Clinical Trials News

Long term treatment with interferon (HALT-C) is huge disappointment

2009-03-28T04:56:00.000-07:00

Results of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial—one of the most anticipated clinical trials in years— were highly disappointing. The multicenter study showed "without question that maintenance therapy with peginterferon does not prevent progression of liver disease among patients who have failed prior treatments," says James Everhart, MD, the National Institute of Health's HALT-C project scientist.1

HALT-C outcomes were death, liver cancer or liver failure, and/or cirrhosis. At the end of the study, 34.1% of the treated group and 33.8% of the control group had experienced at least one outcome. While patients in the treated group had significantly lower blood levels of the hepatitis C virus and improvement in liver inflammation, there was no major difference in rates of their primary outcomes.

Although the protocol did lower the "so-called necro-inflammatory score," it was not associated with any benefit, says John Lake, MD, director of the Liver Transplant Program, University of Minnesota, Minneapolis. "That was really surprising. They achieved what they wanted to achieve, but it didn't have the downstream effect they were looking for," he says.

The Side Effects Of Monotherapy With Lamivudine

2008-09-24T12:19:00.000-07:00

Lamivudine has a high rate of antiviral resistance. Sequential anti-HBV treatment is commonly used for lamivudine resistance. We report 4 cases with rapid re-detection of HBV mutants during the lamivudine re-treatment.
The article was published in the World Journal of Gastroenterology. In this report, four patients received lamivudine as an initial treatment of HBV. They had adefovir and lamivudine as a rescue therapy consecutively. HBV-DNA level, YMDD mutations and adefovir -resistant mutations (RFMP) were tested every 3 mo during the sequential treatment. All the patients showed YMDD mutations during the initial lamivudine therapy. After adefovir therapy for lamivudine resistance, they showed viral breakthrough. Adefovir was switched to lamivudine, however, it did not induce viral suppression at all, rather increased in HBV-DNA with rapid re-emergence of the YMDD mutations. All the patients had ALT flares, and hepatic decompensation occurred in two patients. After switching to adefovir combined with entecavir or lamivudine for a rescue therapy, the patients had reduction in HBV-DNA and ALT improvement. These cases demonstrated that lamivudine re-treatment in patients with pre-exposed lamivudine resistance leads to rapid re-emergence of YMDD mutation with significant viral rebound and subsequent hepatic decompensation. Sequential administration of lamivudine with prior history of YMDD mutation should be abandoned.

The result suggests that lamivudine re-treatment in patients with pre-exposed lamivudine resistance leads to rapid re-emergence of YMDD mutation with significant viral rebound and subsequent hepatic decompensation. Sequential administration of lamivudine with prior history of YMDD mutation should be abandoned.

The study highlights that retreatment with lamivudine in patients with severe liver disease should be avoided.

Debio 025 In Hepatitis C

2008-05-03T08:56:00.000-07:00

Image via WikipediaDebiopharm Group (Debiopharm), a global independent biopharmaceutical development specialist focusing on serious medical conditions, particularly oncology, presented positive efficacy results of a phase IIa study with Debio 025, a selective cyclophilin (Cyp) inhibitor with a potent in-vitro and in-vivo anti-hepatitis C (HCV) effect. Data indicates that Debio 025 shows an important additive anti-HCV effect when co-administered with pegylated Interferon (Peg-IFN) alpha-2a to treatment- naive HCV patients.

Debiopharm presented these findings at the 43rd Annual Meeting of the European Association for the Study of the Liver, in Milan, Italy.

The double-blind, placebo-controlled study investigated different dose regimens of Debio 025 in combination with alpha-2a Peg-IFN 180 Mug/week in treatment naive chronic HCV mono-infected patients. Ninety patients were randomised to receive either of the following treatment regimens during 29 days: Peg-IFN with placebo; Peg-IFN with Debio 025 200 mg/day; Peg-IFN with Debio 025 600 mg/day; Peg-IFN with Debio 025 1000 mg/day; and Debio 025 1000 mg/day.

In patients with genotypes 1 and 4, at day 29, the HCV-RNA reduction was -4.6 log10 IU/mL in the Peg-IFN with Debio 025 600 mg/day arm, and -4.8 log10 IU/mL in the Debio 025 1000 mg/day arm. This was significantly different (p< 0.05) from the Peg-IFN with placebo, as well as the Debio 025 1000 mg/day monotherapy arms, in which the reduction in viral load was respectively -2.49 and -2.20. In these two arms, at day 29, the proportion of subjects with undetectable viral load was 25%. This number increased to 66% in the Peg-IFN with Debio 025 1000 mg/day group.

"To obtain these exciting results after an administration period of only one month is promising and demonstrates that Debio 025 will be a breakthrough in the treatment of HCV infections," said Kamel Besseghir, CEO of Debiopharm S.A. "This unique mechanism of action is the first alternative treatment to classic HCV therapies."

Debio 025

Debio 025 is a synthetic first-in-class Cyp inhibitor, being tested in humans as a potential anti-HCV drug. Debio 025 binds strongly to Cyp, host cell proteins thought to confer a replication advantage to HCV. Its potent inhibitory activity on the HCV replication was shown in preclinical studies.

Previous results of a phase Ib study demonstrate that Debio 025 monotherapy for 15 days induced a strong anti-HCV effect (3.6 log10 reduction) in HIV-1/HCV co-infected patients. (Hepatology, Vol. 47, No 3, 2008, Flisiak et al. "The Cyclophilin Inhibitor Debio-025 Shows Potent Anti-Hepatitis C Effect in Patients Coinfected with Hepatitis C and Human Immunodeficiency Virus)."

Final Results Of Ideal Study Presented At Annual Meeting Of The European Association For The Study Of The Liver (EASL)

2008-04-27T20:07:00.000-07:00

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Final results of the IDEAL study, the first large, randomized, clinical study comparing the leading therapies for chronic hepatitis C, were presented at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL), providing important insights that may help guide clinical practice for physicians worldwide treating this serious and potentially life-threatening disease.

The IDEAL study compared combination therapy with PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) vs. Pegasys (peginterferon alfa-2a) and Copegus (ribavirin, USP),(1) as well as a lower dose of PEGINTRON in an investigational combination with REBETOL. The results showed that sustained virologic response (SVR),(2) the primary endpoint of the study, was similar for all three treatment regimens. The study also showed in secondary analyses that PEGINTRON combination therapy provided greater predictability of response at important treatment milestones and significantly lower relapse rates after the end of treatment than Pegasys and Copegus combination therapy, despite patients in the Pegasys arm overall receiving a significantly higher median ribavirin dose over the duration of the study. Safety and tolerability were similar among the treatment arms.

"IDEAL provides important insights about the similarities and differences of the two leading combination therapies for hepatitis C, and how physicians can use these findings to help manage their patients," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute.

In IDEAL (Individualized Dosing Efficacy vs. flat dosing to assess optimaL pegylated interferon therapy), 3,070 previously untreated U.S. patients with HCV genotype 1, the most common form of the virus worldwide and most difficult to treat, were randomized and treated with one of three treatment regimens:

(1) PEGINTRON 1.5 mcg/kg/week and REBETOL 800-1,400 mg/day;

(2) PEGINTRON 1.0 mcg/kg/week and REBETOL 800-1,400 mg/day; and

(3) Pegasys 180 mcg/week and Copegus 1,000-1,200 mg/day

Patients received up to 48 weeks of combination therapy with 24 weeks of follow-up.

In IDEAL, the combination regimen of Pegasys and Copegus used the recommended doses in accordance with their approved U.S. labeling, which includes a flat dose of Pegasys (180 mcg/week) for all patients regardless of body weight, and 1,000 or 1,200 mg/day of Copegus, adjusted for two weight categories. PEGINTRON was dosed either at 1.5 mcg/kg/week or an investigational combination dose of 1.0 mcg/kg/week with REBETOL at a dose of 800-1,400 mg/day, adjusted by four weight categories.

As a result, 51 percent of patients in the study were assigned the same dose of ribavirin (either REBETOL or Copegus) based on their weight groups, 39 percent of patients in the Pegasys arm were assigned a higher dose of ribavirin and 10 percent of patients in the PEGINTRON arms were assigned a higher dose of ribavirin.

Key Findings from IDEAL

(For the PEGINTRON 1.5 mcg, PEGINTRON 1.0 mcg, and Pegasys combination arms, respectively.)

-- SVR, the primary endpoint of the study, was similar for the three treatment regimens (40 vs. 38 vs. 41 percent, respectively) overall, and among those patients who were assigned equivalent doses of ribavirin based on their weight group (40 vs. 38 vs. 38 percent, respectively) (ITT).(3,4)

-- Predictability of response at early treatment milestones was confirmed in a secondary analysis as an important assessment tool for physicians. More patients in the PEGINTRON combination arms who had undetectable virus (HCV-RNA) in plasma at treatment week 4 or treatment week 12 went on to achieve SVR (positive predictive value, PPV) than patients in the Pegasys combination arm (92 vs. 87 vs. 80 percent, and 81 vs. 83 vs. 74 percent, respectively).(5)

-- Relapse after the end of treatment was lower for patients in the PEGINTRON combination therapy arms compared to patients receiving Pegasys and Copegus (24 vs. 20 vs. 32 percent, respectively). In a multivariate logistic regression analysis, among the factors significantly affecting relapse were: baseline viral load greater than 600,000 IU/mL vs. less than or equal to 600,000 IU/mL (p-value less than 0.001); age greater than 40 vs. less than or equal to 40 (p-value less than 0.001); fibrosis F3/4 vs. F0/1/2 (p-value equal to 0.001); Pegasys regimen vs. PEGINTRON 1.0 mcg regimen (p-value less than 0.001); glucose fasting greater than or equal to 5.6 vs. less than 5.6 (p-value equal to 0.002); steatosis 0 percent vs. greater than 0 percent (p-value equal to 0.002); ALT normal vs. elevated (p-value equal to 0.008); and Pegasys regimen vs. PEGINTRON 1.5 mcg regimen (p-value equal to 0.012).

-- End of treatment response was higher in the Pegasys combination arm (53 vs. 49 vs. 64 percent, respectively).

-- Ribavirin dose: One of the key questions of the study has been whether the protocol-assigned ribavirin dose regimen or the protocol-specified dose reduction schedule disadvantaged patients in any of the treatment arms, particularly in the Pegasys combination arm. However, the final results of IDEAL showed that the majority of patients in the Pegasys therapy arm received a higher ribavirin dose over the duration of the study, including patients with ribavirin dose reductions or discontinuations, based on the actual median ribavirin dose received (mg/kg/day), regardless of treatment outcome (SVR, relapsers and nonresponders) [p-value less than 0.001 for ribavirin dose received in the PEGINTRON 1.5 mcg arm vs. Pegasys arm and p-value less than or equal to 0.001 for ribavirin dose received in the PEGINTRON 1.0 arm vs. Pegasys arm].

-- Safety and tolerability were similar among the three treatment groups, with no new peginterferon or ribavirin related adverse events identified in this large study. Overall adverse events reported for the three treatment regimens were similar. As seen in other studies with these treatments, a range of "flu-like symptoms" were the most commonly reported adverse events for all three treatment regimens. Overall, the proportion of patients reporting serious adverse events was similar (9 vs. 9 vs. 12 percent, respectively). Discontinuation rates due to adverse events were similar across the three treatment arms (13 vs. 10 vs. 13 percent, respectively) as were discontinuations due to psychiatric adverse events (3 vs. 2 vs. 2 percent, respectively).

The complete results of the IDEAL study will be submitted for peer-reviewed publication, as well as to health authorities worldwide.

Hepatitis C Polymerase Inhibitor, R1626, Demonstrated Significant End-of-Treatment Response In Phase IIa Study

2008-04-27T19:57:00.000-07:00

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Roche's investigational therapy for chronic hepatitis C virus (HCV) infection, R1626, has shown a significant end-of-treatment response rate when given in combination with PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin). R1626 also shows a high barrier to the development of resistance.

After four weeks of treatment with this triple combination, followed by 44 weeks of PEGASYS and COPEGUS, levels of HCV were undetectable in 84 percent of patients infected with genotype 1 virus. This was higher than patients treated with PEGASYS and COPEGUS alone for the entire 48-week treatment period (65 percent). These new data were presented in a late-breaker oral session at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL), being held in Milan, Italy.

R1626 was discovered and developed at Roche and belongs to a class of antivirals called polymerase inhibitors, which are being investigated with the current standard of care for hepatitis C combination therapy with pegylated interferon and ribavirin.

"These results demonstrate that R1626 holds significant promise to potentially increase the number of hepatitis C patients who can be successfully treated," said Dr. David Nelson, Director of Hepatology and Liver Transplantation at the University of Florida, Gainesville, Florida. "Since most patients responded very early in treatment with R1626, we expect sustained virological response (SVR) rates that improve significantly on those achieved with the current standard of care. I look forward to SVR data from this Phase IIa study, and to results of the ongoing Phase IIb study."

Patients in this Phase IIa study will be followed for an additional 24 weeks with no treatment to determine the SVR rate, which indicates successful treatment

In Chronic Hepatitis C Silymarin Does Not Affect Virus Activity Or ALT Levels

2008-02-04T03:26:00.000-08:00

In a survey of patients with chronic hepatitis C who participated in a National Institute of Diabetes and Digestive and Kidney Diseases-sponsored long-term treatment trial for patients who had failed to respond previously to antiviral therapy, approximately 40% acknowledged to interviewers at the time of enrollment that they were currently using or had in the recent past used herbal products for health purposes.

This information was somewhat surprising because these were patients with advanced liver disease who were clearly committed to conventional antiviral treatment for chronic hepatitis C, having been so treated previously, some on more than one occasion, but because they had failed to respond, were now willing to accept treatment again with pegylated interferon for another 3 and a half years. Among those who were or had used alternative therapies, silymarin (milk thistle) was the product of choice either on its own or together with other herbal products, representing 72% of all the herbals taken.

These findings are in the February issue of Hepatology, a journal published by Wiley & Sons on behalf of the American Association for the Study of Liver Diseases (AASLD). The article was also available online at Wiley Interscience.

These results do not come from a rigorous scientific study because the products used were self-administered by the patients who entered the trial and no information was obtained on the duration or dose of the herbal taken. Still, in comparing users with non-users, while no difference was found for blood ALT or HCV levels between the two groups, the herbal users did report somewhat fewer symptoms and a better quality of life.

The current recommended treatment for patients with HCV infection is combination therapy with pegylated interferon and ribavirin. However, it leads to a sustained virological response in only a third to a half of all patients with the predominant form of the infection in the U.S., namely genotype 1, and it can cause unpleasant and sometimes serious side effects. The NIH study, referred to as the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial, was designed, therefore, to treat persons with advanced chronic hepatitis C who had failed previous antiviral therapy with the hope that the long-term treatment would reduce progression of the chronic liver disease even if it did not affect the virus itself. The reason for interviewing enrollees in the trial was to determine the extent of use of alternative therapies in this committed group, since the popularity of herbal products has increased in the U.S., many HCV patients choosing to supplement, or even replace, the standard treatment with herbals. Silymarin (milk thistle extract) has been the most popular option for people with liver disease. Although it is the most frequent product utilized, silymarin has not been rigorously studied using accepted scientific approaches, and therefore such studies are clearly required and warranted.

For the present survey, researchers interviewed all HALT-C participants on past and current use of all prescription and non-prescription drugs, including herbal medications, dietary supplements and other botanical products. Of 1145 study participants, 56 percent said that they had never used herbal products, while 23 percent were using them currently, some 60 different varieties. Silymarin was by far the most common. Usage was higher among men, among non-Hispanic whites, and among the more highly educated. Interestingly, the researchers also found geographic disparities in silymarin usage. It was most popular in Colorado, Michigan and Southern California and least popular in Maryland and Massachusetts.

In comparing the clinical data of silymarin users and non-users, the researchers found that "the levels of HCV RNA were not significantly different between silymarin users and non-users," indicating no effect on virus activity. Similarly, the product did not alter serum ALT levels, indicating no effect on hepatic inflammation. However, after adjusting for covariates, the data showed that silymarin users reported less fatigue, nausea, liver pain, anorexia, muscle and joint pain and better general health than non-users.

The better scores in a small number of symptoms among silymarin users compared to non-users are insufficient to support the value of this alternative therapy, the authors conclude. Compelling information can come only if a scientifically valid study is performed. "Currently in progress, therefore, is a properly designed prospective, randomized, controlled trial in which a fully characterized, purified and standardized silymarin formulation is being evaluated," they report.

16 New Treatments For Hepatitis C. Summary Of The Papers Presented At 2007 Meeting of the AASLD

2007-11-15T13:54:00.000-08:00

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.

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