Showing posts with label GS-9190. Show all posts
Showing posts with label GS-9190. Show all posts

Sunday, January 6, 2013

New therapeutic strategies in HCV: polymerase inhibitors

Review Article
Liver International
New therapeutic strategies in HCV: polymerase inhibitors
Ludmila Gerber, Tania M. Welzel, Stefan Zeuzem*
Article first published online: 3 JAN 2013
DOI: 10.1111/liv.12068
Gerber, L., Welzel, T. M. and Zeuzem, S. (2013), New therapeutic strategies in HCV: polymerase inhibitors. Liver International, 33: 85–92. doi: 10.1111/liv.12068

Author Information
  1. Klinikum der J.W. Goethe Universität, Frankfurt am Main, Germany
  2.  Correspondence Stefan Zeuzem, MD, Professor of Medicine, Chief \x96 Department of Medicine I, J.W. Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
    Tel: +49 (0)69 6301 6899 or 4544
    Fax: +49 (0)69 6301 6448
antiviral therapy;
hepatitis C;
non-nucleoside polymerase inhibitors;
nucleoside polymerase inhibitors

The characterization of the viral life cycle facilitated the development of directly acting antiviral drugs. Among those, several inhibitors of the viral RNA-dependent RNA polymerase have proven effectiveness in clinical trials. The characteristics of different nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as their clinical applications and combinations with other classes of directly acting antiviral drugs are reviewed herein.
DAA directly acting antiviral
eRVR extended rapid virological response
HCV hepatitis C virus
HCC hepatocellular carcinoma
PEG-IFN pegylated interferon
PI protease inhibitors
RVR rapid viral response
RBV ribavirin
SOC standard of care
SVR sustained virological response
According to the World Health Organization (WHO), about 3% of the world's population has been infected with the hepatitis C virus (HCV). Of those, approximately 170 million are chronic HCV carriers at risk of developing cirrhosis and hepatocellular carcinoma (HCC) contributing to a large percentage of liver transplantations in Europe and the United States [1].
For almost a decade, the combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) has been the standard of care (SOC) producing sustained virological response (SVR) rates of ~50% in treatment-naive patients infected with HCV genotype 1 and 70–90% in patients infected with HCV genotypes 2 and 3 [2]. Recently, this therapeutic backbone has been supplemented by the addition of first- generation protease inhibitors (Telaprevir, Boceprevir) directly targeting the viral NS3/4A protease. This ‘triple therapy’ improved SVR rates to 70–80% in treatment-naive patients infected with HCV genotype 1 [3, 4].
The development of directly acting antiviral (DAA) HCV therapeutics was facilitated by the adaptation of HCV to a cell culture system allowing the description of the HCV lifecycle and identification of potential novel drug targets. In addition to protease inhibitors (PI), these targets include inhibitors of the non-structural NS5A enzyme, a protein possibly involved in HCV replication, and nucleoside/nucleotide analogue and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase (RdRp/NS5B) [5-7].
The following sections provide an overview of novel therapeutic strategies involving nucleoside/nucleotide analogue and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase (RdRp/NS5B).
Function and biological role of the Hepatitis C Virus (HCV) polymerase inhibitor
A highly structured association of RNA and viral proteins, of cellular proteins and cofactors, and of rearranged intracellular lipid membranes derived from the endoplasmic reticulum are essential for replication of the viral RNA genome [8]. The key enzyme in this process is NS5B, a RNA-dependent RNA polymerase, catalysing the synthesis of a complementary negative-strand RNA by using the positive-strand RNA genome as a template. Numerous RNA strands of positive polarity are produced by NS5B activity from this negative-strand RNA and serve as templates for further replication and polyprotein translation [9].
Schematically, the NS5B protein has the shape of a right hand with an active site located within the palm domain and encircled of a thumb and a finger domain (Fig. 1). The thumb domains act as regulator of nucleic acid binding and the catalytic efficiency of the enzyme's active site, while the palm domains coordinate the function of the active site and carry out the nucleotidyl transfer reaction [10].
Figure 1. NS5B polymerase structure and molecular target sites. Ribbon model of the NS5B polymerase from PDB structure 2IJN. Palm, thumb and fingers are coloured in red, green and blue respectively, with finger loops coloured in yellow. Active site with bound inhibitor (blue space-filling model) and non-nucleoside inhibitor (NNI) sites 1–4 are indicated.

Figure 1. NS5B polymerase structure and molecular target sites. Ribbon model of the NS5B polymerase from PDB structure 2IJN. Palm, thumb and fingers are coloured in red, green and blue respectively, with finger loops coloured in yellow. Active site with bound inhibitor (blue space-filling model) and non-nucleoside inhibitor (NNI) sites 1–4 are indicated.

Two classes of NS5B inhibitors have been developed: nucleoside/nucleotide and non-nucleoside polymerase inhibitors.

Nucleoside/nucleotide analogue polymerase inhibitors
Nucleoside/nucleotide analogues act as natural polymerase substrates leading to termination of RNA chain elongation by inhibition of the active site of the HCV RdRp.
Mostly synthetic prodrugs of nucleotides are administered to facilitate resorption, and additional steps of intracellular phosphorylation are required to gain full functional activity as a nucleosid triphosphate.
Because of high conservation of the active site of the HCV RdRp across all HCV genotypes, these drugs have pan-genotype equivalent antiviral activity in vitro. In vivo data have not yet been completed. In vitro, nucleosidic inhibitors display a low ‘genetic barrier to resistance’ as drug resistance can be observed with single amino acid substitutions. However, because of the poor fitness of resistant variants in the presence of nucleosidic inhibitors, these agents are considered to have a high overall ‘barrier’ to resistance.

Non-nucleoside polymerase inhibitors
Non-nucleoside inhibitors bind outside the active site and target allosteric sites on the surface of the enzyme, downregulating the RdRp activity through induction of conformational changes (Fig.1).
Non-nucleoside inhibitors are so far specific for HCV genotype 1. The efficacy against genotype 1 subtypes, however, may differ. The barrier to resistance of non-nucleoside inhibitors is considered to be low.
Four groups of non-nucleoside inhibitors have entered clinical development
(summarized in Table 1).

Table 1. Polymerase inhibitors in clinical development
Efficiency / log decline (log10 IU/ml)
Generic namePhase of developmentMonotherapyCombinationComment
Nucleosidic inhibitors
NM-283 (Idenix)ValopicitabinPhase Idiscontinued0.87 (15 d)3.90-4.56 (IFN)Gastrointestinal side effects
R-1626 (Roche) Phase IIdiscontinued2.6-3.7 (14 d) 5.2 (IFN/R)Neutropenia, lymphopenia, neurotoxicity
INX-189/BMS-986094 (Inhibitex/BMS) Phase IIIdiscontinued0.6-4.25 (7 d)0.75-3.79 (R/7 d)Liver and severe cardiac & renal toxicity
PSI-938/GS-938 (Pharmasset/Gilead) Phase IIIdiscontinued4.8-5.8 (14 d) Hepatotoxicity
Alios-2200 (Alios) Phase Iongoing4.54 (7 d)n.a.
Alios-2158 (Alios) Phase Iongoingn.a.n.a.
R-7128/RG-7128 (Roche)MericitabinePhase IIongoing2.7 (14 d)5.00
PSI-7977/GS-7977 (Pharmasset/Gilead)SofosbuvirPhase IIIongoing4.7 (7 d)6.4 (IFN/R)
Non-nucleosidic inhibitors
Thumb I inhibitors
BILB-1941 (Boehringer Ingelheim) Phase Idiscontinued> 1 (5 d)/gastro-intestinal side effects
MK-3281 (Merk) Phase Idiscontinued3.75 (7 d)/gastro-intestinal side effects
BI-207127 (Boehringer Ingelheim) Phase IIongoing0.6-3.1 (5 d)5.6 (IFN/R)
Thumb II inhibitors
VX-759 (Vertex) Phase Idiscontinued2.5 (10 d)3.7 (VX222)low anti-viral efficacy
VX-916 (Vertex) Phase Idiscontinued1.5 (3 d)/low anti-viral efficacy
GS-9669 (Gilead) Phase Iongoing3.5 (3 d)/
PF-00868554 (Pfizer)FilibuvirPhase IIongoing0.68-2.13 (8 d)3.44-4.43 (IFN/R)
VX-222 (Vertex) Phase IIongoing3.1-3.4 (3 d)ongoing
Palm I inhibitors
ABT-333 (Abbott) Phase Iongoing0.7-1.5 (2 d)3.5-4.0 (IFN/R)
ABT-072 (Abbott) Phase Iongoing1.19-2-3 (2 d)(ABT-450/-333)
ANA-598 (Roche)SetrobuvirPhase IIongoing2.4-2.9 (3 d)outstanding
Palm II inhibitors
HCV-796 (ViroPharma/Wyeth)NesbuvirPhase Idiscontinued1.4 (14 d)/hepatotoxicity
IDX-375 (Idenix) Phase Idiscontinued0.5-1.1 (1 d)/hepatotoxicity
GS-9190 (Gilead)TegobuvirPhase IIongoing1.4-1.7 (8 d)5.7 (9256/IFN/RBV)

Thumb I inhibitors (benzimidazole site): MK-3281 (Merck, Rahway, New Jersey, USA), B ILB1941 and BI 207127 (Boehringer-Ingelheim, Ingelheim am Rhein, Germany) are thumb I site inhibitors. Pre-existing NS5B substitutions known to reduce sensitivity were identified e.g. for BILB1941 at positions V494I/A, I424V and P496A [11].
Thumb II inhibitors (thiophene site): filibuvir (PF-00868554/Pfizer, New York, USA), VX-759, VX-916 and VX-222 (Vertex, Cambridge, Massachusetts, USA) bind to the thumb II site. Variants at position M423 known to confer resistance to filibuvir from in vitro studies were also selected in most patients in vivo. For VCH-759 as well as VCH-916, viral breakthroughs with selection of resistant variants conferring high (M423T/V/I) and medium (L419V/M, I482L/V/T, V494A/I) levels of resistance were described [11].
Palm I inhibitors (benzothiadiazine site): ABT-333, ABT-072 (both Abbott, Abbott Park, Illinois, USA) and Setrobuvir (ANA598; Anadys/Roche, Basel, Switzerland) are inhibitors of the palm I site. Several variants (M414T, G554D, D559G) were described from in vitro replicon studies to confer resistance to ANA598. Mutations associated with resistance in patients treated with ABT-333 were observed at positions C316Y and Y448C [11].
Palm II inhibitors (benzofuran site): nesbuvir (HCV-796/ViroPharma/Wyeth, Exton, Pennsylvania, USA) and IDX-375 (Idenix, Cambridge, Massachusetts, USA) act at the palm II site. The C316Y mutation in NS5B is associated with resistance to HCV-796 in vitro and in vivo [11].

Polymerase inhibitors in clinical trials
Nucleoside and non-nucleoside inhibitors have been investigated in combination with PEG-IFN and RBV and in PEG-IFN-free therapeutic regimens.

Nucleos(t)ide inhibitors
Several drugs in clinical development were discontinued because of clinically significant side effects including valopicitabine (NM-283), R-1626, PSI-938 and BMS-986094 (formerly known as INX-189) (Table 1).
Promising clinical data have been presented for the following HCV nucleos(t)ide analogues that have entered phase 2/3 clinical testing: mericitabine (RG-7128; prodrug of the pyrimidine (cytosine) nucleoside analogue PSI-6130) and sofosbuvir (PSI-7977/GS-7977; chirally pure isomer form of PSI-7851; prodrug of the nucleotide pyrimidine (uridine) analogue GS-7411). Early results were recently reported for ALS-2200, a novel nucleotide pyrimidine analogue polymerase inhibitor with a median reduction in HCV-RNA of 4.54 log10 after 7 days of dosing [12].

Nucleos(t)ide inhibitors in clinical trials with interferon

Mericitabine (RG 7128)
The PROPEL study investigated safety, tolerability and efficacy of 8 and 12 weeks of mericitabine (1000 mg BID) in combination with PEG-IFN/RBV in 408 treatment-naive patients with chronic HCV genotype 1 or 4 infection. The rapid viral response (RVR) rates were up to 62% in the treatment arms with mericitabine compared with 18% in the control arm with PEG-IFN/RBV alone. SVR rates, however, did not differ between patients receiving mericitabine in combination with PEG-IFN/RBV and patients who received placebo plus PEG-IFN/RBV for 48 weeks. In the response-guided arms, fewer patients achieved SVR (33–49%) because of high virological relapse rates [13].
The JUMP-C trial (phase 2) investigated the safety and efficacy of 24 weeks of response-guided therapy with mericitabine (1000 mg BID), PEG-IFN/RBV in 168 treatment-naive patients with HCV genotype 1 or 4 infection. Patients were randomized (1:1) to response-guided therapy with mericitabine plus PEG-IFN and RBV for 24 or 48 weeks or to placebo, PEG-IFN/RBV for 48 weeks. In the mericitabine treatment arm, therapy was stopped at week 24 in patients with an extended rapid virological response [eRVR], defined as undetectable HCV RNA (<15 IU/ml) from week 4 to 22. Patients without eRVR received PEG-IFN/RBV for another 24 weeks. Overall SVR rates were higher in patients treated with mericitabine plus PEG-IFN/RBV than in patients treated with PEG-IFN/RBV alone (58% vs. 36%). Among 49 patients (60%) who achieved an eRVR with mericitabine plus PEG-IFN/RBV and discontinued therapy at week 24, the SVR rate was 78%. Combination therapy with mericitabine was safe, well-tolerated, demonstrated a high resistance barrier and a low potential for pharmacokinetic drug–drug interactions [14].
The MATTERHORN study, another phase 2 trial, is an ongoing study evaluating the efficacy and safety of various combinations of mericitabine and ritonavir-boosted danoprevir and PEG-IFN/RBV in patients with HCV genotype 1 infection.
The ongoing phase 2 DYNAMO I and II studies investigate quadruple therapy with mericitabine in combination with the protease inhibitors boceprevir or telaprevir and PEG-IFN/RBV in HCV genotype 1 non-responders to PEG-IFN/RBV.

Sofosbuvir (GS-7977, formerly PSI-7977)
The combination of sofosbuvir (400 mg QD), PEG-IFN and RBV was assessed for 12 weeks in 25 treatment-naive patients infected with HCV genotypes 2/3 in an open-label, uncontrolled pilot study (PROTON). Of the patients, who completed therapy (n = 24), 100% achieved an SVR. Based on these favourable results, the PROTON study was expanded to treatment-naive patients infected with HCV genotype 1. Patients were randomized 2:2:1 to different dose groups of sofosbuvir (200 or 400 mg QD) for 12 weeks plus PEG-IFN/RBV for 24 weeks. Patients without RVR were continued on PEG-IFN/RBV through week 48. Reported SVR rates were 88, 91% and <50% for sofosbuvir 200, 400 mg and the control group respectively [15, 16].
The ELECTRON study investigated sofosbuvir (400 mg QD) and RBV for 12 weeks in combination with 0, 4, 8 or 12 weeks PEG-IFN. All patients (n = 10 per group) achieved an SVR after 12 weeks of therapy [17].
The ATOMIC study, a Phase 2 randomized open-label trial investigated sofosbuvir in combination with PEG-IFN/RBV in 316 non-cirrhotic HCV genotype 1, 4 and 6 patients. Patients infected with HCV genotype 1 were randomized to 12 or 24 weeks sofosbuvir, PEG-IFN/RBV, or 12 weeks of the triple combination followed by re-randomization (1:1) to receive additional 12 weeks of either sofosbuvir alone or sofosbuvir plus RBV. Also, 16 patients infected with HCV genotypes 4 and 6 were randomized to the 24-week regimen of sofosbuvir plus PEG-IFN/RBV. Results of an interim analysis showed SVR rates of 90% in patients who received 12 weeks of the triple combination [18].
The phase III trial NEUTRINO, a single-arm study, evaluating a 12-week course of sofosbuvir plus PEG-IFN/RBV in 300 patients infected with HCV genotypes 1, 4, 5 and 6 is currently ongoing.

Nucleos(t)ide inhibitors in clinical trials without interferon
Nucleos(t)ide analogues were also investigated in combination with RBV, NS3/4A protease inhibitors, NS5A inhibitors and/or other nucleotide inhibitors in IFN-free treatment regimens.

Mericitabine (RG 7128)
The INFORM-1 study provided first proof of principle that suppression of HCV RNA with an interferon-free combination of mericitabine and danoprevir (NS3/4 protease inhibitor) is effective. Different doses of mericitabine in combination with danoprevir were administered for 14 days to patients infected with HCV genotype 1. At the highest combination doses tested (1000 mg mericitabine and 900 mg danoprevir BID), the median change in HCV RNA concentration from baseline to day 14 was −5.1 log(10) IU/ml in treatment-naive patients and −4.9 log(10) IU/ml in previous null-responders to PEG-IFN/RBV therapy[19].
INFORM-SVR, a phase 2b trial, subsequently investigated a 12 or 24 week interferon-free regimen of ritonavir-boosted danoprevir (DNV/r, 100/100 mg), and mericitabine (1000 mg BID) with or without RBV in treatment-naive HCV genotype 1 infected patients. Patients with undetectable HCV RNA at week 2 and week 10 were re-randomized at week 12 to stop therapy or to continue until week 24. Rapid viral response was similar and comparable in both arms (91 and 93% respectively). Owing to high relapse rates, however, the 12-week treatment arm was prematurely stopped. Furthermore, patients randomized to the RBV-free group were offered to continue on PEG-IFN/RBV therapy because of insufficient SVR rates. The data show SVR in 71% of HCV genotype 1b patients, but only in 26% of the genotype 1a-infected patients who received 24 weeks of DNV/r, mericitabine and RBV treatment. Higher SVR rates were reported among patients who were rapid virological responders. Among patients with undetected HCV-RNA at week 2, 80% with genotype 1b and 31% with genotype 1a achieved SVR. IL28B genotype appeared to have less impact on SVR rates.

Breakthrough rates were higher among patients not receiving RBV and showed in all patients, the selection of danoprevir-resistant variants, while only one patient showed the NS5B S282T polymerase mutation associated with resistance to mericitabine. Neutropenia or treatment emergent liver toxicity was not observed [20].
The currently ongoing phase II study ANNAPURNA evaluates the safety, tolerability, and efficacy of combination treatment with mericitabine (1000 mg BID), ritonavir-boosted danoprevir (DNV/r 100/100 mg), setrobuvir (ANA-598) and RBV administered for 12–14 or 24–26 weeks to treatment-naive patients or for 24–26 weeks to non-responders to PEG-IFN/RBV therapy with chronic hepatitis C genotype 1 infection.

Sofosbuvir (GS-7977/PSI-7977)
In the ELECTRON trial, the interferon-free combination of sofosbuvir and RBV achieved 100% SVR rates in treatment-naive patients infected with HCV genotype 2/3. In subsequent cohorts, patients with HCV genotype 1 infection and prior non-response to PEG-IFN/RBV received sofosbuvir and RBV for 12 weeks, but showed high relapse rates after the end of 12 weeks of treatment (89%). Reported SVR4 rates in treatment-naive patients infected with genotype 1 or treatment-experienced patients infected with genotype 2/3 receiving sofosbuvir and RBV for 12 weeks were 88 and 80% respectively [17].
The QUANTUM study, a phase 2b study, was planned as the first interferon-free, pan-genotypic, all-nucleotide study, combining a pyrimidine and a purine analogue, sofosbuvir and PSI-938 with or without RBV for 12 weeks. However, PSI-938 had to be discontinued because of liver toxicity. An SVR rate of 59% was reported for 17 HCV genotype 1 patients [21].
Three ongoing US studies for patients with HCV genotype 2/3 infection are FISSION, POSITRON, and FUSION. FISSION will compare 12 weeks of treatment with sofosbuvir and RBV to 24 weeks of PEG-IFN/RBV therapy. POSITRON evaluates the same combination for 12 weeks in interferon ineligible or intolerant patients. FUSION will examine treatment-experienced patients exploring 12 or 16 weeks of treatment with sofosbuvir and RBV.
Furthermore, a phase 3 study (VALENCE) was recently started to investigate the combination of sofosbuvir and RBV for 12 weeks in treatment-naive and treatment-experienced patients with HCV genotype 2 and 3 infection also in Europe.
Different oral combinations of sofosbuvir (400 mg QD) plus daclatasvir (BMS-790052, 60 mg QD) with/without RBV were tested in an open-label Phase 2a pharmaceutical cross-collaboration in treatment-naive non-cirrhotic HCV genotype 1-, 2- and 3-infected patients. SVR rates were 88, 100, and 79% respectively [22]. Furthermore, a combination study of simeprevir (TMC435) plus sofosbuvir is ongoing and a phase III study, investigating the combination of sofosbuvir and GS-5885 (NS5A inhibitor), is currently in preparation.

Non-nucleoside inhibitors
Several non-nucleoside inhibitors were discontinued from clinical development for different reasons. BILB1941 and MK-3281 were discontinued because of gastrointestinal side events [23-25], VX-759 and VX-916 showed only low-to-medium antiviral activity [26, 27], nesbuvir (HCV-796) and IDX-375 showed elevation of liver enzymes [27].
Currently, BI 207127, VX-222, ABT-072, ABT-333, setrobuvir (ANA-598), filibuvir and tegobuvir (GS-9190) are still investigated in clinical trials.

Non-nucleoside inhibitors in clinical trials with interferon

BI 207127
The SOUND C1 trial evaluated the combination of the non-nucleoside polymerase inhibitor BI 207127 with the protease inhibitor BI 201335 and RBV for 4 weeks followed by BI 201335 and PEG-IFN/RBV in treatment-naive patients with HCV genotype 1 infection. The RVR rates ranged from 73% (genotype 1a) to 100% (genotype 1b). An SVR rate of 94% was achieved in the group receiving a higher dose of BI 207127 (600 mg; TID) [28].

The Phase 2 ZENITH study was designed to evaluate the antiviral activity of the protease inhibitor telaprevir and two dose levels of VX-222 administered with or without PEG-IFN/RBV for 12 or 24 weeks in treatment-naive patients with genotype 1 infection. This quad regimen led to SVR rates of 82–93% [29].

Setrobuvir (ANA-598)
Setrobuvir was studied at different doses in combination with PEG-IFN and RBV in treatment-naive and treatment-experienced patients with HCV genotype 1. Both doses of setrobuvir demonstrated a favourable safety and tolerability profile through 12 weeks. SVR was achieved in 8 of 11 patients (73%) who received 24 weeks of treatment [30].

Tegobuvir (GS-9190)
The antiviral activity of tegobuvir and the NS3/4A protease inhibitor GS-9256 alone or in combination with RBV or PEG-IFN/RBV in treatment-naive patients with HCV genotype 1 was assessed in a phase II trial. Patients were randomized to 28 days of tegobuvir/GS-9256, tegobuvir/GS-9256/RBV or tegobuvir/GS-9256/Peg-IFN/RBV, followed by PEG-IFN/RBV for further 44 weeks. Rapid viral response was observed in 100% (14 of 14) of patients receiving tegobuvir/GS-9256/PEG-IFN/RBV [31]. Response-guided quadruple therapy with tegobuvir and GS-9256 plus PEG-IFN/RBV based on a virological response at week 2 enabled to shorten antiviral therapy to 16 weeks and yielded an SVR rate of 95% [32].
Because of pancytopenia in quadruple therapy combinations including tegobuvir, the polymerase inhibitors GS-9256 or GS-9451, Peg-IFN and RBV, dosing of tegobuvir was discontinued [33].

Non-nucleoside inhibitors in clinical trials without interferon

BI 207127
SOUND-C2 (n = 362), an open-label, randomized, phase IIb trial investigated safety and efficacy of the combination faldaprevir (BI 201335; protease inhibitor), BI 207127 with or without RBV for 16, 28, 40 weeks in genotype 1-infected treatment-naive patients, including 10% of patients with compensated cirrhosis. Patients were randomized to one of five treatment arms: (A) 120mg QD BI 201335 (1335QD) plus 600mg TID BI 207127 (7127TID) and RBV for 16 weeks, (B) 28 weeks, or (C) 40 weeks; (D) 1335QD plus 600mg BID BI 207127 (7127BID) and RBV for 28 weeks; (E) 1335 plus 7127TID (no RBV) for 28 weeks. Randomization to Arm E was stopped prematurely according to FDA feedback on study design prior to data analysis. The RBV-sparing arm showed substantial but lower response rates than other arms of the trial.
This combination therapy achieved a SVR rate of 60% in treatment-naive patients with genotype 1 after 16 weeks of treatment, confirming the potent antiviral activity of this treatment regimen. In patients with liver cirrhosis, an SVR rate of 60% in HCV genotype 1a and up to 83% in HCV genotype 1b-infected patients was reported. The BID (for BI 207127) regimen demonstrated the most favourable safety and tolerability profile with a low rate of adverse event-related study discontinuations. Post-hoc subanalyses by IL28B genotype showed clinically important differences in SVR rates: HCV 1a (IL28B: non-CC) 32% vs. HCV 1a (IL28B: CC) 75% and HCV 1b (IL28B: CC and non-CC) 82–84% [34].

ABT-072 and ABT-333
In the PILOT trial, 11 treatment-naive, non-cirrhotic HCV genotype 1 infected patients expressing the IL28B CC genotype were treated with ABT-450/r (150/100 mg QD), ABT-072 (400 mg QD) and RBV for 12 weeks. The SVR rate was 91%.
Another study (Co-Pilot) investigated ABT-450/r in combination with ABT-333 and RBV in 33 treatment-naive HCV genotype-1 infected patients and 17 non-responders to previous PEG-IFN/RBV therapy. Therapy-naive patients were treated with two different doses of ABT-450/r (250/100 mg and 150/100 mg, Arm 1 and 2 respectively) while prior non-responders received open-label ABT-450/r (150/100 mg, Arm 3). ABT-333 was administered in a fixed dose of 400 mg QD across groups. SVR rates in treatment-naïve patients were independent of ABT-450/r dose and IL28B genotype (95 and 93% for arm 1 and 2 respectively. In previous non-responders (Arm 3), the SVR rate was 47% [35].

The phase 2 ZENITH study was designed to evaluate the antiviral activity of the protease inhibitor telaprevir and VX-222 in a dual regimen, in addition with RBV as triple or with PEG-IFN/RBV as quadruple combination therapy in treatment-naive patients with genotype 1 infection. A proportion of 38% of patients receiving 100 mg VX-222 plus telaprevir and 50% of patients receiving 400 mg VX-222 plus telaprevir were able to undergo only 12 weeks of therapy because of RVR (undetectable HCV-RNA at week 2 and 8) and achieved SVR rates of 83 and 90% respectively [29].

Tegobuvir (GS-9190)
Another interferon-free study, investigating the combination of tegobuvir, GS-5885 (NS5A inhibitor), GS-9451 (NS3/4A protease inhibitor) and RBV for 12 and 24 weeks in treatment-naive and experienced HCV genotype 1 patients demonstrated SVR rates up to 89% in patients treated for 12 weeks and up to 100% in patients treated for 24 weeks. Viral breakthrough occurred only in GT1a-infected patients [36].

The optimal treatment regimens for patients with chronic hepatitis C must still be defined. In many trials, nucleos(t)ide and non-nucleoside polymerase inhibitors are key components. The high resistance barrier of the nucleoside analogue inhibitors provides a potential backbone in various interferon-free treatment combinations. The non-nucleoside inhibitors have complementary resistance profiles to protease inhibitors and NS5A inhibitors and are also positioned to become relevant components in combination trials. In the near future, polymerase inhibitors as key components could be clinically available if ongoing clinical trials continue to show promising results on efficacy, safety and tolerability.

We thank Dr C. Welsch for providing Figure 1.

Financial disclosures: Stefan Zeuzem – Consultancies for Abbott, Achillion, AstraZeneca, BMS, Boehringer-Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, Vertex. Tania M. Welzel – Consultancies for Novartis. Ludmila Gerber has no disclosure.

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    Lalezari J, Lawitz E, Rodriguez-Torres M, et al. Once daily PSI-7977 plus peginterferon/ribavirin in a Phase 2b trial: rapid virologic suppression in treatment-naive patients with HCV genotype 2/3. J Hepatol 2011; 54(Suppl): S28.
  • 17
    Gane EJ, et al. Once daily GS-7977 plus ribavirin in HCV genotypes 1-3: the ELECTRON. Hepatology 2012; 56(Suppl): 3067A.
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    Hassanein T, Lawitz E, et al. Once daily sofosbuvir (GS-7977) plus PEG/RBV: high early response rates are maintained during post-treatment follow-up in treatment-naïve patients with HCV genotype 1, 4, and 6 infection in the ATOMIC study. Hepatology 2012; 56(Suppl): 307A.
  • 19
    Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010; 376: 146775.
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    Gane EJ. Interferon-free treatment with a combination of mericitabine and danoprevir/r with or without ribavirin in treatment naive HCV genotype 1 infected patients. J Hepatol 2012; 56(Suppl): 5556.
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    Gilead Announces Early Sustained Virologic Response Rates for GS-7977 Plus Ribavirin in Genotype 1 Treatment-Naive Hepatitis C Patients: Available at;=&#x00A0;69964&p=irol-newsArticle&ID=1684792&highlight. Accessed: October 2012.
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    Sulkowski M, et al. Potent viral suppression with all-oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (NS5B inhibitor), +/-ribavirin, in treatment-naive patients with chronic HCV GT1, 2, or 3. J Hepatol 2012; 56(Suppl): 560.
  • 23
    Erhardt A, Deterding K, Benhamou Y, et al. Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment. Antivir Ther 2009; 14: 2332.
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    Larrey D, Benhamou Y, Lohse AW, et al. Safety, pharmacokinetic and antiviral effect of BI207127, a novel HCV RNA polymerase inhibitor, after 5 days oral treatment in patients with chronic hepatitis C. J Hepatol 2009; 50(Suppl): S3834.
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    Brainard DM, Anderson MS, Petry A, et al. Safety and antiviral activity of NS5B polymerase inhibitor MK-3281, in treatment-naive genotype 1a, 1b and 3 HCV-infected patients. Hepatology 2009; 50(Suppl): 1026-7A.
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    Cooper C, Lawitz EJ, Ghali P, et al. Evaluation of VCH-759 monotherapy in hepatitis C infection. J Hepatol 2009; 51: 3946.
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    Lawitz E, Cooper C, Rodriguez-Torres M, et al. Safety, tolerability and antiviral activity of VCH-916, a novel non-nucleoside HCV polymerase inhibitor in patients with chronic HCV genotype 1 infection. J Hepatol 2009; 50(Suppl): S37.
  • 28
    Zeuzem S, Asselah T, Angus PW, et al. High SVR following IFN-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI 201335, polymerase inhibitor BI 207127 and ribavirin, followed by BI 201335 and PegIFN/ribavirin – the SOUND-C1 study. Hepatology 2011; 54(Suppl): 486-7A.
  • 29
    Nelson DR, Gane EJ, Jacobson IM, et al. VX-222/telaprevir in combination with peginterferon-alfa-2a and ribavirin in treatment-naive genotype 1 HCV patients treated for 12 weeks: ZENITH study, SVR12 interim analysis. Hepatology 2011; 54: 1435A.
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    Lawitz E, Rodriguez-Torres M, DeMicco M, et al. Antiviral activity of ANA598, a potent non-nucleoside polymerase inhibitor, in chronic hepatitis C patients. J Hepatol 2009; 50(Suppl): S384.
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    Zeuzem S, Buggisch P, Agarwal K, et al. The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C. Hepatology 2012; 55: 74958.
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    Nelson DR, Lawitz E, Bain V, et al. High SVR12 with 16 weeks of tegobuvir and GS-9256 with peginterferon-alfa 2a and ribavirin in treatment-naive genotype 1 HCV patients. J Hepatol 2012; 56(Suppl): S67.
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    Vertex Announces Positive Results from Viral Kinetic Study of the Nucleotide Analogue ALS-2200 in People with Hepatitis C: Available at Accessed: October 2012.
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    Zeuzem S, Soriano V, Asselah T, et al. Virologic response to an interferon-free regimen of BI 201335 and BI 207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: week 12 interim results of the SOUND-C2 study. Hepatology 2011; 54(Suppl): 1436A.
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    Poordad F et al., A 12-week interferon-free regimen of ABT-450/r + ABT-333 + ribavirin achieved SVR12 in more than 90% of treatment-naïve HCV genotype-1-infected subjects and 47% of previous non-responders. J Hepatol 2012; 56(Suppl): S54950.
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Sunday, September 4, 2011

Gilead Amends Study Design for GS 9190 four-drug regimen in ongoing Hepatitis C clinical trials

press release
Sept. 4, 2011, 11:00 a.m. EDT

Gilead Amends Study Design for Ongoing Hepatitis C Clinical Trials That Include GS 9190, Pegylated Interferon and Ribavirin, and Another Direct-Acting Antiviral Agent

Change Does Not Affect Ongoing "All Oral" Clinical Trials Evaluating Multiple Direct-Acting Antivirals in Combination

FOSTER CITY, Calif., Sep 04, 2011 (BUSINESS WIRE) -- Gilead Sciences, Inc. today announced that, in consultation with the U.S. Food and Drug Administration (FDA), the company will amend the design of ongoing clinical trials to discontinue dosing of GS 9190 in hepatitis C-infected patients who are receiving that compound in combination with pegylated interferon and ribavirin, and another direct-acting antiviral agent.

This decision follows reports of two serious adverse events in patients enrolled in two separate studies who were receiving a four-drug regimen of GS 9190, an investigational HCV NS5B polymerase inhibitor; pegylated interferon and ribavirin; and one of two protease inhibitors (GS 9451 in one study and GS 9256 in the second study). Patient safety is Gilead's top priority, and the company will therefore immediately halt the dosing of GS 9190 in patients receiving this combination of medications.

Pegylated interferon in combination with ribavirin is currently part of the standard of care treatment for patients with chronic hepatitis C. Because of the side effects that can be associated with interferon, Gilead is working to develop multiple oral antivirals that, when used in combination, may be able to reduce or eliminate the need for interferon.

Gilead does not anticipate any impact on the timelines for or goals of its planned and ongoing clinical studies evaluating an "all oral" regimen for the treatment of chronic hepatitis C. Studies that include GS 9190 but do not include pegylated interferon will continue as planned. Similarly, studies that include the combination of GS 9451 (an investigational protease inhibitor), GS 5885 (an investigational NS5A) and pegylated interferon and ribavirin will continue.

About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in the forward-looking statements, including the risk that further analysis of the laboratory abnormalities, adverse events and other data obtained to date may not support the continued development of GS 9190 and the risk that further clinical testing of Gilead's developmental compounds (including GS 9190, GS 9451, GS 5885 and GS 9256) and all oral regimens containing such compounds result in laboratory abnormalities, adverse events and other clinical data that may not support the continued development of such compounds or regimens. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2011, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company's website at or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
SOURCE: Gilead Sciences, Inc.

Monday, November 8, 2010

AASLD 2010 Summary Of Hepatitis C Oral Inhibitors

This entry of new investigational oral inhibitors is only a brief collection of data accumulated from following sites: HCV Advocate ,CCO, Medpage, AASLD, NATAP HIV and Hepatitis,Medscape, The Biopharma report and TheMedGuru
The links through out this summary provide the additional information needed to give a complete and accurate profile of these new agents.
The AASLD has released "The Best of The Liver Meeting® State-of-the-Art-Lectures" . The presentation's are available in a multimedia format. As the remainder of these lectures are released they will be added to the blog.
*A link to "The Best of the liver meeting" is on the sidebar
This summary will be updated over the next few weeks with a link also on the sidebar with the current review date.
*data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Telaprevir is an investigational oral protease inhibitor used in combination with pegylated interferon plus ribavirin and is being developed by Vertex in collaboration with Johnson & Johnson.
The two trials named "ADVANCE and ILLUMINATE" were for patients with genotype 1 who have not previously treated.

Response-guided therapy (Response guided therapy is intended to enable the physician to determine the duration of combination therapy based on a patient's viral response during treatment) was used in ADVANCE, whereby patients whose virus was undetectable at weeks 4 and 12 of treatment with telaprevir-based therapy were eligible to reduce their treatment from 48 weeks to 24 weeks.

The Phase 3 ILLUMINATE trial was designed to confirm both the use of *response-guided therapy and to evaluate whether there was any benefit to extending total treatment duration from 24 to 48 weeks."

In ADVANCE and ILLUMINATE, 58% and 65% of people, respectively, met these criteria for 24-week total treatment. In ILLUMINATE there was no benefit in extending therapy to 48 weeks.

Trial REALIZE was the second pivotal Phase 3 trial and was designed to evaluate telaprevir-based regimens in people who had received pegylated-interferon-based therapy but did not achieve a cure. REALIZE is the only Phase 3 clinical trial to date of an investigational direct-acting antiviral to include all major subgroups of difficult-to-treat patients including null responders, who were defined as people who had a less than a 2 log10 reduction in viral load by week 12 of a prior course of therapy.

The Results
Overall in ADVANCE, 75% of people treated with a telaprevir-based combination regimen for 12 weeks, followed by an additional 12 or 36 weeks of pegylated-interferon and ribavirin alone, achieved SVR, compared to 44% of people treated with 48 weeks of pegylated-interferon and ribavirin alone.

In ILLUMINATE, 72% of people overall achieved SVR with telaprevir-based therapy. New data from this study showed that 60% of African Americans/Blacks and 63% of people with advanced liver fibrosis or cirrhosis achieved SVR with telaprevir-based therapy in the overall study analysis. Of African Americans/Blacks whose virus was undetectable at weeks 4 and 12, 88% of people achieved SVR in both the 24-week and 48-week randomized treatment arms. There was no control arm of pegylated-interferon and ribavirin alone in ILLUMINATE.

Results of the REALIZE trial showed that 65 percent of patients treated with telaprevir plus the standard of care were cured, or sustained viral response compared to 17 percent of patients in the control group who were re-treated with just the standard of care.

SVR In The Three Different Groups Were As Follows:
86 percent of re-lapsers were cured after telaprevir treatment compared to 24 percent in the control arm.
Among the second group, the cure rate for the telaprevir-treated patients was 57 percent compared to 15 percent for the control arm.

Control Arm = *SOC pegylated interferon plus ribavirin

Finally, in the last group which consisted of the most difficult to treat patients, telaprevir achieved a 31 percent cure rate compared to 5 percent for the control arm. Results across all three patients types were statistically significant in favor of telaprevir over standard of care, officials report.

Complete Information

Side Effects :In ADVANCE, discontinuation of telaprevir or placebo only due to adverse events during the telaprevir treatment phase occurred in 11% of people in the 12-week telaprevir arm, 7% of people in the 8-week telaprevir arm and 1% of people in the control arm. In ILLUMINATE, 12% of people overall discontinued telaprevir only due to adverse events during the telaprevir treatment phase.

Discontinuation of all drugs due to either rash or anemia was low in both studies (1% to 3%). Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. Ninety-two percent and 95% of rash was mild to moderate in ADVANCE and ILLUMINATE, respectively. Rash was managed with the use of topical corticosteroids and antihistamines, and anemia was primarily managed by reducing the dose of ribavirin. The use of erythropoiesis-stimulating agents (ESAs) were not allowed in any of the Phase 3 clinical studies.

Discontinuation (%) of all drugs during the telaprevir treatment phase


12-week telaprevir arm ..................................7%
8-week telaprevir arm......................................8%
Control Arm.................................... 4%

Total .................................................7%*

There was no control arm in ILLUMINATE

Telaprevir may have * fewer side effects (like anemia) than boceprevir.

Vertex announced a new trial which will be called the "OPTIMIZE" and is for genotype 1 patients who have not previously treated.

AASLD/2010 Telaprevir 3 Studies Showed Superior SVR (Viral Cure)Regardless of Race/Stage Of Liver Disease

AASLD:Telaprevir SVR/Decreased Adverse Events Presented Nov 2

Telaprevir will be filing their FDA Application in the next few weeks
Telaprevir® Vertex To File FDA Application “Within Weeks”
The Cost : Telaprevir

Boceprevir is also an investigational oral HCV protease inhibitor used in combination with pegylated interferon plus ribavirin and is being developed by Merck.

The two trials were the SPRINT-2 trial which enrolled genotype 1 patients who have never treated previously. The RESPOND-2 trial enrolled genotype 1 patients who previously treated but did not respond to or relapsed after treatment.

Merck released final results from two phase-3 studies of boceprevir, saying it produced “significantly higher” results compared with patients in the control group.

In the "RESPOND 2" trial at 24 weeks after conclusion of treatment, the patients treating in the *control arm with "no telaprevir" or with only *SOC achieved a SVR of 21 percent.

Adding Boceprevir to the treatment increased SVR to 59 percent for the second arm *(Second arm received 4 weeks of lead-in therapy of peginterferon alpha 2b and ribavirin followed by response-guided therapy of peginterferon alpha 2b and ribavirin combined with 800 mg of Boceprevir three times a day) and 67 percent for the third arm *(Third arm received 4 weeks of lead-in therapy of peginterferon alpha 2b and ribavirin followed by 44 weeks of peginterferon alpha 2b and ribavirin combined with 800 mg of Boceprevir).

It was noted that previous relapsers fared better than nonresponders in all arms. The therapy was well-tolerated, and the most common reason for discontinuing treatment was for patients who still had detectable HCV-RNA at week 12.

From HCV Advocate

The SPRINT-2 study included 1,097 HCV genotype 1
treatment-naïve patients (never been treated). The treatment
protocol consisted of a 4 week lead-in phase of
PegIntron plus ribavirin (without boceprevir), followed
by the triple combination of boceprevir, PegIntron
and ribavirin. Duration and continuation of treatment
was guided by the type of on-treatment response to the
.The SVR or sustained virological response rates (HCVRNA negative 24 weeks after the last dose of medicine is taken) by different treatment arms are listed below:
.a. If HCV RNA (viral load) negative at week 8 through week 24,
triple therapy was continued for a total treatment duration of 28 weeks;
sustained virological response (SVR) = 63%
a. If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 and PegIntron/ribavirin combination therapy (without boceprevir) was continued for a total treatment duration of 48 weeks;SVR = 66%
a. The control arm was standard of care – PegIntron plus ribavirin—with a treatment duration of 48weeks;SVR = 38%
.African Americans/Blacks—Treatment Response
There were also 159 African American/Black patients in the study—
African Americans/Blacks comprised 15% of the patient population in this trial.
The SVR rates by different treatment arms are listed below:
.a. If HCV RNA negative at week 8 through week 24,triple therapy was continued for a total treatment duration of 28 weeks: SVR = 42%
a.If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 andPegIntron/ribavirin combo therapy without boceprevir) was continued for a total treatment duration of 48weeks; SVR = 53%
a. The control arm was standard of care – PegIntron plus ribavirin—with a treatment duration of 48weeks; SVR = 23%
*If any patients were HCV RNA positive at week 24 all treatment was stopped.

The RESPOND 2 study included 403 HCV genotype 1
“treatment-failure” patients. The study included a 4
week lead-in phase of PegIntron plus ribavirin
(without boceprevir), followed by the triple combination
of boceprevir, PegIntron and ribavirin1 and treatment
duration was based on type of on-treatment response.
.The SVR rates and duration of treatment periods for all
patients are listed below.
a. If HCV RNA negative at week 8 and at week 12 the total
treatment duration was 36 weeks; SVR = 59%
a. IF HCV RNA positive at week 8, but undetectable at
week 12, boceprevir was stopped at week 36 and the
combination of PegIntron/ribavirin was continued for a
total treatment duration of 48 weeks; SVR = 66%
a. Control arm was standard of care – combination of
PegIntron plus ribavirin—for a total treatment duration
of 48 weeks; SVR = 21%
*If any patients were HCV RNA positive at week 12 all
treatment was stopped.
.It is important to know that the treatment duration in the
boceprevir containing arms were 28, 36 or 48 weeks
depending on the type of on-treatment response.

Side Effects: Treatment appeared to be associated with two side effects compared with placebo -- anemia and a distorted sense of taste, or disgeusia. Overall, patients on treatment had greater use of erythropoietin "Note (rescue drugs)" to treat anemia compared with controls (43% for short- and full-course, versus 24% of those on placebo). More boceprevir patients also had to reduce their treatment dose due to anemia (20% and 21% versus 13%). Other adverse events included nausea, headache, and fatigue, at similar rates across all three groups".

Merck began submission of a new drug application for boceprevir on a rolling basis and expects to complete that process by the end of the year.

AASLD Presented Nov 2/Final Results of Clinical Trial on Boceprevir
AASLD:Hepatitis C Drug Boceprevir Six Months of Novel Agent Works
Boceprevir Achieved Significantly Higher SVR Rates In Treatment-Failure And Treatment-Naïve Adult Patients With Chronic Hepatitis C Genotype 1 Compare

Telaprevir Over Boceprevir?
AASLD:Telaprevir/Boceprevir/Similar Cure Rates/Shorter Treatment Duration

.TMC435 is a protease inhibitor used in combination with peg-interferon and ribavirin and is being developed by Medivir and Tibotec Pharmaceuticals .

Tibotec is a global pharmaceutical and research development company. The Company's main research and development facilities are in Beerse, Belgium with offices in Titusville, NJ and Cork, Ireland.
*Excerpt :
In the PILLAR study genotype 1 treatment-naive patients were enrolled in a week-24 planned interim analysis of response-guided treatment.

The compound is given once a day -- an easier regimen than that of the two protease inhibitors closest to market, boceprevir and telaprevir, which are administered thrice daily.
As well, the new data reported for the Tibotec protease TMC435 shows potency with 95% achieving week 24 response rate.

The results showed that in the four TMC435 treatment groups between 79 and 86 percent of patients were able to stop all therapy at Week-24, according to the response criteria defined in the study protocol. There were no relevant differences for adverse events between TMC435 treatment groups and placebo

The PILLAR study [Protease Inhibitor TMC435 trial assessing the optimaL dose and duration as once daiLy Anti-viral Regimen] (TMC435-C205; NCT00882908) is an ongoing, five-arm, global phase 2b randomized, double-blind, placebo controlled study in 386 treatment-naive patients. TMC435 was administered in doses of 75mg or 150mg q.d. for either 12 weeks or 24 weeks in combination with 24 weeks of peg-interferon and ribavirin (PR).

Patients in the placebo arm receive 24 weeks of placebo plus peg-interferon and ribavirin followed by 24 additional weeks of peg-interferon and ribavirin treatment. The primary endpoint of the study is sustained virologic response at Week-72 (SVR24). The PILLAR study is being conducted in 13 countries in Europe, North America, and Australasia.

Patients receiving TMC435 were allowed to stop all treatment at week 24 when a) HCV RNA levels less then 25 IU/mL at week 4 and b) HCV RNA less then 25 IU/mL levels at weeks 12, 16 and 20. Patients who did not meet the above response-guided criteria continued with peg-interferon and ribavirin until Week-48.
Majority Of Patients were undetectable at week 12
TMC435 demonstrated potent antiviral activity, at week 4 (rapid virologic response (RVR)) and at week 12 (complete early virologic response (cEVR)) HCV RNA was undetectable (less then 25IU/ml) for the majority of patients. The viral breakthrough rate was 4.9 percent in the TMC435 treatment groups.

(TMC435 is also being studied in HCV genotype-1 treatment-experienced patients who have failed treatment with peg-interferon and ribavirin. The ASPIRE study (Antiviral STAT-C Protease Inhibitor Regimen in Experienced patients; TMC435-C206; NCT00980330) is an ongoing global phase 2b randomized, double-blind, placebo controlled study in 463 patients)

Side Effects: The most common adverse events were headache and fatigue, 46 percent and 42 percent in the TMC435 groups and 51 percent and 47 percent in the placebo group respectively. There were no clinically significant differences in frequency of rash, anemia or gastrointestinal events between the TMC435 groups and placebo. Most AEs were mild to moderate in severity. AEs leading to treatment discontinuation were reported in 7.1 percent of patients in TMC435 arms and 7.8 percent in placebo arm. In laboratory parameters, significant decreases in transaminases (ALT and AST) were observed in all treatment groups. Small and transient bilirubin elevations (direct and indirect) were seen in the TMC435 150mg dose groups.

AASLD: TMC435 Rapid Response for Once-Daily Protease Inhibitor
AASLD:TMC435 PILLAR study in treatment-naive patients/ genotype 1

RG7128, being developed jointly by Roche and Pharmasset

Background on non-nucleoside polymerase inhibitors "(non-nucs), and nucleoside polymerase inhibitors (nucs)".
*From biopharma report:Both Vertex and Merck intend on launching new HCV treatments in 2011 based on a new class of compounds known as NS3 protease inhibitors (PI). These drugs herald a new breed of targeted medicines- sometimes called direct acting antivirals (DAA). The advantage is a significantly higher cure rate and shorter duration of treatment. However, these drugs are susceptible to viral resistance and require concurrent use with both interferon and ribavirin. A second type of compound focuses on inhibition of the NS5B polymerase. Of these there are two classes, non-nucleoside polymerase inhibitors (non-nucs), and nucleoside polymerase inhibitors (nucs). Both have been shown to be effective in combination with interferon + ribavirin, but non-nucs, like protease inhibitors, are also prone to mutation driven resistance.
On the other hand, nucleoside polymerase inhibitors have a high barrier to resistance. In studies shown by Roche, no resistance was observed in cultures treated with R7128, its nucleoside polymerase inhibitor licensed from Pharmasset, for two weeks as monotherapy. Cultures treated with non-nucs or protease inhibitors all developed resistance. R7128 was also shown to reduce the formation of resistant colonies when added to either a non-nuc or PI. These studies show the flexibility of nucs in combination treatment.

Pharmasset’s lead compound is currently in multiple Phase II trials. Results from the 12 week R7128 treatment portion of a 48 week triple combo PROPEL trial with interferon + ribavirin trial have been released showing high rapid virologic responses and a low rate of adverse events. Full SVR data will be available in 2011. A longer trial involving 24 weeks of dosing called JUMP-C is now dosing. Phase III studies are expected to begin in 2011 as well, with an NDA filing anticipated in 2013.
PROPEL trialRG7128 plus peginterferon (pegIFN) alfa-2a with ribavirin (RBV) demonstrated high rapid virologic response (RVR) and complete early virologic response (cEVR) rates in treatment-naive patients with genotype 1 or 4 HCV infection
.RG7128 had safety profile similar to standard of care
RG7128 not associated with treatment-emergent viral breakthrough or resistance
INFORM-1 Trial
Roche is conducting a combination trial of R7128 with the protease inhibitor R7227=( also known as Danoprevir/ITMN-191) from Intermune. Results from a 14 day INFORM-1 trial showed the drugs were safe when administered together and resulted in a sustained viral load reduction. Continuing studies will add the drug Ritonavir to boost R7227 without increasing side effects
From Doctors Guide: INFORM-1 trial was designed to assess the safety, tolerability, and antiviral activity of an oral combination treatment with 2 experimental drugs, RG7128 (a polymerase inhibitor that blocks elongation of the new HCV RNA chain) and danoprevir (also known as R-7227/ITMN-191) (a protease inhibitor that blocks an enzyme the virus needs to replicate itself) in patients with chronic HCV.A total of 88 patients with HCV genotype 1 were recruited into 1 of 7 treatment groups and randomised to receive various doses and schedules of the combined treatment (n = 74) or placebo (n = 14) for up to 13 days. Some patients had never been treated before, while others had failed interferon-based standard therapy.
Change in HCV RNA concentration was measured at the start of the study and at regular intervals during treatment up to day 14.
Patients who had never been treated before who received the highest doses of the 2 drugs (1000 mg RG7128 and 900 mg danoprevir BID) had a median HCV RNA reduction after 14 days of 5.1 log10 IU/ml, compared with a reduction of 4.9 log10 IU/ml in patients who had shown no response to previous standard treatment, and an increase of 0.079 log10 IU/ml in patients taking placebo.The combined treatment of RG7128 and danoprevir was generally well tolerated with no treatment-related severe side-effects, and no safety-related treatment discontinuations.In addition, there was no evidence of treatment resistance, unlike the rapid development of resistance shown by some classes of direct-acting antiviral drugs when given as monotherapy.
The balance of Pharmasset’s HCV pipeline consists of PSI-7977, which is enrolling patients in Phase IIb and PSI-938, which has completed Phase 1b. The company is planning studies combining these two nucs; initial data should be available Q1 next year. Phase II combo studies are expected to begin around the second or third quarter of 2011
Pharmassets candidates nearing preparation for clinical development:
RG7128, a pro-drug of PSI-6130 for the treatment of HCV, is entering a phase 2b clinical trial through a collaboration with Roche;
PSI-7977, an isomer of PSI-7851 is a nucleotide analog for the treatment of HCV, and is currently in a phase 2b trial;
PSI-352938 (PSI-938), a purine nucleotide analog for the treatment of HCV, recently completed a phase 1 trial.
Slide Presentations:
JG. McHutchinson et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010
Clinical synergy of an anti-HCV nucleotide analog with SOC: Viral kinetics of PSI-7977 with SOCE. Lawitz et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010
High Rapid Virologic Response (RVR) with PSI-7977 daily dosing plus PEG-IFN/RBV in a 28-day Phase 2a trial
E. Lawitz et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010
Danoprevir= (RG7227 formerly R7227 also known as ITMN-191) is a investigational protease inhibitor, which targets the hepatitis C virus, used in combination with the standard of care for HCV infection; peg-interferon alpha-2a and ribavirin. It has demonstrated rapid and profound reductions in HCV RNA.

Roche Acquired the rights to InterMune HCV Protease Inhibitor Danoprevir
From Medscape: The investigational protease inhibitor danoprevir, which targets the hepatitis C virus (HCV), combined with the standard of care for HCV infection — peg-interferon alpha-2a and ribavirin — produces rapid and profound reductions in HCV RNA.
.Entry criteria were noncirrhotic treatment-naïve adults (predominately genotype 1 virus) with serum HCV RNA levels of 50 000 IU/mL or more and without advanced fibrosis.
.All patients were administered a standard of care regimen of pegylated interferon alpha-2a plus weight-based ribavirin, and were randomized, for 12 weeks, to placebo or 1 of 3 danoprevir groups: 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours. When danoprevir was stopped, all patients continued on standard therapy for an additional 24 or 48 weeks, depending on whether or not they achieved a rapid virologic response
.The second part of the study was a planned continuation of danoprevir to week 24, but that "never was undertaken" because of incidents of reversible grade 4 ALT elevations in 3 patients in the 900 mg group, the highest dose of the study, said Dr. Terrault. Patients already enrolled in the 900 mg group were rerandomized to 300 or 600 mg.
.The principle measure of efficacy was an undetectable HCV RNA level (less then 15 IU/mL); measurements were taken at baseline and at weeks 2, 4, and 12. Missing data points were considered to be nonresponders.
.Dr. Terrault reported that the interim analysis of those who completed 12 weeks of danoprevir therapy was based on 62 patients receiving 300 mg (93%), 61 receiving 600 mg (94%), and 8 receiving 900 mg (16%).
At week 2, levels of HCV RNA were undetectable in 52% of the 300 mg group, 57% of the 600 mg group, 62% of the 900 mg group, and 0% of the placebo group.
At week 4, that progressed to 73%, 86%, 86%, and 7%, respectively; and at week 12, to 88%, 89%, 92%, and 43%.
.Viral resistance to danoprevir emerged in the low-dose (300 mg) group in 2 patients at week 2 and in 5 patients at weeks 4 and 12. In the 600 mg group, patients fared better, with 3 developing treatment-emergent resistance by week 12. No patients developed resistance in the highest-dose (900 mg) group, but the cumulative exposure was significantly less because of the emerging toxicity and discontinuation of that dosing regimen. All of the resistance was seen in patients with HCV genotype 1a.
.Side Effects
Rates of most common adverse events in the danoprevir groups were at least twice as high as those seen with standard care alone. Often, there was little difference in the incidence of adverse effects with an increase in the dose of danoprevir.Although the serious adverse event of grade 4 ALT elevation was most likely to occur at the highest dose of the drug (3 incidents) and led to the discontinuation of that dosing, there also was 1 incident among the 60 patients in the 600 mg group. Dr. Terrault said that "modeling the available pharmacokinetics data showed a relationship between danoprevir exposure, specifically AUC and the likelihood of having ALT elevation."
.AASLD:HCV Protease Inhibitor Danoprevir is Positive

BMS-790052 and BMS-650032
BARACLUDE, BMS-790052, and BMS-650032 were discovered by Bristol-Myers Squibb Research and Development. PEG-Interferon lambda was discovered by ZymoGenetics, Inc. Bristol-Myers Squibb and ZymoGenetics announced a global collaboration for PEG-Interferon lambda and its related development program in 2009. In September 2010, Bristol-Myers Squibb announced its intent to acquire ZymoGenetics.

*Excerpt: Combination therapy with BMS-790052 and BMS-650032 alone or with pegylated interferon and ribavirin (pegIFNα/RBV) results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders.
Study Objective:
To assess the safety and antiviral activity of BMS-790052 and BMS-650032 alone or combined with pegIFNα/RBV in patients with HCV genotype 1 who have not responded to prior standard of care treatment (null responders)
Materials and Methods
Patients in Group A were treated with BMS-790052 and BMS-650032. Patients in Group B were treated with BMS-790052, BMS-650032 and pegIFNα/RBV. The response rates for both treatment groups are as follows
One patient in Group B did not meet cEVR; however, on retesting the patient’s viral load was undetectable.** Viral breakthrough was defined as a) any increase in HCV RNA more then 1 log10 from nadir, or b) any detectable HCV RNA more then 25 IU/mL on or after week 4, or c) any detectable HCV RNA less then 25 IU/mL on or after week 4 confirmed by retesting.
Study Conclusion:
Seven out of 11 patients receiving BMS-790052 and BMS-650032 without pegIFNα/RBV achieved rapid virologic response, defined as undetectable viral load by week 4. However, viral breakthrough occurred in six of the 11 patients in this treatment group. Nine out of 10 patients receiving the combination of BMS-790052, BMS-650032 and pegIFNα/RBV achieved complete early virologic response (cEVR), defined as undetectable viral load by week 12.
Side Effects:
Two patients experienced a severe (Grade 3 or 4) adverse event – one patient in Group A experienced fatigue and one patient in Group B experienced low white blood cell count (neutropenia). There was no discontinuation of BMS study drugs due to adverse events (AEs).
AEs were mainly mild to moderate in severity. The most common AEs (more than three occurrences) across both study groups were:

Lambda Pegylated Interferon
PEG-IFN-lambda is one of several molecules Bristol-Myers Squibb is studying for the potential treatment of hepatitis C..
The EMERGE study is a two-part, randomized, controlled, multicenter phase II, phase II study of PEG-IFN lambda in treatment-naïve patients with chronic hepatitis C genotype 1, 2, 3 or 4. ...
To assess the safety and antiviral activity of four fixed doses of PEG-IFN-lambda in treatment-naïve patients with HCV genotypes 1, 2, 3, and 4
.These data are from the first part of the EMERGE study. In this ongoing, open-label Phase IIa study, 55 patients were randomized to receive PEG-IFN-lambda at one of four dose levels (80, 120, 180 or 240 mg) or PEG-IFN-alpha at 180 μg.
Patients received PEG-IFN lambda and PEG-IFN alpha administered subcutaneously on a weekly basis, as well as ribavirin on a daily basis, dosed according to HCV genotype and body weight. Patients with HCV genotype 2 or 3 were studied for up to 24 weeks; patients with genotype 1 or 4 were studied for up to 48 weeks.
.Study Conclusion:
At PEG-IFN-lambda’s three highest dosing levels (120 mcg, 180 mcg, 240 mcg), virologic response at 4 and 12 weeks was similar to or greater than that observed and reported with standard interferons (PEG-IFN-alpha).
Adverse events were mild to moderate in severity and led to few treatment discontinuations.
.Genotypes 1 or 4

Genotypes 2 or 3

Side Effects
BI-201335/BI 207127
The Boehringer Ingelheim group who is developing BI-201335, BI 207127 is located in Ingelheim, Germany.
*They are now in Phase Ib deemed "SOUND-C1". Planning is currently underway to begin Phase II trials of BI 207127 with BI 201335 in interferon-sparing regimens both with and without ribavirin.
BI 201335 is an investigational oral HCV NS3/4A protease inhibitor, discovered from Boehringer Ingelheim’s own research and development, which has completed clinical trials through Phase IIb (SILEN-C studies). This Phase II program supports the investigation of BI 201335 in Phase III trials. BI 207127 is an NS5B RNA-dependent polymerase inhibitor that has completed Phase I clinical trials.
Boehringer Ingelheim Oral Hepatitis C Protease Inhibitor and Polymerase Inhibitor Combination Shows Rapid Viral Response without Use of Pegylated Interferon
The Phase Ib study, SOUND-C1, showed the combination of two oral hepatitis C virus (HCV) compounds, the protease inhibitor BI 201335 and the polymerase inhibitor BI 207127, with ribavirin reduced viral load to the lower limit of quantifiable levels in HCV treatment-naïve patients. The regimen did not include interferon through the first 28 days of treatment
New protease-polymerase inhibitor combination resulted in 73-100% rapid virological responses without pegylated interferon. In this randomised open-label trial, 32 treatment-naïve genotype-1 HCV patients received a combination of BI 207127 in either 400mg or 600mg doses three times a day (TID) with BI 201335 120mg once daily (QD) together with ribavirin (RBV) (1000/1200mg daily in two doses) for 28 days.
All patients had a rapid and sharp decline in HCV viral load during the first two days, followed by a slower second phase decline. In the lower and higher dose groups, 73 and 100% of patients achieved a rapid virological response (i.e. had a HCV RNA below thelower limit of quantification after 4 weeks of treatment).
One patient experienced a viral breakthrough (increase by more then 1 LOG10 from nadir during treatment) and one other experienced a 0.7 LOG10 increase in viral load. Both patients were in the lower dose group of BI 207127 and were patients with a high baseline viral load. On day 29, all patients were switched to treatment with BI 201335 and PegIFN/RBV for an additional 44 weeks per the defined study protocol, and will be followed to evaluate sustained virological response.
“These early data suggest that there is the potential for the combination of oral anti-HCV therapies to reduce the viral load in a more tolerable, interferon-sparing regimen.
Side Effects:The PegIFN sparing treatment was well tolerated. Investigators reported that the most common adverse events observed in the study were mild gastro-intestinal effects (diarrhea, nausea, vomiting), rash or photosensitivity. Laboratory parameters did not indicate any relevant changes from baseline, except for a continuous drop in amino alanine transferase (ALT) in all patients, a decrease of hemoglobin (median -1.7 and -2.6 g/dL) and an increase of unconjugated bilirubin (median +9.8 and +11.5 umol/L) similar to reported results from earlier BI 201335 trials. There were no serious or severe adverse events and no discontinuations due to adverse events reported in the study during treatment with BI 207127 and BI 201335. A phase IIb trial testing different dose regimens of this combination with longer durations is planned to evaluate sustained virological response rates
Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127, and ribavirin, in patients with chronic hepatitis C:
The SOUND-C1 trial
The drugmaker Abbott and its investigational drug ABT-450 is used along with NORVIR® (ritonavir) for the treatment of HCV . "NORVIR is in a class of medicines called the HIV protease (PRO-tee-ase) inhibitors. NORVIR is used in combination with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. NORVIR is for adults and for children age greater than 1 month and older."
*Excerpt :
Abbott and Enanta Pharmaceuticals had positive results from a Phase 2 study of ABT-450/r, an investigational, oral protease inhibitor being developed for the treatment of hepatitis C (HCV) infection. Initial 3-day and 4-week results suggest that ABT-450/r (ABT-450 with 100mg of ritonavir to support once-daily dosing) demonstrates potent antiviral activity in genotype 1 treatment-naïve adults.
Results show that more than 90 percent of patients (21 of 23) on study drug achieved HCV-RNA levels less then 25 IU/mL at four weeks. Results were presented at the AASLD.
Key findings:-- After three days, treatment with ABT-450/r alone resulted in statistically significant, 4-log mean reductions of HCV RNA, across the three dose ranges of ABT-450 (50mg, 100mg, 200mg, once-daily dosing) compared to placebo--
At week four, 91.3 percent (21 of 23) of patients receiving ABT-450/r in combination with standard of care (SOC) pegylated alpha interferon and ribavirin (pegIFN/RBV) achieved HCV-RNA less then 25 IU/ml--
Safety appears consistent to that expected with SOC
"ABT-450 was discovered as part of an alliance between Abbott and Enanta and is being developed with low-dose ritonavir, which enhances the pharmacokinetic properties of ABT-450, allowing for once-daily dosing. This Phase 2 study also evaluated ABT-333 and ABT-072, two of Abbott's internally discovered compounds that are part of the company's ongoing non-nucleoside polymerase inhibitor development program. The study findings for these two compounds have been submitted for presentation at a future scientific meeting."

*See Slides @ NATAP Initial Antiviral Activity of the HCV NS3 Protease Inhibitor ABT-450 When Given with Low-dose Ritonavir as 3-Day Monotherapy: Preliminary Results of Study M11-602 in Genotype 1 (GT1) HCV-infected Treatment-naïve Subjects
Anadys investigational polymerase inhibitor ANA598 was studied in treatment-naive patients with genotype-1, used in combination with standard HCV therapy.
From Medpage: Adding the investigational polymerase inhibitor ANA598 to standard care speeded up the clearance of hepatitis C, compared with standard care alone, a researcher reported here.
.An ongoing double-blind, placebo-controlled phase II trial among more than 100 patients, found that after 12 weeks of therapy with one of two doses of ANA598, 73% and 75% of patients had undetectable levels of hep C virus, depending on dose, according to Eric Lawitz, MD, of Alamo Medical Research in San Antonio, Texas.
.In contrast, 63% of those getting only standard care with pegylated interferon alpha-2a and ribavirin had undetectable hep C levels, Lawitz said at the annual meeting of the American Association for the Study of Liver Diseases.
To examine the efficacy and safety of the compound, he and colleagues enrolled 105 treatment-naive patients with genotype-1 virus and randomly assigned them to either 200 or 400 mg of ANA598 twice a day, or to placebo. Those getting active drug also had a loading dose of 800 mg on the first day of therapy.
.All of the trial patients also got standard treatment with pegylated interferon alpha-2a and ribavirin.
.Patients with undetectable hep C virus at weeks four and 12 weeks, Lawitz explained, were re-randomized to continue standard care for another 12 or 32 weeks.
.There was little difference between the two arms in terms of the speed at which the drug cleared the virus, Lawitz said, but viral clearance was always faster than the standard care alone.
Side Effects :The main difference between the two arms was in the adverse events. In the high-dose group "400 mg" 62% of the patients reported rash, including 17 with grade 1, one with grade 2, and three patients with grade 3 rash.

Presidio's drug PPI-461 is a NS5A inhibitor PPI-461 exhibits activity against 1-7 HCV genotypes in laboratory assays.
The pharmacokinetic results indicated that all subjects rapidly achieved substantial blood levels of PPI-461, which far exceeded the concentrations of PPI-461 needed to inhibit HCV (genotypes 1-7) in the laboratory. For PPI-461 doses of 50 mg or more, all subjects achieved blood levels of PPI-461 that would be expected to inhibit HCV replication for 24 hours or longer. This profile suggests that PPI-461 may be effective when administered to hepatitis C patients at relatively low oral doses on a once-daily dosing schedule, which would facilitate its convenient use in future co-formulated combination therapies
First Study of PPI-461 in Hepatitis C Patients UnderwayBased on the encouraging Phase 1a results, Presidio has initiated a Phase 1b proof-of-concept clinical trial of PPI-461 in hepatitis C patients. This dose-ranging trial will evaluate the safety, pharmacokinetics and antiviral efficacy of PPI-461 in previously-untreated patients with HCV genotype-1 infection.
From NATAP : The new Merck also once-daily HCV protease MK5172 also looks very good: "Safety and Antiviral Activity of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients".
The protease has activity against genotype 1 and 3. Multiple oral doses of 400 mg MK-5172 qd for 7 days were generally well tolerated in HCV-infected patients. Mean maximum reductions from baseline of HCV viral RNA (Ses) were 5.4 (0.21) and 3.98 (0.22) log10 IU/mL for GT 1 and 3, respectively.

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

M11-602From NATAP Preliminary Results of Study M11-602 in Genotype 1 (GT1) HCV-infected Treatment-naïve Subjects" Abbott also reported 4 weeks data in a poster here in combination with peg/rbv. Subjects were randomized to one of 3 doses of ABT-450/r (50/100 mg, 100/100 mg or 200/100 mg) or placebo once daily for 3 days, followed by ABT-450/r or placebo in combination with standard of care (SOC) consisting of pegylated interferon alfa-2a 180 µg/week + weight-based ribavirin 1000-1200 mg/day through week 1.
.Merck Vaniprevir MK-7009 protease inhibitor
Idera Pharmaceuticals data on IMO-2125 phase 1 trial.
IMO-2125 is currently in a Phase 1 clinical trial in null-responder patients, defined as those who did not achieve a 2 log10 reduction with prior standard of care treatment, as monotherapy for 4 weeks. IMO-2125 is also being evaluated in a Phase 1 clinical trial in treatment-naive patients in combination with ribavirin for 4 weeks.
From The Street : This Phase 1 clinical trial evaluated 51 null-responder HCV patients; 41 patients received IMO-2125 monotherapy at five dose levels and 10 patients received placebo once per week for four weeks. Most of these patients were infected with HCV genotype 1 and had the CT or TT IL28B gene alleles.
IMO-2125 was well tolerated at all dose levels. IMO-2125 induced a broad immune response with dose-dependent increases in serum concentrations of antiviral proteins and activation of cellular immune responses.
Across the three highest dose levels, 75% of patients achieved a 1 log10 or greater decrease in viral load at least once during the treatment period. Consistent with the proposed mechanism of IMO-2125, induction of higher serum concentrations of interferon-alpha correlated with greater decreases in HCV viral load. Additional patients are being enrolled in this Phase 1 trial to evaluate twice-weekly dosing of IMO-2125.
Inhibitex has initiated a Phase 1b, multiple ascending dose (MAD) clinical trial of INX-189, its nucleotide polymerase inhibitor in development for the treatment of chronic infections caused by hepatitis C virus (HCV).
The trial, which is being conducted under an IND in the United States, is a double-blind, placebo-controlled, dose escalation study designed to evaluate the safety, tolerability, pharmacokinetics and anti-viral activity of INX-189 administered orally once daily for seven days in treatment naïve patients with HCV genotype 1.
Each treatment cohort will include 10 patients, eight of which will receive INX-189 and two of which will receive placebo. The first cohort in the Phase 1b study will receive 9 mg of INX-189 once daily. In addition to evaluating INX-189 as monotherapy, the Company plans to evaluate two dose levels of INX-189 administered once daily for seven days in combination with ribavirin, which is one of the drugs currently approved for the treatment of HCV. The dose levels of INX-189 to be evaluated in combination with ribavirin will be determined based upon the results of the monotherapy cohorts.
Gilead's Investigational Hepatitis C Compounds GS 9190 and GS 9256 in treatment Naïve, genotype 1 HCV Subjects. Used in Combination with Standard of Care Therapies Achieve Substantial Viral Suppression in Phase II Study **See Links For Complete Information
Excerpt: Gilead's three-arm Phase IIa trial (Study 196-0112) evaluated the safety and efficacy of GS 9190, an oral polymerase inhibitor, in combination with GS 9256, an oral protease inhibitor, when used as:
1) a dual antiviral therapy alone
2) a three-drug regimen with RBV
3) a four-drug regimen with RBV and Peg-IFN.
The study found that the all-oral regimen of GS 9190, GS 9256 and RBV produced substantial viral suppression, with a median maximal decline from baseline in HCV RNA of 5.1 log10 IU/mL during 28 days of treatment.
Among patients given the four-drug regimen of GS 9190, GS 9256, RBV and Peg-IFN, 100 percent (14/14 patients) achieved Rapid Virologic Response (RVR) (HCV RNA less then 25 IU/mL) at day 28, with 93 percent (13/14 patients) achieving undetectable viral levels (HCV RNA less then 10 IU/mL). No virologic breakthroughs were observed in this arm
Gilead HCV Pipeline Research In addition to Study 196-0112, data from seven additional studies will be presented at The Liver Meeting highlighting the clinical profile of the company's other HCV pipeline candidates, including another protease inhibitor, GS 9451, and a novel NS5A inhibitor, GS 5885. Gilead's HCV pipeline now includes seven unique molecules spanning six therapeutic classes with different mechanisms of action. Five of these compounds are currently in clinical trials, and two are slated to enter human clinical studies early next year.
Side Effects: The majority of adverse events were Grade 1 or 2 in severity and resolved with continued treatment. The most common adverse events observed in each of the three arms were headache, diarrhea and nausea. Some patients taking the three-drug combination also experienced fatigue and insomnia, and some patients taking the four-drug combination experienced influenza-like illness, fatigue, myalgia and cough. There were two serious adverse events including one case of bursitis and a hospitalization for vasovagal collapse (fainting), which was attributed to gastroenteritis and occurred in a patient who continued therapy and achieved RVR. Elevations in bilirubin were observed across all three study arms, the majority of which were Grade 1 or 2 in severity and none of which resulted in study drug discontinuation.

GlobeImmune Expands GI-5005-02 Phase 2b Trial to Include Additional Treatment Naive IL28B T/T Subjects With Chronic Genotype 1 HCV
Phase 2b Study Demonstrates GlobeImmune's GI-5005 HCV Therapeutic Vaccine Increases Sustained Virologic Response by 12 Percent in Patients Who Previously Failed Therapy With Standard of Care
Results in both subgroups were similar to the overall outcome but did not reach statistical significance compared with standard care, Pockros told a late-breaker session at the annual meeting of the American Association for the Study of Liver Diseases. But the findings, based on just 133 patients, are enough to justify continued development of the vaccine, Pockros said, including tests to see if it can be effective without the standard hepatitis C treatment regimen, which has difficult side effects.
On an intent-to-treat basis (subjects who received at least one dose of combination therapy), prior non-responders receiving GI-5005 plus SOC as a triple therapy had an SVR rate of 17%, compared to an SVR rate of only 5% in patients receiving SOC alone. Prior non-responders in this study were defined as patients who did not clear virus after a minimum of 12 weeks of SOC, including null responders, poor responders, and partial responders. Relapsers and on-treatment breakthroughs were not enrolled in the study. The most common adverse events associated with GI-5005 were injection site reactions that were generally mild and transient in nature. Discontinuation rates due to adverse events in the GI-5005 triple therapy arm were comparable to the discontinuation rates in the SOC alone arm.
."Only 4-7% of patients with genotype 1 HCV who were null, poor or partial responders to their first course of pegylated interferon-based therapy would be expected to achieve a sustained virologic response with a second course of treatment," said Dr. Pockros. "In this study, GI-5005 conferred a three-fold improvement in SVR, an important treatment effect in this challenging patient population."
.Additional immunology data from the study will be presented in a poster on Tuesday, November 2, 2010 by John M. Vierling, M.D., of Baylor College of Medicine. These data show that GI-5005 improved HCV-specific T cell responses 10-fold over SOC alone in patients with the IL28B T/T genotype (~20% of chronically infected patients), the subgroup most likely to fail treatment with SOC alone.
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