Fri
16
Nov
Despite improvements in treatment in recent years of hepatitis C patients , currently treatment with pegylated interferon and ribavirin presents failures in sustained viral response (approximately 50% for genotype 1 and 20% for genotype 2 and 3)
In the last (2007) Meeting of the AASLD were introduced 16 new treatments under development. Providing hope for patients who did not respond to therapy today. Below are summarized the new treatments.
1)Albinterferon
Albinterferon alfa (alb-IFN) is a novel recombinant protein consisting of IFNa-2b genetically fused to human albumin.
Alb-IFN in combination with oral RBV is safe and effective. Treatment with 1800mcg Q2w demonstrates significant antiviral activity in prior IFNa non-responder patients.
2)Bavituximab
Bavituximab, an investigational monoclonal antibody targeting phosphatidylserine (PS) located on the surface of virus infected cells and enveloped viruses, is being developed as an anti-HCV agent.
wice weekly IV doses of bavituximab up to 6 mg/kg were safe and well-tolerated. Single-dose and multiple dose pharmacokinetics of bavituximab are linear, predictable and no accumulation appears to occur over time. Two weeks of dosing is indicative of antiviral effect in a proportion of patients. Future studies designed to optimize the dosing schedule and investigate combining bavituximab with current standard therapy are planned.
3)Glycyrrhizin
A significant number of patients with chronic hepatitis C genotype 1 fail to respond to the standard therapy of PEG-IFN- plus RBV, or cannot be treated for various reasons. There are no options for non-responders to previous standard therapies. Glycyrrhizin (GL) is used in Japan for more than 20 years to treat such cases (SNMC, Minophagen).
GL appears to be effective and well tolerated in the treatment of chronic hepatitis C not responding to IFN or PEG-IFN plus RBV therapy.
4)Infergen
Consensus interferon (CIFN; infergen, interferon alfacon1) demonstrates enhanced activity in vitro compared with other alfa interferons. Genotype 1 patients may benefit from an interferon with increased activity, more favorable viral kinetics from daily dosing, and a longer duration of therapy.
Patients with hepatitis C genotype 1 and "difficult-to-treat" characteristics treated with daily CIFN+RBV demonstrated a high RVR rate, with 33% virus-negative at 4 wks and 67% virus negative by 24 wks. This compares favorably with RVR rates of 19-22% for genotype 1 patients treated with pegylated interferon alfa-2a and ribavirin (Gastroenterology 2006;130:1086 and 131:451). Although adherence and tolerability are limitations, these data indicate that daily CIFN+RBV for initial treatment of U.S. genotype 1 patients have promise primarily via an enhanced RVR rate. (Supported by Valeant Pharmaceuticals; Veterans Affairs Research Service)
5)Infliximab
High levels of TNF may contribute to the pathogenesis of hepatitis C virus (HCV) infection. This study evaluated the safety of infliximab in HCV-infected patients and assessed the effect of infliximab induction therapy on early virologic response and sustained virologic response (SVR).
The anti-TNF effect of infliximab on HCV may provide viral decline during the first 8 weeks of HCV therapy. It is unknown whether infliximab treatment before combination PEG-2b + RBV therapy will translate into greater SVR rates.
6)Locteron
Controlled-release recombinant interferon-alfa 2b (Locteron) is a novel approach to delivery of interferon (IFN) given every 2 weeks with improved tolerability combined with a high level of hepatitis C virus (HCV)RNA reduction.
Locteron, a controlled-release formulation of unmodified IFN-alfa 2b, administered every 2 weeks to treatment-na ve patients with chronic hepatitis C (genotype 1) demonstrated strong anti-viral activity combined with an improved safety and tolerability profile compared to currently marketed IFNs and those in development.
7)Nitazoxanide
Nitazoxanide (NTZ), a thiazolide anti-infective agent approved in the United States for treating emerging intracellular protozoan infections, blocks viral protein synthesis at a cellular level by selectively inhibiting dephosphorylation of eukaryotic initiation factor 2 (eIF2 ).
The addition of NTZ to PegIFN or PegIFN-RBV improved RVR, EVR and ETR rates compared with PegIFN-RBV therapy without increase in adverse events. Patients are being followed to evaluate SVR rates. Further trials are being conducted in the United States in patients with genotype 1.
8)HCV Polymerase ( NM107 ) and Protease ( Boceprevir ) Inhibitors
Combination of small-molecule antiviral agents directed against different molecular targets offer an attractive strategy for the effective therapy of hepatitis C. As monotherapies, valopicitabine (NM283) (Idenix/Novartis), an investigational nucleoside NS5B polymerase inhibitor, and boceprevir (SCH 503034) (Schering-Plough), an investigational NS3 protease inhibitor, have demonstrated antiviral activity against hepatitis C virus (HCV) in clinical studies.
In these in vitro studies, the combination of the polymerase and protease inhibitors showed enhanced anti-replicon activity with no cross-resistance and a greater genetic barrier to resistance. These results support clinical evaluation of this combination in patients with chronic hepatitis C.
9)R1626
The novel nucleoside, R1626, is a potent inhibitor of the HCV RNA polymerase. When administered as monotherapy to patients with chronic hepatitis C, R1626 demonstrates dose-dependent decreases in HCV RNA blood levels.
This Phase 2a study evaluated the safety and efficacy of R1626 administered for 4 weeks in combination with 180 g peginterferon alfa-2a (PEG-IFN -2a) 1000-1200 mg ribavirin (RBV) in HCV genotype 1 treatment-naive patients.
A robust synergistic antiviral effect was observed when R1626 is combined with PEG-IFN -2a RBV, with up to 81% of patients undetectable by week 4. Dosing of R1626 may be limited mainly by neutropenia; additional studies of different dosages of R1626 in combination with PEG-IFN -2a and RBV are underway.
10)R7025
R7025 is a novel human pegylated IFN molecule generated using DNA Shuffling (Maxygen, Inc.) technology that exhibits ~50-fold higher antiviral activity compared to PEG-IFN -2a
R7025 doses up to 80 g were well tolerated with 20 g being the lowest pharmacologically active single dose studied. R7025 doses of 40 g and greater produced a level of serum neopterin and 2,5 OAS induction which was comparable to a 180 g dose of PEG IFN -2a. Most AEs were mild and consistent with those observed after administration of IFN . At a dose of 120 g transient severe flu-like symptoms were observed. Changes in hematological parameters observed across all doses were mild and reversible. The findings from this study warrant further evaluation of R7025 in CHC patients.
11)R7227
Is a potent HCV NS3/4A protease inhibitor in clinical development.
ITMN-191 is a highly potent, slowly dissociating inhibitor of the HCV NS3/4A protease. The strong inhibition of genotype 1-6 proteases supports the use of ITMN-191 to treat multiple genotypes of HCV.
12)R7128
R7128 is a prodrug of PSI-6130, an oral cytidine nucleoside analog polymerase inhibitor, currently in development for the treatment of HCV.
All subjects had HCV genotype 1 , had previously failed alpha-interferon and were non-cirrhotic. There were no SAEs reported and no AEs required dose modification; no clinically significant changes in vital signs, ECGs, hematology, renal or other laboratory parameters occurred. Preliminary data on adverse events (AEs) reported during treatment in subjects receiving R7128 include a total of 32 events in 14 of 24 subjects, most of mild intensity as compared to 26 events in 5 subjects receiving placebo. 18 AEs were reported in 7 subjects that received 750mg QD, 3 AEs in 3 subjects receiving 1500mg QD, and 11 AEs in 4 subjects receiving 750mg BID. The most frequently reported AEs for patients receiving R7128 were headache , dry mouth , nausea, and upper respiratory infection ; in subjects on placebo, headache (3) and diarrhea (3) were most commonly reported. The baseline HCV RNA concentrations, ranging from 5.2 to 7.4 (log10 IU/mL), and mean change from baseline observed, ranging from -0.7 to -2.9 (log10 IU/mL) for active, are summarized in the table below. Plasma exposure to the prodrug, R7128, was negligible; exposure to PSI-6130 and a uridine metabolite, PSI-6206, increased with increasing doses of R7128. Terminal half-life was approximately 5 h for PSI-6130 and 20 h for PSI-6206. Conclusion: R7128 monotherapy was generally well-tolerated and resulted in significant, dose-dependent suppression of HCV replication following 14 days of monotherapy. These results support continued development of R7128 for the treatment of HCV infection in combination with pegylated interferon and ribavirin. Results for the 1500 BID cohort will be available for presentation.
13)Telaprevir
Telaprevir (TVR) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease with highly effective blocking of HCV replication in patients with hepatitis C.
In patients treated with TVR with and without peginterferon alfa 2a for 2 weeks followed by standard therapy with peginterferon and RBV for 24 or 48 weeks mutations conferring resistance to TVR can be detected after relapse. The significance of TVR resistance mutations for the probability of relapse has to be investigated in future studies.
14)Thymosin alpha – 1
Early pilot studies suggested that an immunomodulatory peptide, thymosin alpha-1 (TA-1) may play a role in enhanced viral clearance, histologic improvement and sustained viral response.
Among treatment experienced subjects with HCV infection, retreatment with PEG + TA-1 resulted in a similar sustained virologic response when compared to use of PEG monotherapy. Studies utilizing PEG, TA-1 and ribavirin are in progress.
15)Valopicitabine
Future HCV therapy will likely combine drugs with different modes of action and complementary resistance profiles. We investigated the pharmacokinetics, antiviral activity and safety of valopicitabine, an investigational NS5B polymerase inhibitor, combined with PegIFN and RBV.
Valopicitabine combined with PegIFN/RBV demonstrated additive antiviral activity. HCV RNA PCR-negativity rates at all timepoints were consistently greater in the triple regimen compared with PegIFN/RBV. However, the incidence of GI-related adverse events and lab abnormalities was higher in the valopicitabine-containing arms. After comprehensive review of the valopicitabine clinical program, the development of this molecule has been discontinued due to its overall risk/benefit profile.
16)VCH – 759
VCH-759 is a novel, orally bioavailable non-nucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. It has demonstrated sub-micromolar IC50s against the HCV replicons of genotype 1a and 1b.
VCH 759 achieved a 2 log10 or larger decline in HCV RNA at doses of 800 mg tid and bid. VCH-759 was well tolerated with no serious adverse events and no discontinuation. Genetic sequencing of NS5B is ongoing. Further studies combining VCH-759 with current therapies are warranted.
This post may contain sponsored links
In the last (2007) Meeting of the AASLD were introduced 16 new treatments under development. Providing hope for patients who did not respond to therapy today. Below are summarized the new treatments.
1)Albinterferon
Albinterferon alfa (alb-IFN) is a novel recombinant protein consisting of IFNa-2b genetically fused to human albumin.
Alb-IFN in combination with oral RBV is safe and effective. Treatment with 1800mcg Q2w demonstrates significant antiviral activity in prior IFNa non-responder patients.
2)Bavituximab
Bavituximab, an investigational monoclonal antibody targeting phosphatidylserine (PS) located on the surface of virus infected cells and enveloped viruses, is being developed as an anti-HCV agent.
wice weekly IV doses of bavituximab up to 6 mg/kg were safe and well-tolerated. Single-dose and multiple dose pharmacokinetics of bavituximab are linear, predictable and no accumulation appears to occur over time. Two weeks of dosing is indicative of antiviral effect in a proportion of patients. Future studies designed to optimize the dosing schedule and investigate combining bavituximab with current standard therapy are planned.
3)Glycyrrhizin
A significant number of patients with chronic hepatitis C genotype 1 fail to respond to the standard therapy of PEG-IFN- plus RBV, or cannot be treated for various reasons. There are no options for non-responders to previous standard therapies. Glycyrrhizin (GL) is used in Japan for more than 20 years to treat such cases (SNMC, Minophagen).
GL appears to be effective and well tolerated in the treatment of chronic hepatitis C not responding to IFN or PEG-IFN plus RBV therapy.
4)Infergen
Consensus interferon (CIFN; infergen, interferon alfacon1) demonstrates enhanced activity in vitro compared with other alfa interferons. Genotype 1 patients may benefit from an interferon with increased activity, more favorable viral kinetics from daily dosing, and a longer duration of therapy.
Patients with hepatitis C genotype 1 and "difficult-to-treat" characteristics treated with daily CIFN+RBV demonstrated a high RVR rate, with 33% virus-negative at 4 wks and 67% virus negative by 24 wks. This compares favorably with RVR rates of 19-22% for genotype 1 patients treated with pegylated interferon alfa-2a and ribavirin (Gastroenterology 2006;130:1086 and 131:451). Although adherence and tolerability are limitations, these data indicate that daily CIFN+RBV for initial treatment of U.S. genotype 1 patients have promise primarily via an enhanced RVR rate. (Supported by Valeant Pharmaceuticals; Veterans Affairs Research Service)
5)Infliximab
High levels of TNF may contribute to the pathogenesis of hepatitis C virus (HCV) infection. This study evaluated the safety of infliximab in HCV-infected patients and assessed the effect of infliximab induction therapy on early virologic response and sustained virologic response (SVR).
The anti-TNF effect of infliximab on HCV may provide viral decline during the first 8 weeks of HCV therapy. It is unknown whether infliximab treatment before combination PEG-2b + RBV therapy will translate into greater SVR rates.
6)Locteron
Controlled-release recombinant interferon-alfa 2b (Locteron) is a novel approach to delivery of interferon (IFN) given every 2 weeks with improved tolerability combined with a high level of hepatitis C virus (HCV)RNA reduction.
Locteron, a controlled-release formulation of unmodified IFN-alfa 2b, administered every 2 weeks to treatment-na ve patients with chronic hepatitis C (genotype 1) demonstrated strong anti-viral activity combined with an improved safety and tolerability profile compared to currently marketed IFNs and those in development.
7)Nitazoxanide
Nitazoxanide (NTZ), a thiazolide anti-infective agent approved in the United States for treating emerging intracellular protozoan infections, blocks viral protein synthesis at a cellular level by selectively inhibiting dephosphorylation of eukaryotic initiation factor 2 (eIF2 ).
The addition of NTZ to PegIFN or PegIFN-RBV improved RVR, EVR and ETR rates compared with PegIFN-RBV therapy without increase in adverse events. Patients are being followed to evaluate SVR rates. Further trials are being conducted in the United States in patients with genotype 1.
8)HCV Polymerase ( NM107 ) and Protease ( Boceprevir ) Inhibitors
Combination of small-molecule antiviral agents directed against different molecular targets offer an attractive strategy for the effective therapy of hepatitis C. As monotherapies, valopicitabine (NM283) (Idenix/Novartis), an investigational nucleoside NS5B polymerase inhibitor, and boceprevir (SCH 503034) (Schering-Plough), an investigational NS3 protease inhibitor, have demonstrated antiviral activity against hepatitis C virus (HCV) in clinical studies.
In these in vitro studies, the combination of the polymerase and protease inhibitors showed enhanced anti-replicon activity with no cross-resistance and a greater genetic barrier to resistance. These results support clinical evaluation of this combination in patients with chronic hepatitis C.
9)R1626
The novel nucleoside, R1626, is a potent inhibitor of the HCV RNA polymerase. When administered as monotherapy to patients with chronic hepatitis C, R1626 demonstrates dose-dependent decreases in HCV RNA blood levels.
This Phase 2a study evaluated the safety and efficacy of R1626 administered for 4 weeks in combination with 180 g peginterferon alfa-2a (PEG-IFN -2a) 1000-1200 mg ribavirin (RBV) in HCV genotype 1 treatment-naive patients.
A robust synergistic antiviral effect was observed when R1626 is combined with PEG-IFN -2a RBV, with up to 81% of patients undetectable by week 4. Dosing of R1626 may be limited mainly by neutropenia; additional studies of different dosages of R1626 in combination with PEG-IFN -2a and RBV are underway.
10)R7025
R7025 is a novel human pegylated IFN molecule generated using DNA Shuffling (Maxygen, Inc.) technology that exhibits ~50-fold higher antiviral activity compared to PEG-IFN -2a
R7025 doses up to 80 g were well tolerated with 20 g being the lowest pharmacologically active single dose studied. R7025 doses of 40 g and greater produced a level of serum neopterin and 2,5 OAS induction which was comparable to a 180 g dose of PEG IFN -2a. Most AEs were mild and consistent with those observed after administration of IFN . At a dose of 120 g transient severe flu-like symptoms were observed. Changes in hematological parameters observed across all doses were mild and reversible. The findings from this study warrant further evaluation of R7025 in CHC patients.
11)R7227
Is a potent HCV NS3/4A protease inhibitor in clinical development.
ITMN-191 is a highly potent, slowly dissociating inhibitor of the HCV NS3/4A protease. The strong inhibition of genotype 1-6 proteases supports the use of ITMN-191 to treat multiple genotypes of HCV.
12)R7128
R7128 is a prodrug of PSI-6130, an oral cytidine nucleoside analog polymerase inhibitor, currently in development for the treatment of HCV.
All subjects had HCV genotype 1 , had previously failed alpha-interferon and were non-cirrhotic. There were no SAEs reported and no AEs required dose modification; no clinically significant changes in vital signs, ECGs, hematology, renal or other laboratory parameters occurred. Preliminary data on adverse events (AEs) reported during treatment in subjects receiving R7128 include a total of 32 events in 14 of 24 subjects, most of mild intensity as compared to 26 events in 5 subjects receiving placebo. 18 AEs were reported in 7 subjects that received 750mg QD, 3 AEs in 3 subjects receiving 1500mg QD, and 11 AEs in 4 subjects receiving 750mg BID. The most frequently reported AEs for patients receiving R7128 were headache , dry mouth , nausea, and upper respiratory infection ; in subjects on placebo, headache (3) and diarrhea (3) were most commonly reported. The baseline HCV RNA concentrations, ranging from 5.2 to 7.4 (log10 IU/mL), and mean change from baseline observed, ranging from -0.7 to -2.9 (log10 IU/mL) for active, are summarized in the table below. Plasma exposure to the prodrug, R7128, was negligible; exposure to PSI-6130 and a uridine metabolite, PSI-6206, increased with increasing doses of R7128. Terminal half-life was approximately 5 h for PSI-6130 and 20 h for PSI-6206. Conclusion: R7128 monotherapy was generally well-tolerated and resulted in significant, dose-dependent suppression of HCV replication following 14 days of monotherapy. These results support continued development of R7128 for the treatment of HCV infection in combination with pegylated interferon and ribavirin. Results for the 1500 BID cohort will be available for presentation.
13)Telaprevir
Telaprevir (TVR) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease with highly effective blocking of HCV replication in patients with hepatitis C.
In patients treated with TVR with and without peginterferon alfa 2a for 2 weeks followed by standard therapy with peginterferon and RBV for 24 or 48 weeks mutations conferring resistance to TVR can be detected after relapse. The significance of TVR resistance mutations for the probability of relapse has to be investigated in future studies.
14)Thymosin alpha – 1
Early pilot studies suggested that an immunomodulatory peptide, thymosin alpha-1 (TA-1) may play a role in enhanced viral clearance, histologic improvement and sustained viral response.
Among treatment experienced subjects with HCV infection, retreatment with PEG + TA-1 resulted in a similar sustained virologic response when compared to use of PEG monotherapy. Studies utilizing PEG, TA-1 and ribavirin are in progress.
15)Valopicitabine
Future HCV therapy will likely combine drugs with different modes of action and complementary resistance profiles. We investigated the pharmacokinetics, antiviral activity and safety of valopicitabine, an investigational NS5B polymerase inhibitor, combined with PegIFN and RBV.
Valopicitabine combined with PegIFN/RBV demonstrated additive antiviral activity. HCV RNA PCR-negativity rates at all timepoints were consistently greater in the triple regimen compared with PegIFN/RBV. However, the incidence of GI-related adverse events and lab abnormalities was higher in the valopicitabine-containing arms. After comprehensive review of the valopicitabine clinical program, the development of this molecule has been discontinued due to its overall risk/benefit profile.
16)VCH – 759
VCH-759 is a novel, orally bioavailable non-nucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. It has demonstrated sub-micromolar IC50s against the HCV replicons of genotype 1a and 1b.
VCH 759 achieved a 2 log10 or larger decline in HCV RNA at doses of 800 mg tid and bid. VCH-759 was well tolerated with no serious adverse events and no discontinuation. Genetic sequencing of NS5B is ongoing. Further studies combining VCH-759 with current therapies are warranted.
This post may contain sponsored links
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Friday, November 16th, 2007 at 7:54 am
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