacokinetics , Quinolines , Recombinant Proteins , Ribavirin/administration & dosage , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Viral Load/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/geneticsABSTRACT
Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.
Subject(s)
Antiviral Agents/therapeutic use , Carbamates/pharmacology , Hepacivirus/drug effects , Hepacivirus/physiology , Hepatitis C/drug therapy , Macrocyclic Compounds , Quinolines , Serine Proteinase Inhibitors/therapeutic use , Thiazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Carbamates/administration & dosage , Carbamates/chemistry , Carbamates/pharmacokinetics , Double-Blind Method , Hepacivirus/enzymology , Hepacivirus/genetics , Hepatitis C/virology , Humans , Male , Polyproteins/metabolism , Protein Processing, Post-Translational/drug effects , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Thiazoles/administration & dosage , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Viral Load , Viral Nonstructural Proteins/metabolism , Viral Proteins/metabolismABSTRACT
We analysed viral kinetics from a 2-day treatment with BILN 2061, a serine protease inhibitor of hepatitis C virus, in patients chronically infected with genotype 1 hepatitis C virus. The efficiency (E), describing inhibition of viral production, was above 99.45% in all patients with minor or moderate fibrosis receiving doses of 200mg and 500 mg twice daily and larger than in previous studies for interferon-based treatments. However, epsilon was slightly smaller in patients with cirrhosis given 200mg and markedly smaller in patients given 25 mg. Estimates of viral clearance and infected-cell loss support conclusions on these rates and on treatment mechanisms from previous studies on interferon-alpha-based treatments.
Subject(s)
Carbamates/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Macrocyclic Compounds/therapeutic use , Quinolines/therapeutic use , RNA, Viral/blood , Serine Proteinase Inhibitors/therapeutic use , Thiazoles/therapeutic use , Adult , Antiviral Agents/therapeutic use , Area Under Curve , Carbamates/administration & dosage , Carbamates/pharmacokinetics , Female , Hepatitis C, Chronic/virology , Humans , Interferon-alpha/therapeutic use , Kinetics , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/pharmacokinetics , Male , Middle Aged , Models, Biological , Quinolines/administration & dosage , Quinolines/pharmacokinetics , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/pharmacokineticsABSTRACT
BILN-2061, a specific and potent peptidomimetic inhibitor of the HCV NS3 protease, has recently been shown to markedly lower serum hepatitis C virus (HCV)-RNA levels in patients chronically infected with HCV genotype 1 in three 2-day proof of principle studies. The aim of the current study was to assess the antiviral efficacy of BILN-2061 in patients with genotypes 2 and 3 HCV infection. The antiviral efficacy, pharmacokinetics, and tolerability of 500 mg twice-daily BILN-2061 given as monotherapy for 2 days in 10 patients chronically infected with non-genotype 1 HCV (genotype 2: n = 3; genotype 3: n =7) and minimal liver fibrosis (Ishak score 0-2) were assessed in a placebo-controlled (placebo n = 2), double-blind pilot study. HCV-RNA levels decreased by > or =1 log(10) copies/mL in 4 of 8 patients treated with BILN-2061. One patient showed a weak response of <1 log(10) copies/mL. Three of 8 treated patients showed no response. There was no correlation between baseline viral concentration or genotype and response. BILN-2061 exhibited good systemic exposure after oral administration and was well tolerated. In conclusion, the antiviral efficacy of the HCV serine protease inhibitor BILN-2061 is less pronounced and more variable in patients with HCV genotype 2 or 3 infection compared with previous results in patients with HCV genotype 1. A lower affinity of BILN-2061 for the NS3 protease of genotypes 2 and 3 HCV is most likely a major contributor to these findings.
Subject(s)
Carbamates/therapeutic use , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Macrocyclic Compounds/therapeutic use , Quinolines/therapeutic use , Serine Proteinase Inhibitors/therapeutic use , Thiazoles/therapeutic use , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Adult , Carbamates/administration & dosage , Carbamates/adverse effects , Carbamates/pharmacokinetics , Double-Blind Method , Drug Administration Schedule , Female , Genotype , Hepacivirus/isolation & purification , Hepatitis C, Chronic/metabolism , Humans , Kinetics , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/adverse effects , Macrocyclic Compounds/pharmacokinetics , Male , Middle Aged , Pilot Projects , Prospective Studies , Quinolines/administration & dosage , Quinolines/adverse effects , Quinolines/pharmacokinetics , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/adverse effects , Serine Proteinase Inhibitors/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Viral LoadABSTRACT
BACKGROUND AND AIMS: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine protease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. METHODS: The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, double-blind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). RESULTS: Viral RNA reductions of 2-3 log 10 copies/mL were achieved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction > or =3 log(10) copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or compensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. CONCLUSIONS: BILN 2061 is a well-tolerated and very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity issues.