The protease inhibitor GS-9256 and non-nucleoside polymerase inhibitor tegobuvir alone, with RBV or peginterferon plus RBV in hepatitis C

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Hepatology Jan 2012
Accepted Article (Accepted, unedited articles published online for future issues)

Stefan Zeuzem,1 Peter Buggisch,2 Kosh Agarwal,3 Patrick Marcellin,4 Daniel Sereni,5 Hartwig Klinker,6 Christophe Moreno,7 Jean-Pierre Zarski,8 Yves Horsmans,9 Hongmei Mo,10 Sarah Arterburn,10 Steven Knox,10 David Oldach,10 John G. McHutchison,10 Michael P. Manns,11 and Graham R. Foster 12 From the 1University Hospital, JW Goethe University, Frankfurt, Germany; 2IFI Studien-und Projekte, Hamburg, Germany; 3King's College Hospital, London, United Kingdom; 4Hospital Beaujon, University of Paris, Clichy, France; 5Hospital Saint-Louis, Paris, France; 6Universitatsklinikum Wurzburg, Medizinische Klinik und Poliklinik II, Wurzburg, Germany; 7Erasme Hospital, Universite Libre de Bruxelles, Brussels, Belgium; 8CHU de Grenoble -Hopital Michallon La Tronche, France; 9Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Bruxelles, Belgium; 10Gilead Sciences, Inc., Foster City, CA, USA;11Medical School of Hannover, Hannover, Germany; and 12The Liver Unit, Queen Mary University of London, London, United Kingdom

Abstract

Tegobuvir (GS-9190), a non-nucleoside NS5B polymerase inhibitor, and GS-9256, an NS3 serine protease inhibitor, individually have activity against hepatitis C virus (HCV) genotype 1. The antiviral activity of tegobuvir and GS-9256 as oral combination therapy, or together with ribavirin (RBV) or peginterferon alfa-2a (PEG-IFN) and RBV, was assessed in a phase 2, randomized, open-label trial. Treatment-naïve patients with genotype 1 HCV were assigned 28 days of tegobuvir 40 mg twice daily and GS-9256 75 mg twice daily (n=16), tegobuvir and GS-9256 plus RBV 1000-1200 mg daily (n=15), or tegobuvir and GS-9256 plus PEG-IFN alfa-2a (180 mcg qw)/RBV (n=15). The primary efficacy endpoint was rapid virologic response (RVR), HCV RNA <25 IU/mL at Day 28. After 28 days, all patients received PEG-IFN/RBV. All patients with viral rebound or nonresponse, defined as >0.5-log10 increase in HCV RNA from nadir or <2-log decrease at Day 5, initiated PEG-IFN/RBV immediately. Median maximal reductions in HCV RNA were -4.1 log10 IU/mL for tegobuvir/GS-9256, -5.1 log10 IU/mL for tegobuvir/GS-9256/RBV, and -5.7 log10 IU/mL for tegobuvir/9256/PEG-IFN/RBV. RVR was observed in 7% (1/15) of patients receiving tegobuvir/GS-9256, 38% (5/13) receiving tegobuvir/GS-9256/RBV, and 100% (14/14) receiving tegobuvir/9256/PEG-IFN/RBV. The addition of PEG-IFN/RBV at Day 28 or earlier resulted in HCV RNA <25 IU/mL at Week 24 in 67% (10/15), 100% (13/13) and 94% (13/14) of patients in the 3 treatment groups. Transient elevations in serum bilirubin occurred in all treatment groups. Conclusion: In genotype 1 HCV, adding RBV or RBV with PEG-IFN provides additive antiviral activity to combination therapy with tegobuvir and GS-9256. (HEPATOLOGY 2011.)

For the past decade, standard of care for patients with chronic infection with genotype 1 hepatitis C virus (HCV) has been 48 weeks of peginterferon alfa (PEG-IFN) and ribavirin (RBV). Observed rates of sustained virologic response with PEG-IFN and RBV therapy are 40-52% (1-4). However, the addition of the HCV NS3 serine protease inhibitors telaprevir or boceprevir results in higher rates of sustained virologic response (67-75%), leading to the recent approval of these two drugs in the United States and the European Union (5-10). Because triple therapy can result in higher rates of rapid virologic response (RVR, HCV RNA < lower limit of quantification at Week 4) in the range of 60% to 70% (5,6,9,10), shortened treatment duration from 48 to 24 weeks is possible in a significant proportion of patients.

Several novel inhibitors of viral replication, including those targeting the NS3 serine protease and NS5B RNA-dependent RNA polymerase, are in clinical development (11). Although many of these direct-acting antiviral agents (DAAs) can cause rapid and substantial reductions in viral load, their use as monotherapies has been limited by inadequate suppression of replication and/or the development of resistance (12,13). In the context of polymerase or protease inhibitor therapy, PEG-IFN and RBV have repeatedly demonstrated their importance in reducing viral load and suppressing viral breakthrough (14-16). In studies of regimens containing telaprevir or boceprevir, excluding RBV or using a reduced dose results in higher rates of viral breakthrough and relapse (5,7,17).

Several recent studies have explored combining two DAAs to enhance early antiviral activity and to theoretically minimize development of resistance. In a study of treatment-naïve patients with HCV genotype 1, 14 days of combination therapy with the nucleoside analog RG7128 and the NS3 protease inhibitor danoprevir resulted in 5-log10 IU/mL HCV RNA reductions from baseline (18). More recently, the combination of the non-nucleoside NS5B polymerase inhibitor VX-222 with telaprevir improved early antiviral response but was associated with high rates of viral breakthrough (19).

Tegobuvir (GS-9190) is a novel, non-nucleoside inhibitor of the NS5B polymerase. Studies to elucidate tegobuvir's mechanism of action are ongoing; however, current data indicate the inhibitory effect may be exerted via an interaction with the ß-hairpin in the NS5B thumb subdomain (20). Tegobuvir and the NS3 protease inhibitor GS-9256 each have demonstrated antiviral activity in HCV-infected patients (21-23). Tegobuvir demonstrated median reductions in HCV RNA of 1.5 log10 IU/mL for individual patients with 8 days of monotherapy (21) and enhanced rates of RVR (HCV RNA <25 IU/mL at Week 4) when combined with PEG-IFN and RBV (22). At 200 mg twice daily for 3 days, GS-9256 monotherapy demonstrated a median HCV RNA reduction of 2.7 log10 IU/mL (22). Both tegobuvir and GS-9256 were well-tolerated in these short-term monotherapy studies. We therefore evaluated the antiviral activity of tegobuvir and GS-9256 dual therapy, tegobuvir and GS-9256 plus RBV, and tegobuvir and GS-9256 plus PEG-IFN and RBV for 28 days. After 28 days of treatment, patients then continued treatment with PEG-IFN and RBV for 48 weeks.

RESULTS

Patient Population

Between February and October of 2010, a total of 46 patients were randomized and treated in 4 European countries (Belgium, France, Germany, United Kingdom). Among the treatment arms, patients were predominately male (73% to 88%) and white (80% to 93%), and mean age ranged from 45 to 54 years (Table 1). Of the 46 patients treated, 45 patients completed Week 6 of the study (Table 2), and 42 were still on PEG-IFN/RBV at Week 24. Treatment with PEG-IFN/RBV is ongoing at the time of this report. As evaluated at Baseline with the LiPA 2.0 assay, 15 (33%) patients were HCV genotype 1a, 30 (65%) were genotype 1b, and 1 (2%) was unable to be genotyped. Upon subsequent NS5B sequencing/phylogenetic analysis, 4 patients were identified as having HCV genotypes 1e, 1l, 1e/m, and 4r (refer to supplementary table for virologic outcomes). These patients were therefore excluded from the primary efficacy analysis.

The majority of patients were genotype CT (ranging from 53% to 63%) at the IL28B polymorphism rs12979860. A higher percentage of patients were IL28B genotype CC in the tegobuvir/GS-9256/RBV arm (40%) versus the tegobuvir/GS-9256 arm (12.5%) or tegobuvir/GS-9256/PEG-IFN/RBV arm (26.7%).

Efficacy Assessments

HCV RNA

Patients in all treatment arms had an initial sharp decline in plasma HCV RNA levels during the first 48 hours of therapy (Figure 1). In the tegobuvir/GS-9256 arm, this decrease was generally maintained through Day 7, after which HCV RNA levels began to rebound, associated with the emergence (detection) of resistance-associated variants. The addition of ribavirin to the treatment regimen increased the magnitude, extent, and duration of viral reduction; in the tegobuvir/GS-9256/RBV arm, reductions in HCV RNA levels were observed through Day 14 and were generally maintained through Day 28. The addition of PEG-IFN alfa-2a had a similar additive effect; in the tegobuvir/GS-9256/PEG-IFN/RBV arm, reductions in HCV RNA levels were observed through Day 28. The association of IL28B genotype and initial antiviral response was variable, with a trend towards a greater magnitude of HCV RNA reductions in IL28B-CC patients. No differences in mean maximal HCV RNA reduction by HCV subtype (1a or 1b) were observed. Virologic responses in the four patients infected with other HCV-1-subtypes are presented in the Supplementary table. In each case, HCV RNA reductions from Baseline during randomized therapy ranged from -0.75 to -2.84 log10 IU/mL. Following the switch to PEGIFN/ RBV, continued viral load reductions were observed ranging from -2.98 to -5.23 log10 IU/mL from Baseline by Week 6.

In the primary efficacy analysis, a greater percentage of patients achieved RVR after receiving tegobuvir/GS-9256 in combination with RBV (38%) compared with tegobuvir/GS-9256 alone (7%) (Table 3). All patients (14/14) receiving tegobuvir/GS-9256 in combination with PEGIFN/RBV achieved RVR.

Excluding datapoints following the early introduction of PEG-IFN/RBV, the median (Q1, Q3) maximal reduction in HCV RNA was highest for patients receiving tegobuvir/GS-9256/PEGIFN/RBV, -5.7 (-5.9, -5.5) log10 IU/mL, versus -5.1 (-5.3, -4.4) for tegobuvir/GS-9256/RBV, and -4.1 (-4.4, -2.9) for tegobuvir/GS-9256 alone.

Viral breakthrough was most common in the tegobuvir/GS-9256 arm, where the majority of patients (80%) started standard of care with PEG-IFN and RBV prior to Day 28. Although RBV decreased and delayed breakthrough, in the tegobuvir/GS-9256/RBV arm, 31% started standard of care early because of the observed increases in HCV RNA at or prior to Day 28. None of the patients receiving tegobuvir/GS-9256/PEG-IFN/RBV experienced viral plateau or rebound through Day 28. For patients in the tegobuvir/GS-9256 arm who had an increase in HCV RNA levels observed at Day 14 or Day 21, HCV RNA levels declined again by Day 28 after initiating PEG-IFN and RBV.

Among the patients who either did not experience early response or had viral rebound, several achieved RVR after starting either PEG-IFN or PEG-IFN and RBV early. Two patients in the tegobuvir/GS-9256 arm who started PEG-IFN and RBV early achieved RVR, as did 3 patients in the tegobuvir/GS-9256/RBV arm who started PEG-IFN early (Table 3).

Viral suppression continued through 24 weeks for many patients, especially those initially assigned to therapy with RBV (arm 2) or PEG-IFN/RBV (arm 3). All patients (13/13) receiving tegobuvir/GS-9256/RBV initially and continuing on PEG-IFN/RBV had HCV RNA <25 IU/mL at Week 24; 13 of 14 (94%) of patients assigned to tegobuvir/GS-9256/PEG-IFN/RBV and continuing on PEG-IFN/RBV maintained HCV RNA <25 IU/mL at Week 24.

Resistance Mutants

Population sequence analysis was performed in 15 rebound patients whose HCV RNA was ≥1000 IU/mL at the time of rebound. In 14/15 of these patients, mutations were detected in both the NS3 and NS5B genes (Table 4), and the mutations are known to cause lowered antiviral susceptibility to GS-9256 and tegobuvir in vitro. The remaining patient had only the NS3 R155K mutation detected. The dual therapy arm with tegobuvir/GS-9256 had the highest rate of detected mutations. In HCV genotype 1a patients, NS3 R155K and NS5B Y448H were the most common mutations selected; in HCV genotype 1b patients, NS3 D168E/V and NS5B Y448H were most common. In 4 of 5 patients with HCV genotype 1b with either NS5B C316N or C445F at Baseline, the viral rebound was associated with the emergence of NS3 D168E/V/H/L mutations without the selection of additional NS5B mutations.

Safety Assessments

Tegobuvir/GS-9256 was well tolerated, and most adverse events were mild to moderate in severity. Adverse events were more common in the tegobuvir/GS-9256/PEG-IFN/RBV treatment arm, with events consistent with those reported for IFNs (Table 5). Two serious adverse events were reported during the study: infective bursitis and vasovagal collapse. Both were considered by the investigator to be unrelated to study drug. One patient, in the tegobuvir/GS-9256 arm, discontinued tegobuvir and GS-9256 on Day 22 because of fatigue. This patient had initiated PEG-IFN and RBV on Day 19 but continued with PEG-IFN/RBV after discontinuing tegobuvir and GS-9256. The patient completed study participation to Week 6 but was later lost to followup.

No Grade 4 adverse events or lab abnormalities were observed. Reductions in hemoglobin and neutrophils were consistent with those associated with RBV and PEG-IFN alfa-2a administration. Transient bilirubin elevations, primarily Grades 1 and 2, occurred in all treatment groups but were generally indirect and not associated with elevations in ALT or AST. Overall, while taking assigned therapy, 9 patients experienced Grade 1 elevations in total bilirubin, 4 had Grade 2 elevations, and 2 had Grade 3 elevations (3.2 mg/dL maximum). The overall incidence of hyperbilirubinemia (Grade 1 and above) in treated patients was 4/16 (25%), 5/15 (33%) and 6/15 (40%) in the tegobuvir/GS-9256, tegobuvir/GS-9256/RBV, and tegobuvir/GS-9256/PEGIFN/ RBV arms, respectively.
No clinically significant impact on cardiac repolarization (prolongation of the QTcF interval >60 msec change from Baseline or increase to >500 msec) was observed for the tegobuvir/GS-9256 combination following multiple dosing.

DISCUSSION

This study of tegobuvir plus GS-9256 is the first to explore the additional contribution of RBV to a 2-drug oral DAA regimen during a limited 4-week dosing period. The two oral DAAs exhibited additive antiviral activity: tegobuvir 40 mg BID monotherapy induces median HCV RNA reductions of 1.5 log10 (21), whereas GS-9256 monotherapy induces median HCV RNA reductions of 2.7 log10 (22), and in this study, the combination of the two drugs resulted in median HCV RNA reductions of 4.1 log10. The additive antiviral effect we observed is consistent with the additive interaction of tegobuvir and GS-9256 in the replicon system (Gilead Sciences, unpublished data). Even with the additive antiviral activity of these 2 classes of HCV inhibitors, viral breakthrough was common, especially in patients with genotype 1a HCV infection. The addition of RBV enhanced antiviral activity, delayed the emergence/selection of resistance, and resulted in a greater proportion of patients achieving an RVR. Adding PEG-IFN plus RBV to the 2 antiviral agents further enhanced viral suppression, with 100% of patients reaching RVR. In the majority of patients, treatment with PEG-IFN plus RBV after 28 days maintained HCV RNA suppression to <25 IU/mL up to Week 24. Virologic response data beyond Week 24 is awaited. Four patients with non-1 HCV genotype were treated in the study. The virologic responses in these patients were sub-optimal. Three patients discontinued randomized treatment and initiated PEG-IFN/RBV. The fourth patient, assigned to tegobuvir/GS-9256/RBV/PEG-IFN, remained on assigned therapy for 28 days per protocol. The virologic response rates observed in these patients are consistent with the specificity of tegobuvir and GS-9256 for HCV genotypes 1a and 1b.

A small imbalance in the proportion of IL28B-CC patients was observed across groups (Figure 1). The small sample size limits interpretation; however, it is possible that the apparent impact of ribavirin in reducing viral load and suppressing resistance could be partially related to a relatively high proportion of IL28B-CC patients in the tegobuvir/GS-9256/RBV arm.

Most adverse events occurring in the tegobuvir/GS-9256 arm were mild to moderate in severity. Although the number of adverse events was highest in the tegobuvir/GS-9256/PEG-IFN/RBV treatment arm, these events were consistent with those associated with IFNs. Transient bilirubin elevations were also observed, consistent with the known class effects of NS3 serine protease inhibitors on bilirubin transporters, such as organic anion transporting polypeptide 1B1 (OATPB1), with resulting increase in unconjugated bilirubin (25,26).

The emergence of resistance-associated variants with non-nucleoside NS5B or NS3 inhibitors has been described in other studies and is consistent with the lower genetic barrier against resistance for non-nucleoside analogs and NS3 protease inhibitors (for review see [13]). The high rate of emergence of the protease resistant variant R155K in genotype 1a, but not in genotype 1b infected patients has also been described previously with this class of agents, and is reflective of single-nucleotide change that is required for the development of resistance in genotype 1a patients, but two-nucleotide changes in the majority of genotype 1b patients (27). It is of note that single-nucleotide change is required for both mutations at NS3 R155 and D168 in genotype 1a patients; however, a mutation at only R155, and not D168, was identified in genotype 1a patients by population sequencing. The R155 nucleotide sequence may be more susceptible to change than D168, or the R155K may be more fit than mutations at D168 in this genotype. Mutations at D168 were commonly selected in genotype 1b-infected patients, consistent with genotype 1b replicon data.

The Y448H mutation observed with tegobuvir has been observed frequently in monotherapy studies and is consistent with in vitro mutational data indicating the tegobuvir interaction likely involves the ß-hairpin in the thumb sub-domain of the NS5B polymerase (20). In the present study, 7/8 genotype 1a patients developed dual-class resistance: R155K against the NS3 protease inhibitor and Y448H for the NS5B polymerase inhibitor. However, with the addition of RBV, the incidence of resistance was significantly reduced, with none of genotype 1a patients (n=3) exhibiting drug resistant variants. While RBV has been shown to have modest antiviral activity (28), its ability to significantly reduce development of resistance highlights a distinct mechanism of action. This may indicate a broader mutational effect of RBV on viral fitness, which renders a proportion of virus non-infectious, regardless of oral antiviral resistance mutations. Although similar trials have been reported (29), the present study is the first report of an interferon-free NS5B polymerase/NS3 protease combination both with and without RBV, thus allowing for prospective evaluation of the contribution of RBV to the antiviral effect of the regimen. The emergence of various classes of DAAs for treating chronic HCV infection has enabled evaluation of multiple combination approaches either with or without PEG-IFN and RBV (19,30,31). Specifically, the strategy of quadruple therapy with a non-nucleoside analog, a protease inhibitor, and PEG-IFN and RBV has been supported by results from a recently reported study in which the non-nucleoside NS5B polymerase inhibitor VX-222, telaprevir, and PEG-IFN/RBV resulted in RVR in 51/59 (86%) of treatment-naïve patients (19), which is higher than those reported with telaprevir and PEG-IFN/RBV (6,9). In this study, 100% of patients receiving quadruple therapy achieved RVR at Week 4, and a high proportion of patients (71%) had HCV RNA below 25 IU/mL at Week 2. The rapidity of viral clearance in patients with quadruple therapy provides a basis for examining response-guided therapy in which total duration of treatment could be fewer than 24 weeks. To explore this possibility, phase 2 combination studies of tegobuvir plus GS-9256 with PEG-IFN and RBV are underway.

Source

Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 in HCV genotype 1b-infected null responders

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"In conclusion, the combination of BMS-790052 and BMS-650032 achieved a high rate of SVR24 in patients with HCV genotype 1b infections and prior null response to pegIFN/RBV. These results support the concept that HCV infection can be cured with two DAAs without pegIFN/RBV even in difficult-to-treat populations that lack robust interferon responsiveness. Further research will assess the benefits of DAA combinations in larger and more diverse patient populations.....In the nine patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all nine patients achieved SVR12 and SVR24. HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in three patients but did not result in discontinuation."

AASLD: Dual Oral Combination Therapy with the NS5A Inhibitor Daclatasvir(DCV; BMS-790052) and the NS3 Protease Inhibitor Asunaprevir(ASV; BMS-650032) Achieved 90% Sustained Virologic Response (SVR12) in Japanese HCV Genotype 1b-Infected Null Responders - (11/08/11)

Hepatology Jan 2012
Accepted Article (Accepted, unedited articles published online for future issues)

Kazuaki Chayama1, Shoichi Takahashi1, Joji Toyota2, Yoshiyasu Karino2, Kenji Ikeda3, Hiroki Ishikawa4, Hideaki Watanabe4, Fiona McPhee5, Eric Hughes6, Hiromitsu Kumada3 1Hiroshima University, Hiroshima, Japan; 2Sapporo Kosei General Hospital, Sapporo, Japan; 3Toranomon Hospital, Tokyo, Japan; 4Bristol-Myers KK, Tokyo, Japan; 5Bristol-Myers Squibb Research and Development, Wallingford, CT, USA; 6Bristol-Myers Squibb Research and Development, Princeton, NJ, USA

Abstract

Patients with chronic hepatitis C virus (HCV) infection and prior null response to peginterferon and ribavirin have limited therapeutic options. HCV genotype 1 is the most common worldwide and the most difficult to treat; genotype 1b is the most common subtype of genotype 1 outside North America. The enhanced antiviral activity achieved by combining two direct-acting antiviral (DAA) agents may improve clinical outcomes. This open-label, phase 2a study included ten patients with chronic HCV genotype 1b infection and prior null response (<2 log10 reduction in HCV RNA after 12 weeks) to peginterferon and ribavirin. Patients received dual DAA treatment for 24 weeks with the NS5A replication complex inhibitor BMS-790052 (60 mg once daily) and the NS3 protease inhibitor BMS-650032 (initially 600 mg twice daily, subsequently reduced to 200 mg twice daily). The primary efficacy endpoint was the proportion of patients with sustained virologic response at 12 weeks post-treatment (SVR12). Nine patients completed 24 weeks of treatment; one patient discontinued treatment after 2 weeks. In the nine patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all nine patients achieved SVR12 and SVR24. HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in three patients but did not result in discontinuation.

Conclusions:

Dual therapy with BMS-790052 and BMS-650032, without peginterferon and ribavirin, can achieve high SVR rates in difficult-to-treat patients with hepatitis C virus genotype 1b infection and prior null response to peginterferon and ribavirin. (HEPATOLOGY 2011.)

Chronic hepatitis C virus (HCV) infection affects approximately 180 million individuals worldwide and is a common cause of chronic liver disease and hepatocellular carcinoma in Japan, the USA, and many European countries.(1, 2) Among the six major HCV genotypes, genotype 1 is the most common and the most difficult to treat, and its two main subtypes may differentially influence therapeutic outcomes.(3, 4) Genotype 1b is the most prevalent worldwide and predominates in Japan and China, while genotype 1a is most common in the USA; subtype prevalence in Europe is similar.(5-7)

Treatment of chronic HCV infection with pegylated interferon alfa (pegIFN) and ribavirin (RBV) elicits a sustained virologic response (SVR) in 40% to 50% of treatment-naïve patients with genotype 1 infections; SVR rates in this population increase to 66% or 75% when boceprevir or telaprevir, respectively, is added to the regimen.(8-12) Response rates are influenced by viral load and genotype and by patient demographics, disease history, and genetics.(10) PegIFN/RBV retreatment of patients with prior non-response to pegIFN/RBV is frequently unsuccessful, with SVR rates of only 6% to 9%.(13, 14) Null responders are the subset of non-responders who have responded most poorly to pegIFN/RBV, and their urgent need for more potent therapies has prompted evaluation of regimens containing direct-acting antivirals (DAAs). SVR rates of 27% (genotype 1a) and 37% (genotype 1b) were achieved in null responders with a regimen combining telaprevir with pegIFN/RBV in a study of nonresponders.(15) These results suggest that DAA-containing regimens can benefit this population, but greater antiviral potency is needed to increase response rates further.

Combinations of two DAAs may overcome interferon non-responsiveness in null responders by increasing antiviral activity and reducing the risk of developing resistance-associated variants.(16) In HCV-infected human hepatocyte chimeric mice, dual DAA treatment eradicated HCV without resistance, while resistance emerged rapidly with single DAA treatment.(17) In a clinical study that included null responders, marked antiviral effects were observed after 13 days of dual DAA treatment, supporting the evaluation of longer-term dual DAA therapy reported in this study.(18) BMS-790052 is a first-in-class, highly selective NS5A replication complex inhibitor with picomolar potency and broad genotypic coverage; BMS-650032 is an NS3 protease inhibitor active against HCV genotypes 1a and 1b.(19, 20) BMS-790052 and BMS- 650032 are associated with different resistance-associated variants, consistent with their different molecular targets, and showed no meaningful pharmacokinetic interactions in healthy volunteers.(20-22)

In a 24-week study of null responders in the USA, BMS-790052 and BMS-650032 demonstrated potent antiviral effects both as a dual DAA regimen and in a quadruple regimen that included pegIFN/RBV.(23) Overall 36% of dual therapy recipients achieved SVR, including both of the two patients with genotype 1b infection. However, patients with genotype 1a experienced frequent viral breakthrough with the dual regimen and only two of nine achieved SVR, suggesting subtype-associated differences in resistance barrier and response. We present the results of an open-label trial evaluating dual therapy with BMS-790052 and BMS-650032 in Japanese patients with chronic HCV genotype 1b infection and prior null response to pegIFN/RBV.

All patients received oral combination therapy with BMS-790052 and BMS-650032 from the beginning of the study. BMS-790052 was dosed as two 30-mg tablets once daily. BMS-650032 was initially dosed as three 200-mg tablets twice daily; subsequently, the dose of BMS-650032 was reduced to 200 mg twice daily following reports of hepatic enzyme elevations in a clinical study of BMS-650032 and pegIFN/RBV.(24)

Treatment was continued to week 24 for patients with HCV RNA below the assay lower limit of quantitation (LLQ; 15 IU/mL) on or after week 2; treatment was discontinued for patients with <2 log10 IU/mL decrease of HCV RNA from baseline, on or after week 2. For patients with viral rebound on or after week 2, or HCV RNA above LLQ on or after week 4, treatment was discontinued or weight-based pegIFN/RBV therapy was added for up to 48 additional weeks at the investigator's discretion, based on expected tolerance of pegIFN/RBV. Viral rebound was defined as an increase ≥1 log10 IU/mL from nadir at more than one time point, or HCV RNA ≥15 IU/mL after declining to below that level.

Results

Patient characteristics and disposition

Twelve patients were screened; two failed to meet entry criteria (for hepatocellular carcinoma and elevated direct bilirubin, respectively) and 10 patients were enrolled and treated. Enrolled patients were generally older (median 62 years); six were female and all were Japanese (table 1). All enrolled patients were infected with genotype 1b, reflecting the predominance of this subtype in Japan, although the study protocol did not exclude patients with HCV genotype 1a.(6) Two patients were IL28B genotype CC (single-nucleotide polymorphism rs12979860) and eight were CT. Nine patients completed 24 weeks of therapy; one patient discontinued at week 2 due to a grade 4 total bilirubin elevation (see Safety). Among the nine patients treated for 24 weeks, BMS-650032 was dosed at 600 mg twice daily for 12 to 21 weeks before the dose was reduced to 200 mg twice daily (figure 1).

Virologic response

Serum HCV RNA levels decreased rapidly in all patients (figure 2); mean reductions from baseline were 4.4 log10 IU/mL at week 1, 5.3 log10 IU/mL at week 2, and 5.8 log10 IU/mL from week 4 through the end of treatment. At week 4, HCV RNA was undetectable (RVR) in four of ten (40%) patients and below the assay LLQ in nine of ten (90%; figure 3). No patients qualified for discontinuation or addition of pegIFN/RBV. At week 8, HCV RNA was undetectable in nine of ten patients (all who remained on treatment) and remained undetectable through the end of treatment and follow-up. SVR12, the primary endpoint, and SVR24 were achieved by 90% of patients including all nine who completed 24 weeks of therapy. The patient who discontinued treatment at week 2 had low-level HCV RNA at discontinuation (1.8 log10 IU/mL), but HCV RNA was undetectable at follow-up visits 2, 3, 4, 13, and 24 weeks after discontinuation.

Viral breakthrough and relapse

There was no viral breakthrough during treatment or relapse of HCV RNA post-treatment. Analysis of baseline samples revealed variants reported to confer minimal to low levels of resistance to BMS-790052.(22) NS5A substitutions L28M and L31M were detected in one patient each and Y93H was detected in two other patients. NS3 protease substitutions reported to confer resistance to telaprevir, boceprevir, and TMC-435 were detected;(25) T54S was identified in one patient and Q80L was identified in three. In one patient, both NS3 protease substitutions (T54S, Q80L) and an NS5A substitution (Y93H) were detected. There was no consistent association between detection of these variants and virologic outcomes.

Safety

The most frequently reported adverse events were diarrhea and headache, all mild (grade 1) (table 2). The patient who discontinued (see below) experienced multiple grade 3 or 4 adverse events and laboratory abnormalities on treatment. In the other nine patients, there were no grade 3 or 4 transaminase elevations or other grade 3 or 4 events, no clinically relevant changes in electrocardiogram parameters, and no lymphopenia of any severity. Two transient grade 1 ALT elevations were reported, and one grade 2 elevation that began at week 16 and persisted until the end of treatment, after which it normalized within two weeks (figure 1). There were no notable differences in ALT before and after BMS-650032 dose reduction.

There were two serious adverse events. A 54 year-old male was hospitalized with grade 3 pyrexia and persistent diarrhea 11 days after initiating study treatment. Loxoprofen was initiated, and body temperature normalized and diarrhea improved after four days. The patient remained on study treatment. The second event concerned a 60 year-old woman with a history of ulcerative colitis who discontinued study treatment after two weeks due to a grade 4 bilirubin elevation with multiple complicating features. Five days before discontinuation, she presented with infectious gastroenteritis and was treated with cefotiam and subsequently hospitalized with fever, vomiting, and diarrhea. Meropenem, human serum albumin, and furosemide were initiated. At discontinuation of study drugs, laboratory findings included total bilirubin of 7.7 mg/dL and grade 3 lymphopenia and serum phosphorus reduction; transaminases and alkaline phosphatase were within normal ranges. In the week following discontinuation, white cell and eosinophil counts became elevated; total bilirubin improved and transaminases remained normal. Two weeks after discontinuation, grade 4 ALT and aspartate aminotransferase (AST) elevations and a grade 3 lipase elevation were reported. Six weeks after discontinuation, bilirubin and transaminase elevations were resolved and lipase improved to within 2 xULN.

Discussion

This study assessed combination oral DAA therapy in a difficult-to-treat population with multiple adverse prognostic features, including HCV genotype 1b infection, primarily IL28B CT genotype, generally older age, and null response to previous pegIFN/RBV therapy.(10, 13, 14) These patients represent a group with a significant need for new therapeutic options.

A DAA-only therapeutic strategy may be particularly appropriate for null responders, who have previously shown only marginal response to pegIFN/RBV.(13, 14) The combination of two highly potent DAAs cleared detectable virus rapidly in this study; HCV RNA was undetectable by week 8 in all nine patients treated for 24 weeks. This outcome compares favorably with those observed when null responders received a combination of pegIFN/RBV and a single NS3 protease inhibitor, telaprevir or TMC435.(15, 26) In these studies HCV RNA remained detectable in 36% to approximately 50% of patients after 12 weeks. HCV RNA remained undetectable 12 weeks (SVR12) and 24 weeks (SVR24) post-treatment in all patients who completed treatment. This contrasts with the poor results obtained with pegIFN/RBV retreatment and the reported 37% SVR rate of genotype 1b null responders who received pegIFN/RBV and telaprevir.(10, 13-15) Additional follow-up of patients from this study will assess whether SVR24 is predictive of long-lasting viral clearance with this dual DAA therapy, as it is with pegIFN/RBV. It is interesting that HCV RNA was persistently undetectable post-treatment in the patient who discontinued after only two weeks of treatment. With early discontinuation data from only this single case, at present the result must be considered an anomaly. The factors that contributed to viral clearance are uncertain, although the patient's IL28B CC genotype suggests increased sensitivity to endogenous interferon;(27) the possible influence of concurrent acute gastroenteritis or other complicating factors is unknown. However, coupled with the attainment of SVR12 in all other patients, this outcome suggests that required duration of therapy, which is currently predicated on data from pegIFN-based regimens, may need reassessment for DAA-only regimens, and possibly that certain patient populations can be treated for very short durations.

The high SVR rate is consistent with limited data from a related USA-based study, in which 2 of 2 null responders with HCV genotype 1b and treated with BMS-790052 and BMS-650032 achieved SVR24.(23) However, only 2 of 9 patients with genotype 1a achieved SVR24 with the dual DAA regimen, compared with 9 of 10 patients who received both DAAs and pegIFN/RBV. These differences suggest that viral genotype can influence responses to DAA regimens that do not include pegIFN/RBV, and outcomes can be optimized with individualized therapy that considers viral genotype, among other factors. Because of the high SVR rate, the potential influence of other baseline and on-treatment parameters cannot be assessed, other than to observe that unfavorable predictors of pegIFN/RBV response, such as older age and IL28B CT genotype,(27, 28) had no measureable impact on outcomes.

There was no viral breakthrough on treatment. In view of the rapid emergence of resistance in some studies of short-term DAA monotherapy,(29, 30) these findings support the concept that dual DAA therapy reduces the risk of viral breakthrough in addition to increasing antiviral activity. Resistance analyses revealed that before treatment, some patients carried NS5A and NS3 polymorphisms predicted to reduce sensitivity to BMS-790052 and some HCV protease inhibitors, respectively.(22, 25) There was no clear relationship between the presence of these polymorphisms and minor inter-patient differences in the rate of early virologic response; however, further study in larger patient cohorts will help determine whether baseline polymorphisms can influence virologic response with this regimen.

The adverse event profile of the dual DAA regimen compares favorably with the more frequent and severe events reported with pegIFN/RBV, although patient numbers in this study were limited. The mild diarrhea experienced by several patients has been reported previously with BMS-650032 and is common with other drugs of this class.(15, 18, 24) While a role for BMS-790052 and/or BMS-650032 in the two serious adverse events cannot be ruled out and the investigator considered these events drug-related, multiple confounding factors existed. The case of pyrexia was consistent with a viral infection and resolved with treatment. In the case of hyperbilirubinemia that led to discontinuation, the time course of laboratory abnormalities and related events suggests a link to the use of cefotiam and meropenem for treatment of infectious gastroenteritis. Both of these agents have been associated with vomiting, diarrhea, and hyperbilirubinemia.(31, 32)

The BMS-650032 dose was reduced during treatment due to transaminase elevations observed with 600 mg twice daily in a concurrent study.(24) In this sentinel cohort, viral suppression was maintained in all patients after dose reduction, and no grade 3 or 4 transaminase elevations occurred during treatment at either dose of BMS-650032. One patient experienced grade 2 transaminase elevations that began at week 16 and persisted during treatment despite BMS-650032 dose reduction at week 19. Although these elevations were not severe, their rapid normalization post-treatment suggests a possible relationship to study treatment. None of the nine patients treated for 24 weeks experienced transaminase elevations post-treatment. Although grade 4 transaminase elevations occurred two weeks post-treatment in the patient who discontinued, the timing of these events and multiple other complications suggest that they were not related directly to study treatment.

In conclusion, the combination of BMS-790052 and BMS-650032 achieved a high rate of SVR24 in patients with HCV genotype 1b infections and prior null response to pegIFN/RBV. These results support the concept that HCV infection can be cured with two DAAs without pegIFN/RBV even in difficult-to-treat populations that lack robust interferon responsiveness. Further research will assess the benefits of DAA combinations in larger and more diverse patient populations.

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The end of the beginning for hepatitis C treatment

Download the PDF here

"The development of an oral regimen of DAA's that can produce SVR in a high proportion of patients is the grail that we seek. It will prolong life and prevent death from liver disease, just as the epidemic reaches crisis proportions. The two studies in this issue of Hepatology bring us much closer to providing the answer to the epidemic."

1. Douglas Dieterich Mt Sinai Hosp NYC
Hepatology Jan 2012

Accepted Article (Accepted, unedited articles published online for future issues)

THE END OF THE BEGINNING FOR HEPATITIS C TREATMENT

"Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning." Winston Churchill.

These are extraordinary times in the history of HCV drug development. We waited 13 years between the approval of ribavirin in 1998 and the approval of telaprevir and boceprevir in 2011. The trajectory of drug discovery and clinical trials has gone from exponential to warp speed since the EASL meeting in April 2011, and these two articles are perfect examples of what has changed the world of hepatitis C; interferon-free combination therapy and in one of the trials, leading to eradication of the virus. The first demonstration in man of IFN-free combination therapy with direct acting antivirals (DAA's) was the INFORM-1 trial presented first at EASL 2009 and published in 2010(1) It showed that a nucleoside analogue polymerase inhibitor (now known as mericitabine) and a protease inhibitor (now known as danoprevir (now boosted with ritonavir) together without PEG or RBV could reduce HCV viral load by 5·1 log10 IU/mL in 14 days with no sign of resistant virus. This was the proof of principle that two DAA's by themselves could render most patients undetectable without PEG or RBV. This combination hit a snag with some danoprevir toxicity issues, and development has slowed. Those issues were successfully resolved with ritonavir boosting and the follow up study to INFORM is now proceeding apace and data will be forthcoming from that trial in 2012 or 2013.

The Zeuzem study published in this journal (2) compared an all-oral combination of tegobuvir a nonnucleoside polymerase inhibitor given twice daily plus GS 9256 an NS3 serine protease inhibitor with and without ribavirin in two arms for 28 days, at which point they received peginterferon and ribavirin standard of care. The third arm used quadruple therapy with both DAA's plus peginterferon and ribavirin for 28 days and then peginterferon and ribavirin alone. All patients with viral rebound of >.5 log10 from nadir or non response defined as < 2.0 log10 decline at day 5 received peginterferon and ribavirin immediately. Median maximal reductions in HCV RNA were -4.1log10 IU/ml, -5,1 log10 IU/ml and -5.7 log10 IU/ml for tegobuvir plus GS 9256, tegobuvir , GS9256 plus ribavirin and the tegobuvir, GS9256, peg and ribavirin arms. The results were quite instructive. RVR for the two DAA's alone was 7%, for the two DAA's plus ribavirin 38% and for the quadruple therapy arm 100%. The importance of ribavirin in preventing resistance is very clear with this combination and reemphasizes the continuing value of using ribavirin in all oral regimens of DAA's. It also demonstrates the real, but weak antiviral activity of ribavirin (3). Why was this result so much different than that of INFORM where virtually all patients were undetectable at 14 days of dual therapy? The answer lies in the barrier to resistance (4). The nucleoside/nucleotide analogues in general have a very high barrier to resistance and the INFORM study used the nucleoside mericitabine. The barrier to resistance for protease inhibitors is relatively low, and lower still for genotype 1a as opposed to genotype 1b, since the 1a virus only requires one mutation to generate resistance to protease inhibitors, while the 1b virus requires two. Most nonnucleoside polymerase inhibitors have a relatively low barrier to resistance. When you combine two DAA's with relatively low barriers to resistance, it is easy for the virus to produce the double mutants that are resistant to both drugs. Ribavirin slows this down somewhat, but does not add enough antiviral activity to prevent resistance over 60% of the time with tegobuvir and GS 9256. There is one other factor involved in preventing resistance and that is the activity of the DAA. Extremely potent agents, which drop the viral load down to undetectable rapidly, also prevent resistance. A good example of this is the combination study of BI 201335 and BI 207127 (5). This study compared two groups: BI201727 400 mg or 600 mg given thrice daily plus BI 201335 and ribavirin 1000-1200 mg for 4 weeks. In the 400 mg group, the RVR was 73 %( with better response in genotype 1b than 1a, as one would expect with a protease inhibitor in the regimen). In the 600 mg group, the RVR was 100% and did not differ between genotype 1a and 1b. From this data one can infer that the potency of either the protease inhibitor or the nonnucleoside polymerase inhibitor was different, since the same two classes of drugs, plus ribavirin yielded a much higher RVR. To be fair, there was no arm without ribavirin in this study and, of course, it is hard to compare results between studies. The designs of both studies are elegant, simple and easy to understand and advance the field enormously. Gilead is now aggressively addressing the issue of potency by adding a third DAA to tegobuvir and GS 9256 with and without ribavirin. (6)

The other study in this issue of Hepatology (7) advances the field dramatically further. Not only does it move us from RVR without interferon to SVR, but it does it in null responders! This represents a giant step towards the "Holy Grail" of HCV therapy: once daily, oral interferon-free treatment. The world of HCV treatment changed forever in April of 2011 when the first interferon-free SVR's were presented using an NS5A inhibitor and a protease inhibitor, the same two drugs used in the Chayama paper. (8) The 100% SVR with quadruple therapy was overshadowed by the all-oral double DAA combination, without ribavirin that resulted in a 36% SVR. This was the long awaited proof of principle that HCV could be eradicated without interferon. Of note in the all-oral arm was that both of the genotype 1b patients achieved an SVR, but only 2/9 of the genotype 1a patients achieved an SVR demonstrating the differences in activity of protease inhibitors in genotypes 1a and 1b.

The Chayama study in this issue examined the combination of the NS5A BMS-790052 60 mg qd ( now called daclatasvir) and the protease inhibitor BMS-650032 600mg (now called asunaprevir) in null responders, but only in genotype 1b, the most common genotype in Japan. Ten patients received both drugs for 24 weeks. Of the nine patients who completed the study, all achieved an SVR. HCV RNA remained undetectable in the patient who discontinued treatment after two weeks. This is truly a remarkable achievement in the field of HCV treatment. It is only partially applicable to genotype 1a patients around the world, but nonetheless brings us closer to what we seek in HCV therapy: all oral highly effective treatment. This publication marks a turning point in the HCV drug development world. It demonstrates that a protease and an NS5A inhibitor together can achieve an extremely high SVR in null responders, at least in genotype 1b. It is the second trial to show that an SVR is possible without either interferon or ribavirin in null responders.

In the patois of HCV drug development, we often speak of an all-oral regimen as the "Holy Grail" we all seek. In history that term has had many meanings, particularly in Arthurian legends beginning in the late 12th century. The meaning that comes closest, though to what we really intend, is in Wolfram von Eschenbach's Parzival. In it he portrays the grail as a stone that prevents anyone who sees it from dying. The development of an oral regimen of DAA's that can produce SVR in a high proportion of patients is the grail that we seek. It will prolong life and prevent death from liver disease, just as the epidemic reaches crisis proportions. The two studies in this issue of Hepatology bring us much closer to providing the answer to the epidemic.

Source

Scientists show brain vulnerable to Hepatitis C virus

January 18, 2012

(Medical Xpress) -- Scientists at the University of Birmingham have demonstrated for the first time that human brain cells can become infected with the Hepatitis C virus (HCV), it is reported today.

The team of virologists found that the endothelial cells in the brain possess the four main protein receptors necessary for the blood-brain barrier to be targeted by HCV.

The findings, which are published online today in Research Highlights in the journal Nature Reviews Gastroenterology and Hepatology, show that cells other than liver hepatocytes can be vulnerable to HCV infection.

Working with the Manhattan Brain Bank in New York, USA, the researchers, led by Dr Nicola Fletcher, of the University’s School of Immunity and Infection, detected HCV genomic materal in the brains of four of ten infected patients who posthumously donated brain and liver tissue.

The team went on to demonstrate in laboratory tests that brain cells isolated from the blood-brain barrier could be infected with HCV.

‘This is the first report that cells of the central nervous system support HCV replication,’ says corresponding author Professor Jane McKeating, chair of molecular virology at the University of Birmingham. ‘These observations could have clinical implications providing a reservoir for the virus to persist during anti-viral treatment’

"The endothelial cells make up the security system of the brain, a kind of bouncer at the door that keeps out undesirable elements," explains Dr Fletcher. "If this barrier is compromised all kinds of substances can gain access to the brain, which may explain the fatigue and other symptoms reported by HCV-infected patients."

The current standard of care for treating HCV-infected patients is only partially effective, she says, so there is a considerable drive to develop agents that target viral specific enzymes as alternative therapies.

"We anticipate that such agents will be less able to cross the blood-brain barrier compared to existing drugs. We believe our data provides a detailed mechanistic view of how an infectious agent can target the brain."

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family that poses a global health problem. Infection leads to progressive liver disease and has been associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities.

More information: Hepatitis C virus infects the endothelial cells of the blood-brain barrier (Gastroenterology, November 2011)

Provided by University of Birmingham

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Israelis find vitamin D helps against liver diseases

By JUDY SIEGEL-ITZKOVICH
01/17/2012 05:46

Research teams first to discover benefits of treatment against hepatitis C and cirrhosis.

Two Israeli research teams have separately become the first to discover two different benefits from vitamin D against common liver diseases – hepatitis C and cirrhosis.

One involved the mechanism in human cells in the lab, while and the other proved itself on liver tissue in rats. The two discoveries have not yet been tested clinically.

Prof. Ran Tur-Kaspa, from the Rabin Medical Center- Beilinson Campus, and his team worked on hepatitis C, the major factor in chronic liver disease that can lead to cirrhosis. It is also the main cause in the Western world of organ failure requiring a liver transplant and is one of the causes of primary liver cancer.

Antiviral treatment can help in half the cases, but the side effects are serious even if the treatment is effective.

Tur-Kaspa, a liver specialist and researcher who is dean of the Galilee Medical Faculty in Safed, said there is a constant search for medications and other technologies that are more effective and accompanied by fewer side effects.

He and his team investigated ordinary vitamin D, which is already taken by many people as prevention for numerous diseases, to see whether it had any effect on hepatitis C and on liver cells that host it. They discovered, and published in Hepatology, a peer-reviewed medical journal, that vitamin D directly halts the activity of viruses in general and hepatitis C in particular. They also found that a system for actively producing vitamin D is found in liver cells and can activate the immune system and repress the virus.

The research showed without doubt that vitamin D functions in the liver cell, and it causes an increase in naturally produced interferon and repression of the production of the virus, said Dr.
Romy Zemel, who was part of the team. The research proves that integrating the use of interferon and vitamin D boosts the effects synergistically, beyond the effects of each alone.

Interferons are a family of naturally occurring proteins that are made and secreted by immune-system cells. Thus, with the right combination, said the Beilinson researchers, one could destroy the virus. Their discovery was made serendipitously.

Vitamin D is produced as a result of exposure to the sun or taken in the diet or by supplements.

Its classic role, said Tur-Kaspa, is to protect the balance of calcium and phosphorus in the body. Over the years, additional influences such as on the immune system became clear, and at the same time, vitamin D became popular as a number of health benefits were reported.

The Beilinson discovery of the weakening of the hepatitis C virus in the presence of the vitamin opens up a potential treatment for the infections, so one can improve the efficacy of treatment while reducing the dosage of interferon, said Tur- Kaspa.

Meanwhile, the latest issue of Tel Aviv Sourasky Medical Center’s newsletter published an article by Prof. Shimon Reif and colleagues on how vitamin D fights liver cirrhosis, in which liver tissue is replaced by fibrotic scar tissue, usually collagen, leading to the loss of liver function.

Special cells in the liver called hepatic stellate cells (HSCs) collect vitamin D when they are “resting.”

After they are activated, they produce collagen, which leads to fibrosis. Using liver tissue taking from rodents, the Sourasky team treated them with vitamin D and increased the expression of a receptor for the vitamin. This significantly repressed the growth of HSCs, they found.

The same effect was then found in live rats.

Source

ArQule advances drug candidate for liver cancer

Boston Business Journal by Julie M. Donnelly, Reporter

Date: Tuesday, January 17, 2012, 9:12am EST

ArQule Inc. (NASDAQ: ARQL) Said Tuesday that its experimental therapy for the most common form of liver cancer showed positive results in a Phase 2 trial. The Woburn, Mass. biotech said the drug target, tivantinib, when used alone, extended the cancer's time to progression by 56 percent. There are few approved treatments for liver cancer outside of traditional chemotherapy.

The 107 patients in the study either had continued to see their disease progress on currently approved treatments, or could not tolerate them.

The most common primary cancer of the liver, Hepatocellular carcinoma, (HCC) has risen to be the third leading cause of cancer-related death, the company said

“These findings represent the first randomized data reported with a c-Met inhibitor administered as a single agent in HCC,” ArQule chief medical officer Dr. Brian Schwartz said in a statement. “Second-line treatment for HCC remains a challenge, lacking an approved agent. We look forward to presenting complete data from this trial at a peer-reviewed forum later this year, including secondary endpoint, sub-group and biomarker analyses.”

The company reported that side effects of the drug candidate include fatigue neutropenia and anemia. The company said the risk of neutropenia and anemia declined after lowering the dosage of tivantinib.

The company is also studying the potential therapy in two Phase 3 trials to treat non-small cell lung cancer.

The drug candidate is part of a 2008 partnership agreement between ArQule and Japanese drug maker Daiichi Sankyo, Co. Ltd. to co-develop tivantinib in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan, where Kyowa Hakko Kirin Co. Ltd. has exclusive rights for development and commercialization of tivantinib.

Source

Dream of making artificial body parts becoming a reality

by Lachlan Mackinnon, Daily Mirror 17/01/2012

It sounds like a sci-fi movie – doctors growing body parts to cure our ills. But thanks to incredible breakthroughs, bionic repairs for humans are fast becoming a reality.

Experts yesterday revealed they are perfecting “off the shelf” blood vessels, which could revolutionise treatment of heart attacks and strokes.

If the Cambridge University blood vessel team is successful, patients could be spared major operations. The test tube vessels may also treat kidney dialysis patients and repair injuries.

And because the patient’s own skin cells are used, there is less chance of rejection.

Professor Jeremy Pearson, of the British Heart Foundation, said: “This is very advanced. Growing blood vessels means they could be used off the shelf and be put into patients who need bypasses in a leg or heart, which is currently done using their own veins.”

Here are other ways science is giving nature a helping hand...

1. EYES

Experts are working on a cure for blindness - and have taken huge strides towards their goal.

Miikka Terho, 46, from Finland, who suffered an inherited form of blindness called retinitis pigmentosa, was fitted with an experimental chip behind his retina in Germany.

It works by converting light that enters the eye into electrical impulses fed into the optic nerve, restoring some vision.

2. EARS

Bionic ears are transforming the lives of patients. They send sounds from a microphone through a metal coil to electrodes inside the inner ear.

A seven-year-old boy, Troy Probert, who was left deaf after seven meningitis bouts, was able to hear again thanks to computer-activated cochlear implants.

3. WINDPIPE

Patients whose windpipes are ravaged by cancer can have new ones grown in the lab. Scientists at University College London crafted a fake windpipe filled with cells taken from a patient’s own bone marrow.

Once fitted, the cells divided and grew to make an organ indistinguishable from a normal one.

4. BRAIN

Brain “pacemakers” are being developed to treat conditions such as Parkinson’s disease.

Patients with the implants, which send electronic impulses deep inside the brain, reported fewer tremors and stiffness. It involves inserting a wire with electrodes at its tip, which is connected to a small “neurostimulator” unit.

5. FACE

A liquid that can be injected into the face is being developed to help treat disfigured people. Surgeons could use it to rebuild areas damaged by disease or injury.

The liquid, created by Alexander Hillel and his colleagues at Johns Hopkins University, Maryland, US, can be massaged into shape and set using a special light beam.

6. ARM

Amputees could be given a new lease of life with bionic limbs. Livingston-based Touch Bionics’ prostethic arm allowed Patrick Kane, 13, who lost his arm through meningitis, to squash grapes between his fingers.

When he tenses a muscle, tiny pulses of electricity from nerves beneath the electrodes cause the hand to close - and the same process applies for opening his fist.

7. SPINE

Paralysed people have been given hope of using their legs again thanks to research using electrodes.

Baseball star Rob Summers, who was told he would be wheelchair-bound after being hit by a speeding car in Portland, Oregon, US, made medical history as the first person paralysed from the chest down to stand and take a step unaided.

Summers’ legs were able to move because of electrical stimulation from a device implanted in his lower spine.

8. SKIN

Artificial skin used to heal wounds has been developed by UK researchers.

Writing in the journal Regenerative Medicine, UK-based company Intercytex said it had produced promising results in early trials. The skin is made from fibrin gel, a blood clotting protein, and fibroblast cells found in human skin.

9. LEGS

A prosthetic leg that can be programmed for different types of activity and adjusted by Bluetooth has developed by a UK firm.

The limb, which was designed by Otto Bock Healthcare and fitted by ProActive Prosthetics in Elstead, contains a micro-processor which can differentiate between 10 types of activity.

Amputee Matthew Newbury, who is said to be the first person to have the limb fitted, said: “I don’t have to think about every step and therefore I’m not tiring myself out.”

10. PANCREAS

An artificial pancreas has been developed that could be a major advance in the treatment of diabetes.

The metal pancreas, which holds a supply of the hormone insulin kept in place by a gel barrier, could lead to daily insulin injections to control blood sugar levels being unnecessary in the future.

Invented by Professor Joan Taylor at De Montfort University in Leicester, it could move to clinical trials within the next few years.

11. WOMB

Doctors are developing artificial wombs in which embryos can grow outside a woman’s body.

Embryos successfully attached themselves to the walls of these laboratory wombs and began to grow. However, experiments had to be terminated after a few days to comply with in-vitro fertilisation regulations.

12. MUSCLES

Scientists are working on providing replacement muscles for people who suffered serious sporting injuries or damaged limbs in accidents.

They are using gels that expand and contract in response to small electrical currents to create synthetic muscles for replacing heart valves.

Scientists at Nasa’s Jet Propulsion Laboratory in Pasadena are aiming to develop an arm powered by bionic muscles made from these “electroactive polymers” that would be capable of winning an arm-wrestling contest.

13. BLOOD

Artificial blood created from stem cells could soon be tested on Britons.

The Edinburgh and Bristol university scientists behind the research, which could provide industrial-scale quantities of blood, believe it will transform transfusions by preventing hospital shortages and save thousands of lives on battlefields and at the scene of car crashes.

If they crack the recipe, just one human embryo could theoretically provide all the cells ever needed for Britain’s blood supply.

14. LIVER

Scientists have managed to produce a small-scale version of a human liver in the laboratory using stem cells.

The success increases hope new transplant livers could be manufactured, although experts say this is still many years away. UK researchers said it was an “exciting development” but insisted it was not yet certain a fully-functioning liver was possible.

Source

Deadly Dangers from Drugstore Pain Meds a Painful Surprise

Pills, glorious pills - but are they safe? (Image via Wikipedia)

1/17/2012 @ 5:54AM

Could your attempts to cope with common headaches, sore knees or backache be putting you at risk for heart attack, stroke and liver disease? Recent research suggests that both ibuprofen and acetominophen — the two most popular over-the-counter painkillers — carry some potentially and even deadly risks.

Advil and Motrin Linked to Stroke and Heart Attack
Taking ibuprofen and other common NSAIDs (non-steroidal anti-inflammatories) over a long period of time triples the risk of strokes and increases the likelihood of a heart attack, according to this week’s headliner study, published in the British Medical Journal. The new research, conducted at the University of Bern in Switzerland, involved a huge number of subjects; the data were drawn from more than 31 clinical trials involving 116,429 patients. Those who suffered strokes were found to be taking a normal recommended dose (400-600 mg) of ibuprofen three or four times a day.

Meanwhile, the study also found a greatly increased risk of heart attack from all the prescription NSAIDs in the class known as Cox-2 inhibitors. Several years ago, the prescription NSAIDs Vioxx and Bextra were pulled from the market after they were found to put people at risk for heart attack. Another such drug, Celebrex, is still on the market and has also come under attack; a prior study found that people taking Celebrex had twice as many heart attacks as those taking a placebo. The FDA has suggested that people consider alternatives to Celebrex but hasn’t withdrawn its approval. The BMJ study raises the spectre that all the drugs in this class could carry this deadly risk.

Tylenol just as risky – but for your liver
Then there’s last month’s shocker: If you’re regularly taking just a little too much Tylenol (generic name: acetominophen) over the course of the day, you could be permanently damaging your liver and not even know about it. In fact, people who regularly take slightly too much acetominophen over a period of time to relieve pain could be at a higher risk of dying than those who take single overdose of the drug. That’s the message from a study published in the British Journal of Clinical Pharmacology in which researchers tested the blood of people admitted to the hospital and found that the danger of a “staggered overdose,” was much greater than previously thought, often because doctors can’t identify the problem in time to help.

If Tylenol is your go-to painkiller of choice, you’re in good company; acetaminophen is one of the most commonly used drugs in the country, with more than 28 billion doses purchased in the U.S. a year. But since it’s so common, it’s easy to forget it’s an extremely powerful drug; Tylenol overdose is the leading cause of acute liver failure in the U.S., leading to 26,000 hospitalizations and nearly 500 deaths annually, according to the Food and Drug Administration.

Another problem with acetominophen is that’s it’s a standard ingredient in many combination drugs, such as almost all the popular multi-symptom cold remedies, and it’s also in some prescription painkillers like Vicodin. So it’s possible to overdose by mistakenly taking acetominophen in several forms at the same time.

So which painkillers are safe?
Ah, good question. There’s good old aspirin, which hasn’t been associated with serious risks, but also hasn’t been well-studied since it went on the market long before the FDA’s stringent approval proccess was put in place. Aspirin is an NSAID, and as such carries the risk of the standard side effects such as gastrointestinal bleeding and ulcers. However, aspirin has not been linked with heart attack, stroke or liver damage, so that’s something.

Best of all, though, would be to find a treatment that gets at the root cause of your pain, whether it’s headache, back pain, or arthritis. Preventing or eliminating pain through physical therapy, better ergonomic practices, or one of the new biomechanical or neuromuscular therapies. There’s also surgery, of course, but before going that far you might consider one of the new treatments available as an alternative.

At this point, it’s worth considering all your options. Given the risks of these common pain meds, there are many approaches that may be safer in the long run than trying to medicate your pain away.

Source

Enzyme blueprint may improve HIV, hep C treatment

A cartoon of a 'ribbon' presentation of the three dimensional structure of endomannosidase. Red regions are alpha helices, green arrows are beta strands. Credit: Spencer Williams/PNAS

Tuesday, 17 January 2012

by Laura Greenhalgh

Cosmos Online

LONDON: The structure of a unique enzyme in the human body has been identified in a discovery that could lead to treatment against deadly viruses such as HIV and hepatitis C.

Researchers from the University of Melbourne participated in an international collaboration to successfully determine the molecular blueprint of the enzyme endomannosidase, which is involved in synthesising sugar-coated proteins in human cells, and is exploited by viruses to aid their replication.

By describing the structure and activity of the enzyme in unprecedented detail, the new findings published in Proceedings of the National Academy of Sciences pave the way for development of a treatment to prevent viruses from hijacking human cells.

"The implications are quite significant," said Spencer Williams from the University of Melbourne's Bio21 Institute. "Drugs that target the pathway this enzyme is in could be used to stop viruses replicating. And if they can't replicate, then they can't cause disease."

The challenge of HIV, Hepatitis C

Previous efforts to develop treatments have focussed on another group of human enzymes used earlier in the infection process, but these have proved unsuccessful.

"The problem has been that this group of viruses, including HIV, hepatitis C, dengue fever and West Nile virus, are able to bypass the main pathway if inhibited and replicate via a second pathway using endomannosidase. Thus for a treatment to be effective, both pathways need to be blocked," said Williams.

Despite growing knowledge on the location of endomannosidase, scientists remained unable to determine its structure or discover anything about the enzyme's catalytic mechanism. "This endomannosidase bypass pathway has proved a considerable challenge to study," said Gideon Davies, leader of the second research team from the University of York in England.

However, by combining international resources and expertise, the Melbourne and British research teams have for the first time successfully mapped the shape of endomannosidase. In doing so, they also discovered that the enzyme may function via a completely new mechanism.

Unusual endomannosidase

The scientists studied a bacterial version of endomannosidase as a model for the same human enzyme, which they manufactured in sufficient quantities using the bacteria E. coli. They then placed a crystallised form of the enzyme under a powerful X-ray light source and collected the light reflected by individual atoms of the crystal, a state-of-the-art technique known as synchrotron technology.

Using computer software, the researchers then combined the patterns of reflected light to construct a three-dimensional picture of the enzyme. This indicated that endomannosidase contains a barrel-shaped fold in its molecular structure, which houses the enzyme's catalytic centre. The results also indicated the enzyme has some unexpected characteristics.

"It is a surprise in that we expected certain amino acids to be present in specific arrangements, and they were not. As a result we hypothesise that the enzyme is doing its job in an unprecedented new way," said Williams.

The key enzyme

Now the researchers have the molecular blueprint for the enzyme, they can begin to develop drug treatments. "These findings have revealed how we can block the bypass route, stopping the viruses from hijacking human enzymes," said Williams.

This could have significant consequences for the 180 million people infected by viruses like HIV and hepatitis worldwide, and ultimately could benefit an even greater number of people. "We hope that the work will lead beyond viruses and will point the way towards similar treatments for other diseases, including cancer," said Davies.

Commenting on the findings, Keith Stubbs from the University of Western Australia in Perth said, "This research addresses a key enzyme in N-glycan processing that has not been rigorously studied from a structural and biochemical perspective. It now opens the door for further study into how this enzyme is involved in the processing pathway from both a biotechnological and therapeutic perspective."

Williams cautioned that successful treatment may be some way off, but that their latest findings mark a significant breakthrough in this area. "Science moves slowly and in small steps," he said, "but now that we have inhibitors of both pathways we will see if dual inhibition can assist in curing a cell of hepatitis C infection. If this is the case then we will have 'proof-of-concept' that our strategy can be developed further."

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Kidney failure risk higher for liver transplant patients following allocation policy change

Pratima Sharma, M.D., M.S., is an assistant professor in the Department of Internal Medicine

January 16, 2012

ANN ARBOR, Mich.

Media Contacts : Justin Harris: juaha@umich.edu 734-764-2220

U-M researchers identify modifiable risk factors that could limit the incidence of post-transplant end-stage renal disease

Research from the University of Michigan Health System shows the risk for kidney failure among liver transplant recipients is higher following the implementation of Model of End Stage Liver Disease (MELD), a policy change in 2002 that altered how liver transplant allocation is decided.

The study, led by Pratima Sharma, M.D., M.S., an assistant professor in the Department of Internal Medicine, examined the effect of MELD score-based allocation on post-liver transplant kidney failure. MELD, which was introduced in 2002, is a scoring system that evaluates liver disease severity and has since become the basis for deciding which patients receive liver transplants.

The researchers found that the risk of developing post-transplant kidney failure among liver transplant recipients has increased by 15 percent in the MELD era compared to pre-MELD era. The findings were featured in the November 2011 issue of the American Journal of Transplantation.

“We’re not aware of any prior study that has evaluated the impact of MELD-based liver allocation on the risk of new-onset post-transplant kidney failure,” says Sharma. “These findings identify risk factors that could help prevent new-onset end stage renal failure in liver-transplant recipients.”

The researchers previously found that the MELD score excessively weighs the presence of serum creatinine in deciding which patients receive liver transplants. Higher levels of serum creatinine are a sign of renal dysfunction.

When MELD was implemented, more patients with pre-transplant kidney dysfunction began receiving liver transplants. The incidence of simultaneous liver and kidney transplant has also increased significantly in the MELD era.
Researchers say that along with the increasing incidence of post-transplant kidney failure, chronic kidney disease could also be on the rise, affecting health care costs in the future.

“The higher incidence of post-transplant kidney failure may represent the tip of the iceberg,” Sharma says. “Patients with chronic kidney disease could develop kidney failure in the future, which may add to already skyrocketing healthcare costs in terms of additional dialysis cases and increased hospitalization.”

The findings also highlight several modifiable risk factors that could be addressed before, during or after liver transplant and help prevent post-transplant kidney failure.

The researchers found that along with African American race, hepatitis C, pre-liver-transplant diabetes, higher creatinine, lower albumin, low bilirubin and high sodium were significant predictors of post-liver transplant kidney failure.

“Modification of some of these risks that would improve renal function may help prevent or delay post-liver transplant kidney failure,” Sharma says.

# # #

Additional authors: From U-M: D. E. Schaubel, A. O. Ojo and R. M. Merion; From Arbor Research Collaborative for Health: M. K. Guidinger, N. P. Goodrich

Citation: American Journal of Transplantation, DOI: 10.1111/j.1600-6143.2011.03703.x; Nov. 1, 2011. “Impact of MELD-Based Allocation on End-Stage Renal Disease After Liver Transplantation.”

Disclosures: None

Funding: The research was supported by the American Society of Transplantation, the National Institutes of Health and the Scientific Registry of Transplant Recipients.

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Researchers Discover Means for Blocking Hepatitis C Infection

By Adam Daley

Researchers in Canada have discovered a new approach to blocking infection from the hepatitis C virus in the liver that could lead to new therapies.

HCV requires fat to replicate, and a team of scientists at the University of British Columbia have developed an inhibitor that decreases the size of host fat droplets in liver cells and stops the virus from multiplying and infecting other cells.

"Our approach would essentially block the lifecycle of the virus so that it cannot spread and cause further damage to the liver," said François Jean, Associate Professor in the Department of Microbiology and Immunology and Scientific Director of the Facility for Infectious Disease and Epidemic Research (FINDER) at UBC.

The research is published in the journal PLoS Pathogens

Read the full article here …

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A Recently Published Study Investigating Anti-Oxidants For Diabetics Suggests A Nutrient, Alpha Lipoic, Resulted in General Systemic Improvement, Including Liver Health

A recently published study, in the European Journal of Nutrition, investigating the effects and benefits of Alpha Lipoic and diabetic disturbance in the red blood cells of the animals, revealed Alpha Lipoic, a vital biological co-enzyme, also found in food, increased antioxidant activities in the red blood cells, elevated the glutathione (a biological anti-oxidant), lowered Glycation, reduced triglycerides, reduced hyperglycemia and reduced two enzymes, ALT and AST, which are normally elevated in human diabetes. Expanding on this study, Nutri-Med Logic Corp states that another recently published report, summarizing the results of the studies of last 10 years on R-Alpha Lipoic, concluded that R-Alpha Lipoic is the most effective anti-oxidant in Diabetic Neuropathy, in humans, as well

Miami, FL (PRWEB) January 16, 2012

Nutri-Med Logic Corp: Over the last 40 years, many studies have reported the benefits of R-Alpha Lipoic in Diabetes. A search of all published studies in PubMed reveals that this recently published study, in the European Journal of Nutrition, is the first to report a reduced level of ALT (Alanine Aminotransferase), an indicator of liver injury, as well as reduced levels of AST (aspartate aminotransferases ), also a marker of liver health but also found in heart (cardiac muscle), kidneys, brain and red blood cells, in the study of diabetes and Alpha Lipoic.

According to the American Diabetes Association, chronic or even mild elevations of ALT and AST is frequently found in type 2 diabetic patients and/or generally conveys an underlying insulin resistance. The concentration of intracellular hepatic (liver) enzymes that have leaked into the circulation could be a predicator of liver injury. (1)

High AST levels, also, generally manifest liver damage or muscle damage or both, which arises from metabolic disorders, as well.

The reduced form of R-Alpha Lipoic Acid is a vital and biological co-enzymes, produced by the cells in the metabolism of glucose (production of energy). R-Alpha Lipoic is found in variety of food but its concentration does not increase significantly form food but only from its dietary supplementation.

In Germany, R-Alpha Lipoic (also known as R-Lipoic Acid) has been used, for more four decades, as a co-therapy in the treatment of Diabetic Poly-Neuropathy. As the matter of fact, a newly published report on clinical trials of last 10 years, relating to the benefits of R-Alpha Lipoic and the various claims made about it, found Diabetic Polyneuropathy receiving the clearest benefit from R-Alpha Lipoic. (2)

In Japan, Alpha Lipoic Acid was previously sold only as a medicine. In June 2004, the Ministry of Health, Labor, and Welfare of Japan reclassified Alpha Lipoic Acid as a nutrient.

Interestingly, the first human clinical studies in the United States was carried out in late 70's by Dr. Fredrick C. Bartter and Dr. Burton M. Berkson, two associates of the National Institutes of Health for the treatment of chronic liver damage, with about 95% improvement (75 out of 79).

Dr. Burkson, subsequently, received a special license from FDA for the intravenous application of Alpha Lipoic Acid and has been the FDA principal Investigator for intravenous application of Alpha Lipoic Acid for the last 23 years.

In 1996, Professor Lester Packer a senior anti-oxidant researcher and scientist at the University of California (Berkley) declared R-Alpha Lipoic as a universal antioxidant, since it dissolves in water and fat, thus, capable of reaching the entire body.

In the United States, R-Alpha Lipoic Acid is dietary supplement and its application as nutrient should not be confused with its IV application.

In conclusion, Nutri-Med Logic Corp agrees with this recent study and adds that R-Alpha Lipoic is also an effective dietary supplement for Diabetes Neuropathy. Additionally, when taking the results of this study, improvement of ALT and AST in liver of diabetic animals, together with the reversal of liver disease, by Dr. Burkson, R-Alpha Lipoic may have extended its benefits beyond its sole association with diabetes and might offer benefits as a general liver dietary supplement, as well.

Nutri-Med Logic Corp. is a producer of dietary supplements, including a Pharmaceutical Grade R-Alpha Lipoic Acid, the dietary supplement of choice for the Diabetics, in Germany for more than 40 years.

Nutri-Med Logic Corp is also producer of a Natural, Balanced, Deodorized and Concentrated Omega-3, which is also a Pharmaceutical Grade Omega-3;

Producer of PolyEnylPhosphatidylCholine (PPC 425mg), an extract of soy and the recommended dietarty supplement for those with Fatty Liver and Alcoholic Liver Disease, in Europe for about 50 years.

Nutri-Med Logic's products are Formulated Based on Nutritional Logic, made from the highest quality raw materials that are manufactured in pharmaceutical facilities, encapsulated in pharmaceutical facilities and packaged in pharmaceutical facilities.

It must be noted that the studies, sources or statements above or below have not been evaluated by The FDA and, thus, one should not relate the cause of any diseases, stated herein, to lack of the dietary supplements, stated herein, nor equate their supplementation to prevention, treatment or cure.

1. Clinical Diabetes July 2005 vol. 23 no. 3 115-119
2. Front Pharmacol. 2011;2:69. Epub 2011 Nov 17.

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Response to Comments on An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection

An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases

These evidence-based guidelines are developed and updated regularly by a committee of hepatology experts and include recommendations of preferred approaches to the diagnostic, therapeutic, and preventive aspects of care.

You will need Adobe Acrobat Reader to view these documents.

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Response to Comments on An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection

1) I think the guidelines are fine. I do have a question as to follow up of a Genotype 1 patient who does not want treatment and also the Genotype 1 patient who fails triple therapy?

Response:
Monitoring of patients with all genotypes who do not warrant or want treatment was not addressed in the guidelines. Frequency of monitoring should be based on underlying disease severity. Patients with mild disease could be seen every six months while those with more advanced disease should be seen every three to four months; this recommendation is based on expert opinion. Patients with cirrhosis need to be considered for periodic surveillance for esophageal varices and hepatocellular carcinoma as per AASLD guidelines on Management of Esophageal Varices and Hepatocellular Carcinoma.
2) There is no consideration for IL28B testing to determine if some patients are good candidates for double therapy with Pegylated Interferon with Ribavirin vs. triple therapy. Since, compliance is a major issue with the triple therapy, providing an option with double therapy to patients who would respond well based on IL28B should be addressed.

Response:
The advantages of using PI-based treatment even in persons with IL28B genotype CC are that more persons will qualify for abbreviated therapy with telaprevir and possibly boceprevir, and there are higher SVR rates than double therapy. The advantages of treating IL28B genotype CC patients with peginterferon and ribavirin alone are fewer side effects, fewer drug-drug interactions, and lower cost. However, until cost effectiveness studies are published, we recommend the PI-based approach in most patients.

3) I am surprised there is so little commentary on which patients warrant treatment. This is a significant omission. Future guidelines and commentary should include a balanced discussion framing the pros and cons of treatment according to typical patient scenarios. These therapies are still prone to many side effects, and many patients have little urgency to treat, yet are feeling pressured to participate.

Response:
This question was beyond the scope of our mandate and will be reconsidered in the next full update to the guidelines. The issue is a highly controversial one with many different opinions. Many factors go into the decision regarding whom to treat including disease severity, likelihood of response, benefits and risks of treatment, as well as the likelihood of new therapeutic options. As efficacy and safety of therapy improves many of these factors may become less important and it is likely that most patients will become candidates for therapy.

4) The #16 recommendation of the guideline is somewhat contradictory to the #9 recommendation: In #9, the futility rule is described as the following: "telaprevir, peginterferon alfa and ribavirin should be stopped if the HCVRNA level is >1,000 IU/ml at treatment weeks 4 or 12". But in #16 it says that "the protease inhibitor should be discontinued if virological breakthrough (>1 log increase in serum HCVRNA above nadir) is observed". If telaprevir was used, there are occasions HCVRNA measured 10 times higher from nadir (e.g. Around 10 IU/ml to the hundreds but well within 1000 IU/ml futility limit) during telaprevir dosing period. If the clinician follows #9, telaprevir should be continued but if #16 was followed, telaprevir needs to be stopped. Therefore, this inconsistency needs to be addressed.

Response:
The two statements are not contradictory. To clarify, the stopping rule in #9 applies to patients who reach a virological plateau after which continued therapy would significantly increase the risk for antiviral resistance. Recommendation #16 deals with compliant patients who experience virological breakthrough signifying the emergence of antiviral resistance. Although the author is correct, among the patients with virological breakthrough, their HCV RNA may increase from undetected to 100 IU/ml and still be under the 1,000 IU/ml rule; the important point is the change from a negative to a positive test.

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Idenix Seeks Partner for Hepatitis C Combination, CEO Says

January 13, 2012 9:05 PM

(Updates with closing share price in sixth paragraph.)

Jan. 13 (Bloomberg) -- Idenix Pharmaceuticals Inc., the developer of an experimental hepatitis C drug, is in talks to find a partner to create a combination treatment to fight the virus, Chief Executive Officer Ron Renaud said.

“If we think about how we can be very competitive, it is going to be about combining our compound with others,” Renaud said in an interview at the J.P. Morgan Healthcare Conference in San Francisco. That will be “our whole strategy.”

The Cambridge, Massachusetts-based biotechnology company finished the year with $118 million in cash, “enough to take us through to the end of this year,” Renaud said. There is a mid- year goal to find a partner for their drug, as part of a process of “evaluating paths forward,” he said.

The development of drug cocktails for HIV, the virus that causes AIDS, “is a very good road map for what could happen in hepatitis C,” Renaud said. HIV treatment involves a “combination of compounds with different mechanisms of action and compensating resistance profiles that beat the disease.”

Renaud declined to comment on whether the company may be acquired as the result of other recent purchases in the hepatitis C field.

Idenix gained 13 percent to $14.42 at the close in New York. The shares have more than doubled since Jan. 7 when Bristol-Myers Squibb Co. said it would pay about $2.5 billion in cash for Inhibitex, a rival in a possible $20 billion hepatitis C market. Pharmasset, the maker of another experimental treatment for the virus, agreed on Nov. 21 to be acquired by Gilead Sciences Inc. for $10.8 billion.

Safer Treatments

As many as 170 million people worldwide carry the hepatitis C virus, and current drugs, given through injection, can have side effects that make therapy difficult to endure. The new medicines are designed to be taken as pills, with a higher cure rate and fewer side effects.

On Jan. 9, Idenix reported that its lead drug candidate for hepatitis C, called IDX184, showed no serious side effects in patients after 28 days of treatment. Renaud said the company had submitted the data to the U.S. Food and Drug Administration, and expects to hear whether restrictions on its trials are lifted within a month.

“We are certainly going to combine IDX184 with protease inhibitors, and maybe a NS5A inhibitor,” Renaud said yesterday, describing drugs that attack different checkpoints for the disease as it moved through the human body.

While people are “very excited about the prospects” of an Idenix takeover, at current trading levels, the “valuation is very rich for M&A,” said Brian Skorney, an analyst at Brean Murray Carret & Co in New York.

Skorney said IDX184 needs another potent drug to “cover for its weaknesses” and pointed toward Merck & Co., the second- largest U.S. drugmaker, as an ideal suitor with its experimental protease inhibitor, MK-5172. He said Johnson & Johnson, the world's biggest health-care products company, also may have an interest because of its hepatitis C research program.

--Editors: Andrew Pollack, Angela Zimm

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Adjuvant interferon doesn't prevent HCC recurrence

Last Updated: 2012-01-06 15:13:29 -0400 (Reuters Health)

By David Douglas and Nancy Lapid

NEW YORK (Reuters Health) - Postoperative therapy with interferon alfa-2b doesn't keep hepatitis-related hepatocellular carcinoma (HCC) from recurring, Taiwanese researchers have found.

As Dr. Pei-Jer Chen, who headed the study, told Reuters Health by email, "Interferon alfa 2b adjuvant therapy failed to reduce HCC recurrence or (improve) overall survival in patients receiving surgical resection. Now other combination adjuvant therapies are urgently needed."

In a report this month in Annals of Surgery, Dr. Chen of National Taiwan University College of Medicine, Taipei and colleagues note that although most individual trials of adjuvant interferon in this setting had failed, meta-analyses had suggested that interferon alfa-2b could be of benefit after curative ablation.

To investigate further, the researchers enrolled 268 patients in a randomized trial of adjuvant interferon alfa-2b, or no interferon, after curative surgery. Eighty percent of the patients had hepatitis B virus (HBV) surface antigen; the others had hepatitis C.

During a median follow-up of slightly more than five years, 58% had tumor recurrence and 31% died. Intention-to-treat analysis gave a five-year recurrence-free survival of 44.2% and overall survival of 73.9%.

Overall, the median recurrence-free survival was 42.2 months in the interferon group and 48.6 months in controls. Broken down by etiology, disease-free survival in the interferon and control groups, respectively, was 42.2 and 31.1 months with HCV and 42.4 and 49.1 months with HBV. None of these differences was statistically significant.

As could be expected, side effects were more common with interferon. Treated patients had a significantly higher incidence of leukopenia and thrombocytopenia.

Viral replication was only temporarily suppressed during the treatment, and the researchers suggest that "studies to investigate a more permanent inhibition of HCV replication by pegylated interferon alfa/ribavirin combinations deserve further exploration." For HBV, they add, oral nucleoside analogs may be of use.

Dr. Chen and colleagues began enrolling patients in this trial more than seven years ago. Dr. Yuman Fong from Memorial Sloan-Kettering Cancer Center in New York City, who was not involved in Dr. Chen's study, confirmed for Reuters Health that in the years since that trial was designed, nothing more promising has appeared on the horizon.

It's "very sad," he said in an email, "since 750,000 patients get HCC each year."

If he were doing the study now, Dr. Fong added, he "would take only patients with detectable virus in blood and randomize to current generation antivirals."

SOURCE: http://bit.ly/uMPbn6

Ann Surg 2011

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Lab in Hep C progress

By Jonathan Mayo | Last updated: 11:47, 12/01/2012

The first clinical trial in humans of a new hepatitis C vaccine has shown promising results, Oxford University researchers have announced.

The results of the trial suggest it may be possible to develop a vaccine which will offer protection against hepatitis C for over a year, and could allow those with infections to be treated. The team of researchers, led by Professor Paul Klenerman and Dr Ellie Barnes of the Nuffield Department of Clinical Medicine, carried out the trial on 41 healthy adults for a year. Professor Klenerman said: “The immune responses we’ve seen are exciting and we are beginning the next stage of trials.” However, he also emphasised that: “While we are hopeful, it could be a long road to any vaccine that protects people against hepatitis C.”

There are currently thought to be around 250,000 people in England and Wales who are infected with hepatitis C. The disease leads to chronic liver damage, often requiring a transplant.

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Also See: Experimental hepatitis C vaccine shows early promise