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Direct-Acting Antiviral Agents (DAA’s)

 

ABT-450

Pre-conference summary:  HCV Protease Inhibitor—Phase I studies.  Studies are underway to assess multiple doses for a 3-day period.  These studies will be followed by ABT-450 in combination with pegylated interferon plus ribavirin for 12 weeks followed by an additional 36 weeks of pegylated interferon plus ribavirin.  All patients are HCV genotype 1 treatment naïve. 

·        1855. Initial antiviral activity of the HCV NS3 protease inhibitor ABT-450 when given with low dose ritonavir as 3-day monotherapy: Preliminary results of study M11-602 in genotype-1 (GT1) HCV-infected treatment-naïve subjects. (Updated November 4, 2010)

·        LB-10.  4-week virologic response and safety of ABT-450 given with low-dose ritonavir (ABT-450/r) in combination with pegylated interferon alpha-2a and ribavirin (SOC) after 3-day monotherapy in genotype 1 (GT1) HCV-infected treatment-naïve subjects (Updated November 4, 2010)

Post-conference highlights:  ABT-450 is a protease inhibitor that is being tested in HCV treatment-naïve genotype 1 subjects as a combination therapy that includes ritonavir (boosting agent) and pegylated interferon plus ribavirin.   For three days the trial participants were given ABT-450 (boosted with ritonavir) at doses ranging from 50 to 200 once a day followed by quadruple therapy of ABT-450 (with ritonavir) plus pegylated interferon and ribavirin for 12 weeks followed by 36 weeks of pegylated interferon.  At the end of week 4, 21 of 23 (91.3%) were HCV RNA negative (<25IU/mL) compared to 1 of 8 (12.5%) of those who received the placebo.  The medications were safe and well-tolerated. 

 

ACH-2684

Pre-conference summary: HCV Protease Inhibitor—no data available

·        1859. ACH-2684: HCV NS3 Protease Inhibitor with Potent Activity against Multiple Genotypes and Known Resistant Variants.  (Updated November 8, 2010)

Post-conference highlights:  ACH-2684 was found to be active against genotypes 1 to 6 (pan genotypic) and was found to work with multiple protease inhibitors.  The development of the drug will move forward.

 

ACH-2928

Pre-conference summary:  HCV NS5A Inhibitor—no data available

·        1880. In Vitro Combination Studies of ACH-1625 (HCV NS3 Protease Inhibitor) and ACH-2928 (HCV NS5A inhibitor) in Presence and Absence of Ribavirin(Updated November 8, 2010)

Post-conference highlights:  It was found that when ACH-1655 (protease inhibitor) and ACH2928 (NS5A inhibitor) were combined there was a synergistic affect that was enhanced when combined with ribavirin. 

 

ANA598

Pre-conference summary:  HCV Polymerase Inhibitor—Phase II studies.  In a small study of people who received triple therapy of ANA598, pegylated interferon and ribavirin 75% of patients taking the twice-daily dose of 400 mg were HCV RNA after 12 weeks.

·        31. Safety and Antiviral Activity of ANA598 in Combination with Pegylated Interferon α2A Plus Ribavirin in Treatment-Naïve Genotype-1 Chronic HCV Patients  (Updated November 5, 2010)

·        1852. IL28B Polymorphism and Kinetics of Antiviral Activity for ANA598 in Combination With Pegylated Interferon α2A Plus Ribavirin in Treatment-Naïve Genotype-1 Chronic HCV Patients. 

Post-conference highlights:  There is an ongoing study of ANA598 (in multiple doses) combined with pegylated interferon plus ribavirin.  29 HCV genotype 1 treatment-naïve patients received the triple therapy for 12 weeks and were randomized (depending of treatment response) to an additional 12 or 36 weeks.  The SVR 12 results in the patients who completed 24 weeks of treatment was 73% (in eight patients).  The most common side effect was rash and it was observed in 59% of the patients who received the 400 mg dose. 

 

BI 201335

Pre-conference summary:  HCV Protease Inhibitor—Phase II studies.  Interim 12 week results of 280 HCV genotype 1 prior non-responders who will be treated for a total of 24 weeks with BI 201335 in combination with pegylated interferon plus ribavirin found that 54 to 59% were HCV RNA negative at week 12.  

·        804. Virological Response and Safety of 4 weeks treatment with the protease inhibitor BI 201335 combined with 48 weeks of Peginterferon alfa 2a and Ribavirin for treatment of HCV GT-1 patients who failed peginterferon / ribavirin. 

 

BI 207127

Pre-conference summary:  HCV Polymerase Inhibitor—Phase II studies.  In a 5 day monotherapy study of HCV Genotype 1 patients a median 3.8 log10 viral load decrease was reported. 

·        LB-7. Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127 and ribavirin in patients with chronic hepatitis C (Updated November 1, 2010)

·        1862. Genotypic and phenotypic analysis of the NS5B polymerase region from viral isolates of HCV chronically infected patients treated with BI 207127 for 5-days monotherapy (Updated November 8, 2010)

Post-conference highlights:  In this study (without interferon) the triple regime of BI 201335 (protease inhibitor) plus BI 207127 (polymerase inhibitor) and ribavirin to treat HCV genotype 1 treatment-naïve patients was found to provide strong antiviral activity—additional studies with longer durations are planned to evaluate sustained virological response rates. 

 

BMS-65032 (HCV Protease Inhibitor); BMS-650032 (Protease Inhibitor); BMS-790052 (NS5a inhibitor); BMS-791325 (Polymerase Inhibitor); BMS-824393 (NS5A Inhibitor)

Pre-conference summary:  BMS has multiple drugs in Phase I and Phase II studies combined with pegylated interferon and ribavirin and in combination studies of their DDA’s without pegylated interferon or ribavirin.

·        LB-8. Combination therapy with BMS-790052 and BMS-650032 alone or with pegIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders (Updated November 4, 2010)

·        827. Co-administration of BMS-790052 and BMS-650032 does not result in a Clinically Meaningful Pharmacokinetic Interaction in Healthy Subjects.  (Updated October 31, 2010)

·        1853. Genotypic and Phenotypic analysis of HCV NS5A Inhibitor Resistance Variants: Correlations Between In vitro and In vivo Observations.

·        1858. BMS-824393 is a Potent Hepatitis C Virus NS5A Inhibitor with Substantial Antiviral Activity when given as Monotherapy in Subjects with Chronic G1 HCV Infection (Updated November 8, 2010)

·        1881. BMS-790052, a First-in Class Potent Hepatitis C Virus NS5A Inhibitor, Demonstrates Multiple-Dose Proof-of-Concept in Subjects with Chronic GT1 HCV infection.  

Post-conference highlights: In an important study the combination of BMS-650032 (protease inhibitor) and BMS-790052 was given to genotype 1 null-responders to a prior course of therapy.  The interim results at 12 weeks (total study duration is 24 weeks) produced early antiviral activity, but 6 out of the 11 people treated had viral breakthrough indicating that pegylated interferon and/or ribavirin will be needed to completely suppress the virus at least in this study.  When the combination was combined with pegylated interferon and ribavirin 9 out of 10 patients became HCV RNA undetectable by week 12.

 

Boceprevir

Pre-conference summary:  HCV Protease Inhibitor—Top line results from 2 Phase III studies of boceprevir, pegylated interferon plus ribavirin used to treat HCV genotype 1 patients reported that in treatment naïve patients (never been treated) 63 to 66% of patients achieved an SVR; People who had been treated with a prior course of pegylated interferon plus ribavirin, but did not achieve an SVR and who were treated with the triple combination achieved 59-66% SVR rates.  For more information click here to view the boceprevir HCSP Fact Sheet. 

·        LB-15. Response-Guided Therapy (RGT) with Boceprevir (BOC) + Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1 Was Similar to a 48-Wk Fixed-Duration Regimen with BOC + P/R in SPRINT-2. (Updated November 9, 2010)

·        LB-4. Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results.

·        216. HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/Ribavirin (Updated November 9, 2010)

·        801. Frequencies of Resistance-Associated Amino Acid Variants Following Combination Treatment with Boceprevir Plus PEGINTRON (PegInterferon Alfa-2b)/Ribavirin in Patients With Chronic Hepatitis C (CHC), Genotype 1 (G1).

·        1871. Impact of ribavirin on HCV replicon RNA decline during treatment with Interferon alfa and the protease inhibitors boceprevir or telaprevir.  

 

Danoprevir (RG7227)

Pre-conference summary:  HCV Protease Inhibitor—Phase II studies.  Currently in combination with pegylated interferon plus ribavirin and ritonavir (boosting agent).  A small study found that after 15 days of treatment that 50% to 100% of patients were HCV RNA negative. 

·        802. Low rate of viral load rebound observed among treatment-naive genotype 1 patients with chronic hepatitis C treated with danoprevir (RG7227) plus PegIFN α-2a (40KD) (PEGASYS®) plus ribavirin: interim analysis. (Updated November 8, 2010)

·        32. Phase II randomized, partially-blind, parallel-group study of oral danoprevir (RG7227) with PegIFNα-2a (PEGASYS®) plus ribavirin in treatment-naive genotype 1 patients with CHC: Results of planned Week 12 interim analysis of the ATLAS study.  (Updated November 5, 2010)

·        1884. High exposure to danoprevir (RG7227) increases the probability of ALT elevations in patients treated with danoprevir plus PegIFN α-2a (40KD) (PEGASYS) plus ribavirin

Post-conference highlights:  Interim results using various doses of danoprevir combined with pegylated interferon plus ribavirin found that 88 to 92% were HCV RNA negative by week 12 compared to 43% in the placebo group.   More studies are planned including a study using ritonavir as a boosting agent.

 

Filibuvir

Pre-conference summary:  HCV Polymerase Inhibitor—Phase II studies.  Study results from 35 patients who were treated with filibuvir, pegylated interferon and ribavirin found that 75% were HCV RNA negative after 4 weeks of treatment.

·        834. Genotypic characterization of filibuvir (PF-00868554) resistance in patients receiving four weeks co-administration of filibuvir with pegIFN/RBV. 

 

GS-9256/GS-9190

Pre-conference summary:  HCV Protease Inhibitor/Polymerase Inhibitor—Phase II studies.  Studies include GS_9356 with and without ribavirin and the combination of GS-9256 and GS-9190 with and without ribavirin (both regimes contain pegylated interferon)

·        LB-1. Dual, Triple, and Quadruple Combination Treatment with a Protease Inhibitor (GS-9256) and a Polymerase Inhibitor (tegobuvir-GS-9190) alone and in Combination with Ribavirin (RBV) or PegIFN/RBV for up to 28 days in Treatment Naïve, Genotype 1 HCV Subjects (Updated November 8, 2010)

·        824. Safety, pharmacokinetics, and antiviral activity of single oral doses of the HCV NS3 protease inhibitor GS 9256.

·        833. Antiviral Response and Resistance Analysis of Treatment-Naïve HCV Infected Subjects Receiving Single and Multiple Doses of GS-9190.  (Updated October 31, 2010)

·        1867. Enhanced in vitro Antiviral Activity by Combining GS-9256, a Novel Protease Inhibitor, with GS-9190, a Non-nucleoside NS5B Inhibitor.  

·        1876. Characterization of HCV Resistance from Single and Multiple Dose Clinical Trials of GS-9256, a novel NS3 Protease Inhibitor.  

Post-conference highlights:  The combination of GS-9256 (HCV protease inhibitor) plus tegobuvir (GS-9190 – polymerase inhibitor) when combined with pegylated interferon plus ribavirin produced the best results.  The quadruple group was given for 4 weeks followed by 44 weeks of pegylated interferon plus ribavirin.  14 out of 14 patients were HCV RNA negative by day 28.   There is an ongoing 4 month study of the quadruple therapy.

 

IDX184

Pre-conference summary:  HCV Polymerase Inhibitor—Phase II studies –currently the studies are on hold due to safety concerns.

·        34. A Phase IIa Study of IDX184 in Combination with Pegylated Interferon (pegIFN) and Ribavirin (RBV) in Treatment-Naïve HCV Genotype 1-Infected Subjects.  

 

IDX320

Pre-conference summary:  HCV Polymerase Inhibitor—Phase II studies—currently the studies are on hold due to safety concerns. 

 

IDX375

Pre-conference summary:  HCV Polymerase Inhibitor—Phase 1 studies. IDX375 given in 5 doses once daily or twice daily was found the drug to be safe and well-tolerated. 

·        1891. Phase I Study in Healthy Volunteers and Patients with IDX375, a Novel Non-Nucleoside HCV Polymerase Inhibitor (Updated November 8, 2010)

 

IMO-2125

·        33. IMO-2125, a TLR9 Agonist, Induces Immune Responses which Correlate with Reductions in Viral Load in Null Responder HCV Patients

 

INX-189

Pre-conference summary:  HCV Polymerase InhibitorPhase I studies.  INX-189 was found to be safe and well-tolerated and had the potential for a once-a-day dose.

·        1874. Metabolite Characterization of INX-189, a Potent HCV Inhibitor, in Fresh Human Primary Hepatocytes and Human Liver and Kidney Cell Lines.  

 

MK-3281

Pre-conference summary:  HCV Polymerase Inhibitorphase I study results from a small group of 22 HCV treatment-naive and treatment-experienced patients.  In the genotype 1b group there was found to be a 3.75 log10 decrease in HCV RNA. 

 

MK-5172

Pre-conference summary:  HCV Protease Inhibitor—no data available

·        807. Safety and Antiviral Activity of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-infected Patients. 

·        1885. Safety, Tolerability, and Pharmacokinetics after Single and Multiple Doses of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Healthy Subjects.  

 

MK-7009 (Vaniprevir)

Pre-conference summary:  NS3/4a Protease Inhibitor —no data available

·        82. Sustained Viral Response (SVR) Rates in Genotype 1 Treatment-naïve Patients with Chronic Hepatitis C (CHC) Infection Treated with Vaniprevir (MK-7009), a NS3/4a Protease Inhibitor, in Combination with Pegylated Interferon Alfa-2a and Ribavirin for 28 Days (Updated November 2, 2010)

Post-conference highlights:  Vaniprevir—A study of 45 HCV genotype 1 treatment-naïve patients who were administered 1 of 5 regimens—placebo, 300 mg BID (twice a day), 600 mg BID, 600 mg QD (once a day) or 800QD in combination with pegylated interferon plus ribavirin for 4 weeks followed by an additional 44 weeks of pegylated interferon resulted in SVR rates of 78 to 84% compared to 63% in the placebo (only pegylated interferon and ribavirin).  Note:  the high SVR rate in the placebo group is likely due to the small patient population in this group. 

 

PPI-461

Pre-conference summary:  NS5A Inhibitor —no data available

·        LB-12. Safety and Pharmacokinetics of PPI-461, a Potent New Hepatitis C Virus (HCV) NS5A Inhibitor with Pan-Genotype Activity (Updated November 8, 2010)

Post-conference highlights:  A total of forty healthy volunteers were given PPI-461, an NS5A inhibitor for up to 5 days and it was found that the plasma levels of PPI-461 were reached within 1-4 hours.  No serious adverse events were noted.  PPI-461 is pan-genotypic (activity against all genotypes).  This study warranted exploring a once-a-day dosing in HCV patients.  

 

PSI-352938

Pre-conference summary:  HCV Polymerase Inhibitor—no data available

·        1890. Pharmacokinetics, Safety, and Tolerability of PSI-352938, a Novel Nucleotide Polymerase Inhibitor for HCV, Following Single Ascending Oral Doses in Healthy Subjects.  (Updated November 8, 2010)

Post-conference highlights:  PSI-352938, a protease inhibitor, was tested in healthy volunteers at doses ranging from 25 to 1600 mg and was found to be generally safe and well-tolerated. Based on this study a mono-therapy study is being conducted in genotype 1 patients. 

 

PSI-7977

Pre-conference summary:  HCV Polymerase Inhibitor—in Phase IIa studies.  PSI-7977 used in combination with pegylated interferon plus ribavirin for the treatment of people with HCV genotype 1 treatment naïve (never been treated) patients.  Interim results found that 88 to 94% of patients were HCV RNA negative after 28 days of treatment. 

·        806. High Rapid Virologic Response (RVR) with PSI-7977 QD plus PEG-IFN/RBV in a 28-day Phase 2a Trial.  (Updated October 31, 2010)

·        815. IL28B SNP Geographical Distribution and Antiviral Responses in a 28-day Phase 2a Trial of PSI-7977 Daily Dosing plus PEG-IFN/RBV.  (Updated November 8, 2010)

·        1861. Clinical synergy of an Anti-HCV Nucleoside Analog with SOC: Viral Kinetics of PSI-7977 with SOC (Updated November 8, 2010)

Post-conference highlights:  PSI-7977, a polymerase inhibitor, dosed once a day (100, 200 and 400 mg) combined with pegylated interferon plus ribavirin for 28 days produced 4 week RVRs of 88 to 94% compared to 21% in the pegylated interferon plus ribavirin group (without PSI-7977).  AT week 12 the cEVR (complete early virological response) was highest in the 200 mg QD (94%) and 400 (87%) compared to 64% cEVR in the pegylated interferon plus ribavirin (placebo) group.  Based on these results a 12 week study is being planned.  In addition PSI-7977 appears to work against different genotypes. 

 

RG7128

Pre-conference summary:  HCV Polymerase Inhibitor—Phase II studies.  The studies will enroll 400 HCV genotype 1 or 4 patients in combination with Pegasys/ribavirin.  Interim results found that more than 80% of patients were HCV RNA undetectable after 12 weeks of treatment with the triple combination therapy.

·        799. No evidence of drug resistance or baseline S282T resistance mutation among GT1 and GT4 HCV infected patients on nucleoside polymerase inhibitor RG7128 and Peg-IFN/RBV combination treatment for up to 12 weeks: Interim analysis from the PROPEL study

·        81. High rates of early viral response, promising safety profile and lack of resistance-related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12 interim analysis from the PROPEL study. (Updated November 5, 2010)

Post-conference highlights:  RG7128 (500 or 1000 mg - BID) combined with pegylated interferon plus ribavirin was given in different doses and time lines based on response and it was found that RG7128 was safe and well-tolerated in HCV genotype 1 and 4 treatment-naïve patients with and without cirrhosis.  The group that received the 8 or the 12 week regime of 1000 mg BID achieved the highest declines in HCV RNA (viral load) levels.  RG7128 appears to have a high barrier to drug resistance.   

 

SCY-635

Pre-conference summary:  Cyclophilin Inhibitor —no data available

·        36. The Non-Immunosuppressive Cyclophilin Inhibitor SCY-635 Inhibits the Association of NS5A and Cyclophilin A

 

Telaprevir

Pre-conference summary:  HCV Protease Inhibitor—Phase III studies. Top line results from 3 clinical trials of the triple combination of telaprevir, pegylated interferon plus ribavirin in people with HCV Genotype 1 found that in treatment naïve patients (never been treated) there was a sustained virological response (SVR) of 69-75% and up to 76% SVR in people who had been treated with pegylated interferon plus ribavirin but who did achieve an SVR. For more information click here to view the Telaprevir HCSP Fact Sheet.

·        LB-11. Clinical Virology Results from Telaprevir Phase 3 Study ADVANCE.

·        LB-2. Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naïve Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response: Final Results of Phase 3 ILLUMINATE Study (Updated November 9, 2010)

·        211. Telaprevir in Combination with Peginterferon and Ribavirin in Genotype 1 HCV Treatment-Naïve Patients: Final Results of Phase 3 ADVANCE Study.   (Updated November 9, 2010)

·        227. Long-term Follow-up of Patients with Chronic Hepatitis C Treated with Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin: Interim Analysis of the EXTEND Study.  (Updated November 2, 2010)

·        805. No Impact of Insulin Resistance on Antiviral Efficacy of Telaprevir-based regimen in HCV Genotype 1 Treatment-Naive Patients: Subanalysis of C208 Study. 

·        828. Activity of Telaprevir Monotherapy or in Combination with Peginterferon-alfa-2a and Ribavirin in Treatment-naïve Genotype 4 Hepatitis-C Patients: Final Results of Study C210

·        1871. Impact of ribavirin on HCV replicon RNA decline during treatment with Interferon alfa and the protease inhibitors boceprevir or telaprevir.  

Post-conference highlights:  Telaprevir – see HCSP Fact Sheet.

 

TMC435

Pre-conference summary:  HCV Protease Inhibitor—Phase IIa studies.  Interim data (SVR12) from a 24-week triple combination therapy of TMC435, pegylated interferon and ribavirin to treat HCV genotype 1 treatment naïve patients found that in those patients who completed the entire 24 treatment duration achieved a 80% to 90% SVR12. 

·        LB-5. Efficacy and safety of TMC435 in combination with peginterferon α-2a and ribavirin in treatment-naïve genotype-1 HCV patients: 24-week interim results from the PILLAR study. 

·        812. Virologic analysis of genotype-1-infected patients treated with once-daily TMC435 during the Optimal Protease inhibitor Enhancement of Response to therApy (OPERA)-1 study.  (Updated October 31, 2010)

·        1873. Pharmacokinetic-pharmacodynamic analyses of TMC435 in patients infected with hepatitis C virus (HCV) genotypes 2 to 6.  

Post-conference highlights:  Interim results for a study of TMC435 (75 and 150 mg QD) combined with pegylated interferon plus ribavirin given for up to 24 weeks produced significant viral load reductions.  In patients who completed 24 weeks treatment or stopped treatment for any reason by week 24 the SVR results ranged from 88 to 97% (119 out of 130 patients). So far there is a low rate of viral breakthrough.