1058 Antiviral Activity and Safety of Tmc435 Combined With Peginterferon Alpha-2a and Ribavirin in Patients With Genotype 1 Hepatitis C Infection Who Failed Previous Ifn-Based Therapy

Marcellin, Patrick; Reesink, H.W.; Berg, Thomas; Cramp, M.; Flisiak, Robert; Vlierberghe, Hans Van; Verloes, René; Lenz, Oliver; Peeters, Monika; Sekar, Vanitha; Smedt, Goedele De

doi:10.1016/s0168-8278(09)61060-6

Cited by 14 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the high trough levels infer that patients of a higher body mass index, as would be the case in US patients, would have sufficient drug available to maintain viral suppression; moreover, our phase II trial confirmed antiviral activity of lower drug doses. 20 Viral variants with aa changes at one or more of the aa positions 80, 155, and/or 168 of NS3 were detected in each of the treated patients as early as day 3. Mutations at these positions were previously characterized in vitro to confer reduced susceptibility to TMC435 in a transient replicon system, with changes in EC 50 values ranging from low (below 10-fold, for example, for Q80K and Q80R) to high (above 100-fold, for example, for D168V and D168A) depending on the residue.…”

Section: Discussionmentioning

confidence: 93%

Rapid HCV-RNA Decline With Once Daily TMC435: A Phase I Study in Healthy Volunteers and Hepatitis C Patients

Reesink

Fanning

Farha³

et al. 2010

Gastroenterology

149

117

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 93%

Rapid HCV-RNA Decline With Once Daily TMC435: A Phase I Study in Healthy Volunteers and Hepatitis C Patients

Reesink

Fanning

Farha³

et al. 2010

Gastroenterology

149

117

View full text Add to dashboard Cite

“…All three TMC435 doses (25,75 and 200 mg QD) in combination with pegIFN/RBV showed antiviral activity superior to pegIFN/RBV alone. Interim analysis of evaluation of the antiviral activity of TMC435 combined with pegIFN-2a/RBV for 28 days in non-responders or relapsers to previous IFN-based therapy also revealed that 4/9 (44%), 7/9 (78%) and 7/10 (70%) patients receiving 75, 150 and 200 mg QD TMC435 in combination with pegIFN-2a/RBV achieved HCV RNA below the lower limit of quantification (\25 IU/mL), compared to 0/9 patients in the pegIFN-2a/RBV group [41]. No serious adverse events or discontinuations due to adverse events were reported.…”

Section: Tmc435mentioning

confidence: 90%

“…HCV SPRINT-1 study Naı¨ve treatment-naïve [27,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][93][94][95][96][97][98] assessed the safety and efficacy of boceprevir, an oral inhibitor of HCV-NS3 protease, plus pegIFN alpha-2b and ribavirin (Table 4). SVR was significantly increased in the 28-and 48-week boceprevir arms compared to pegIFN alpha-2b and RBV control.…”

Section: Boceprevirmentioning

confidence: 99%

New antiviral therapies for chronic hepatitis C

2010

View full text Add to dashboard Cite

Chronic hepatitis C is an important health issue worldwide. The current standard therapy is based on a combination of pegylated-interferon (pegIFN) and ribavirin (RBV), but this treatment leads to only ~50% sustained virological response (SVR) in patients with HCV genotype 1 and high viral loads, who were mostly null-responders or relapsers. Among HCV genotypes other than HCV genotype 1, especially HCV genotype 4 patients show only 40-70% SVR by this treatment. Although new drugs also depend on the combination of pegIFN and RBV, it appears that these drugs improve not only rapid virological response (RVR) but also early virological response, leading to SVR in these patients. In the near future, we predict higher SVR rates in chronic hepatitis C patients treated with these new drugs.

show abstract

“…In vitro replicon studies have shown that the use of TMC435 with IFN-␣ and an HCV NS5B polymerase inhibitor results in synergistic activity and that the use of TMC435 with ribavirin results in additive activity (21). In clinical studies, a once-a-day dosing schedule of TMC435 has shown potent antiviral activity in genotype 1-infected treatment-naïve and treatment-experienced patients when it is used alone and in combination with Peg-IFN-␣/ribavirin (30,32,42).…”

mentioning

confidence: 99%

In Vitro Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor TMC435

Lenz¹,

Verbinnen²,

Lin³

et al. 2010

Antimicrob Agents Chemother

207

218

View full text Add to dashboard Cite

TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC 50 s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to ϳ2,000-fold for those with the D168V or D168I mutation, compared to the EC 50 for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC 50 s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC 50 s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.Hepatitis C is a blood-borne infection that can ultimately result in severe liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma (7). The chronic nature of the disease and the significant possibility of long-term liver damage have led to the current global health burden, with an estimated 180 million people being infected, of whom 130 million are chronic hepatitis C virus (HCV) carriers (54).The current standard-of-care therapy for HCV-infected patients consists of a combination of weekly injected pegylated alpha interferon (Peg-IFN-␣) and twice-daily oral ribavirin. Treatment of HCV genotype 1-infected patients with this regimen for 48 weeks has a limited success rate (a 40 to 50% sustained virological response [SVR]) and is associated with a wide range of side effects, including flu-like symptoms, anemia, and depression, leading to treatment discontinuation in a significant proportion of patients (31, 48). Therefore, specifically targeted antiviral therapies for hepatitis C (STAT-C) have been a major focus of drug discovery efforts. Treatments with several NS3/4A protease inhibitors and NS5A and NS5B polymerase inhibitors, alone or in combination with Peg-IFN-␣-ribavirin, have recently shown encouraging results in clinical trials (17,36).HCV NS3 is an essential, bifunctional, multidomain protein that possesses protease and RNA helicase activiti...

show abstract

1058 Antiviral Activity and Safety of Tmc435 Combined With Peginterferon Alpha-2a and Ribavirin in Patients With Genotype 1 Hepatitis C Infection Who Failed Previous Ifn-Based Therapy

Cited by 14 publications

References 0 publications

Rapid HCV-RNA Decline With Once Daily TMC435: A Phase I Study in Healthy Volunteers and Hepatitis C Patients

Rapid HCV-RNA Decline With Once Daily TMC435: A Phase I Study in Healthy Volunteers and Hepatitis C Patients

New antiviral therapies for chronic hepatitis C

In Vitro Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor TMC435

Contact Info

Product

Resources

About