Presidential Plenary I and Award Presentations Moscone West - General Session Room 11/14/2005 8:00 AM - 10:00 AM 11/14/2005 8:45 AM - 9:00 AM

Abstract ID: 67484

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

Anti-viral Activity of SCH 503034, a HCV Protease Inhibitor, Administered as Monotherapy in Hepatitis C Genotype-1 (HCV-1) Patients Refractory to Pegylated Interferon (Peg-IFN-á).

S. Zeuzem, Saarland University Hospital, Homburg, Germany, C. Sarrazin, Saarland University Hospital, Homburg, Germany, R. Rouzier, Centre Cap, Montpelleir, A. Tarral, Biotrial, Rennes, N. Brion, Biotrial, Rennes, France, N. Forestier, Saarland University Hospital, Homburg, Germany, S. Gupta, Schering-Plough reserach Institute, kenilworth, NJ, D. Deckman, SChering-Plough Research Institute, Kenilworth, NJ, K. Fellows, Schering-Plough Research Institute, Kenilworth, NJ, M. Hussain, Schering-Plough Research Institute, Kenilworth, NJ, D. L. Cutler, Schering-Plough Research Institute, Kenilworth, NJ, J. Zhang, Schering-Plough research Institute, Kenilworth, NJ

Background

Approximately 50% of chronic HCV infections are refractory to interferon-based therapies. SCH 503034, is a novel, orally active HCV protease inhibitor that exhibits potent and specific antiviral activity in HCV replicon assays.

Methods

In this rising multi-dose, double-blind study, adult patients with HCV-1 who did not respond to a previous course of peg-IFN-α (<2 log reduction in HCV RNA after 12 wks) were randomized 3:1 to receive SCH 503034 capsules (in oral form) or placebo:

100 mg BID, 200 mg BID, 400 mg BID, 400 mg TID, for 14d. Pharmacokinetics were assessed on days 1 and 14, Viral load (VL) was determined daily by qRT- PCR (Taq-Man™/LOQ = 29 IU/ml).

Results

61 patients (45 active, 16 placebo) have completed the study. SCH 503034 was rapidly absorbed following oral administration of capsules (mean Tmax = 1 to 2h across doses), and exhibited dose-related increases in Cmax and AUC. SCH 503034 trough plasma concentration in the 400 mg TID group approximated the IC90 derived from HCV replicon assays. SCH 503034 exhibited potent dose-related antiviral activity that was first detectable 24h post-dose. Reductions in mean VL positively correlated with SCH 503034 exposure. Mean max VL reduction in the 400 mg TID group was 2.06 log¹⁰ from baseline (1.1 to 2.7 log¹⁰, n=10) – the dose that showed the largest reduction in HCV RNA. A dose-related decline in AST/ALT occurred during treatment and correlated with VL reductions. SCH 503034 was well tolerated at all dose levels. The adverse event profiles were similar in patients receiving SCH 503034 and placebo.

Conclusions

SCH 503034 exhibited dose-dependent HCV antiviral activity in patients with HCV-1 who previously failed peg-IFN- α therapy.

Abstract ID: 63186

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

Randomized Trial of Valopicitabine (NM283), Alone or with Peg-Interferon, vs. Retreatment with Peg-Interferon plus Ribavirin (PegIFN/RBV) in Hepatitis C Patients with Previous Non-Response to PegIFN/RBV: First Interim Results.

C. O'Brien, University of Miami, Miami, FL, E. Godofsky, Bach & Godofsky, Bradenton, FL, M. Rodriguez-Torres, Fundacion de Investigacion de Diego, Santurce, Puerto Rico, N. Afdhal, Beth Israel Deaconess Medical Center, Boston, MA, S. C. Pappas, St. Luke's Episcopal Hospital, Houston, TX, P. Pockros, Scripps Clinic, La Jolla, CA, E. Lawitz, Alamo Medical Research, San Antonio, TX, N. Bzowej, Sutter Health, San Francisco, CA, V. Rustgi, Metropolitan Research, Fairfax, VA, M. Sulkowski, Johns Hopkins University School of Medicine, Baltimore, MD, K. Sherman, University of Cincinnati Medical Center, Cincinnati, OH, I. Jacobson, Weill Medical College of Cornell University, New York, NY, G. Chao, Idenix Pharmaceuticals, Inc., Cambridge, MA, S. Knox, Idenix Pharmaceuticals, Cambridge, MA, K. Pietropaolo, Idenix Pharmaceuticals, Inc., Cambridge, MA, N. A. Brown, Idenix Pharmaceuticals, Cambridge, MA

Background

Patients (pts) with chronic hepatitis C (CHC) who have failed treatment with peginterferon (pegIFN) plus ribavirin (RBV) are an expanding group with no proven treatment options. Valopicitabine (NM283) has shown anti-HCV activity in Phase I-IIa trials, alone and in combination with pegIFN, with no viral resistance detected for study periods up to 6 months.

Methods

This randomized open-label Phase IIb trial is comparing 5 treatments in HCV genotype-1 CHC pts. All pts previously failed to clear HCV RNA with ≥ 3-months of pegIFN/RBV. Known responder-relapsers were excluded. Enrolled pts had baseline serum HCV RNA ≥ 105 IU/mL (by TaqMan PCR) and compensated liver disease. The 5 treatments are NM283 monotherapy (monoRx, 800 mg/d), 3 investigational combination (comboRx) arms with different NM283 dosing (400 mg/d; 800 mg/d; or dose-ramping 400 to 800 mg/d followed by 800 mg/d) + pegIFN, and pegIFN/RBV retreatment. PegIFNa-2a is dosed at 180 mg SQ/week with RBV 1000-1200 mg p.o. daily. Pts were randomized 2:2:2:2:1 to the 5 regimens (min 38 pts for each comboRx arm; 19 pts for NM283 monotherapy).

Results

The study is ongoing with 190 pts. Week 12 data is available: the two regimens of valopicitabine in combination with pegylated interferon (Pegasys) produced significant improvement in suppression of hepatitis C replication compared to the group that did not receive valopicitabine.

At week 12, mean HCV RNA reductions in the two high-dose arms of valopicitabine plus Pegasys were 2.5 log¹⁰ and 2.8 log¹⁰, with 63% and 71% of patients achieving an EVR (> 2 log ¹⁰ reduction in viral load from baseline). This compares to a mean HCV RNA reductions of 1.9 log¹⁰, with 41% of patients achieving and EVR.

Valopicitabine demonstrated satisfactory safety and tolerance level overall.

Conclusions

In HCV genotype-1 non-responders to pegIFN/RBV, NM283 (valopicitabine) + pegIFN produces significantly greater suppression of HCV replication compared to retreatment with pegIFN/RBV. Antiviral efficacy for the NM283 + pegIFN arms was proportional to NM283

dose. These results support continued evaluation of NM283 + pegIFN in pegIFN/RBV nonresponders as well as treatment-naïve pts with CHC.

11/14/2005 9:15 AM - 9:30 AM

Abstract ID: 62580

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

Final Results of a Phase 1B, Multiple-dose Study of VX-950, a Hepatitis C Virus Protease Inhibitor.

H. W. Reesink, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, S. Zeuzem, Saarland University Hospital, Homburg/Saar, Germany, C. J. Weegink, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, N. Forestier, Saarland University Hospital, Homburg/Saar, Germany, A. van Vliet, Pharma Bio-Research, Zuidlaren, Netherlands, J. van de Wetering de Rooij, Pharma Bio-Research, Zuidlaren, Netherlands, L. A. McNair, Vertex Pharmaceuticals, Cambridge, MA, S. Purdy, Vertex Pharmaceuticals, Cambridge, MA, H. Chu, Vertex Pharmaceuticals, Cambridge, MA, P. L. Jansen, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands

Background

VX-950 is an orally administered, highly selective peptidomimetic inhibitor of the Hepatitis C virus (HCV) NS3·4A protease that is designed to block HCV replication. The preliminary safety and anti-viral results from the interim analysis of a phase 1b clinical study, in healthy subjects and patients with HCV, were presented in May 2005. The final results of the clinical study are presented here.

Methods

The VX04-950-101 clinical study included three panels of eight healthy subjects. 23 of the patients failed a previous course of HCV therapy.

Part A:

· A total of 34 patients were dosed for 5 days:

o 10 patients -450 mg, three times a day

o 8 patients – 750 mg, three times a day

o 10 patients – 1250 mg, twice a day

o 6 patients – placebo group

Part B:

Patients were dosed for 14 days at doses of 450 mg or 750 mg everyone 8 hours, or 1250 mg every 12 hours, or with placebo.

Results

All groups exhibited a substantial reduction in HCV RNA—26 of the 28 patients receiving any dose of VX-950 achieving more than a 3-log reduction in HCV RNA within two day. After 14 days, patients in the dosing group (750 mg, three times a day) achieved a mean reduction of HCV RNA of 4.4 log ¹⁰ , a 25,000-fold reduction in viral load.

In the Phase Ib study, VX-950 in all dose groups exhibited substantial antiviral effects, with 26 of 28 patients receiving any dose of VX-950 achieving more than a 3-log reduction in plasma HCV-RNA within two days. After 14 days, patients in the best dose group (750 mg every 8 hours) achieved a mean reduction in HCV-RNA of 4.4 log10, a 25,000-fold reduction in viral levels. There was no change in viral load in the placebo group. VX-950 was well tolerated and adverse events similar to the group that received the placebo—headache, frequent urination and gastrointestinal symptoms.

Conclusion

VX-950 was well tolerated with no serious adverse events and no discontinuations with substantial reductions in HCV RNA at the end of the 14 day dosing.

Presidential Plenary II and Award Presentations Moscone West - General Session Room 11/14/2005 11:00 AM - 12:30 PM 11/14/2005 11:15 AM - 11:30 AM

Abstract ID: 67782

Category: JO2: HCV: Virology

Entry Inhibitor GNS 037 Exhibits Potent Anti-HCV Activity in vitro

P. Halfon, Genoscience, Marseille, France, J. Sabatier, Genoscience, Marseille, France, R. Perbost, Genoscience, Marseille, France, B. Jouirou, Genoscience, Marseille, France, P. Cacoub, Pitié-Salpétrière Hospital, Paris, France, D. Lavilette, U412 INSERM – ENS de Lyon, Lyon, France, F. Cosset, U412 INSERM - ENS de Lyon, Lyon, France

Introduction

Candidate receptors for HCV E2-based binding interaction are the human CD81, the low-density lipoprotein receptor (LDLR) , the human scavenger receptor class B type, and the liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN). Recent studies indicate that small molecules interfering with the CD81/E2 interaction can inhibit the binding of HCV to their host cells.

Aim

The aim of this study was to evaluate the antiviral potency of synthetic peptides that were selected by a computational drug design approach to block HCV entry into target cells.

Methods

Peptides were selected by drug design using the Genmol software from Genoscience. A detailed molecular modeling of the interaction between CD81 and the HCV envelope was the basis of peptide selection. The peptides were then produced by solid-phase chemical synthesis, and tested for their potential antiviral properties on HCV pseudo-particles, which are thought to be representative of the early infection steps of parental HCV.

Results

In this assay, five peptides were found to be active at the low micromolar concentration range, without any detectable peptide-induced cytotoxicity. The peptides have been also evaluated on pseudo-particles corresponding to distinct HCV genotypes.

Conclusions

The data suggest that, like many other viruses, the various steps of HCV entry (i.e., binding, internalization, and cell penetration) rely on different molecules. Specific E2-derived peptides, such as GNS 037, behave as potent HCV entry inhibitors. The use of HCV pseudo-particles allows detailing the early events of HCV infection and helps identifying actual viral receptors or coreceptors.

Abstract ID: 63449

Category: JO5: HCV: Clinical Trials and Therapeutic Developments

Pharmacokinetics of VX-950, and its effect on Hepatitis C Viral Dynamics.

H. Chu, Vertex Pharmaceuticals Inc., Cambridge, MA, E. Herrmann, Saarland

University Hospital, 66421 Homburg/Saar, Germany, H. Reesink, Academic Medical

Center, Amsterdam, Netherlands, N. Forestier, Saarland University Hospital,

Homburg/Saar, Germany, C. Weegink, Academic Medical Center, Amsterdam,

Netherlands, L. McNair, Vertex Pharmaceuticals, Cambridge, MA, S. Purdy, Vertex

Pharmaceuticals, Cambridge, MA, S. Zeuzem, Saarland University Hospital, Homburg,

Germany, E. I. Ette, Vertex Pharmaceuticals, Cambridge, MA

Introduction

VX-950 is an orally administered, highly selective peptidomimetic inhibitor

of the Hepatitis C virus (HCV) NS3·4A protease that is designed to block HCV replication and is being developed for the treatment of HCV infection.

Purpose

To characterize the pharmacokinetics (PK) of VX-950 in patients with Hepatitis C, and its effects on the dynamics of HCV RNA.

Method

A 14 day placebo-controlled, multiple dose escalation study was performed in genotype 1 HCV patients. Thirty four patients were divided into 3 panels, and each panel was dosed for 14 days at one of three dose regimens, 450 mg q8h, 750 mg q8h, or 1250 mg q12h, or placebo. A mixed sampling design – intensive on day 1, and sparse on days 2 to 14 was implemented for PK and viral HCV RNA. A non-compartmental PK modeling approach was used to analyze the PK data. The nonlinear mixed effects modeling approach was used to fit the viral dynamic data.

Results

The drug accumulated to steady state with a median accumulation index of 1.8. At steady state, median area under the curve at steady state (AUCss) values for the 3 doses were 9277, 9477, and 13923 hr*ng/mL and median maximum plasma concentrations (Cmax) were 1919, 1722, 2147 ng/mL for the 450 mg q8h, 750 mg q8h and 1250 mg q12h regimen, respectively. The average steady state trough concentration (Ctrough) was 781.1, 1054.6, and 675.5 ng/mL for the 450 mg q8h, 750 mg q8h, and 1250 mg q12h regimens, respectively.

VX-950 induced a biphasic HCV RNA decline, with a rapid slope at day 1, followed by a second slower slope. This resulted in non-detectable HCV RNA levels (less than 10 IU/mL) in two subjects in the 750 mg q8h group. Most patients in the 450 mg q8h and 1250 mg q12h groups experienced an increase in HCV RNA after relative stabilization of decline during the second half of the dosing period. The mean values of maximum HCV

RNA drop from baseline values in log¹⁰ scale were 0.40, 3.70, 4.65 and 3.45, for placebo, 450 mg q8h, 750 mg q8h and 1250 mg q12h, respectively. VX-950 was highly efficacious with the median antiviral efficacy exceeding 0.999 for the 750 mg q8h regimen. Ctrough is a key determinant of drug activity, with the average inhibitory quotient (Ctrough/IC50replicon) of 3.25, 4.39, 2.81, respectively, for the three regimens.

The median lag time of the decline of viral RNA was approximately 3.5 hours, there was no correlation between baseline value and the lag time.

Conclusion

· VX-950 was well absorbed in patients with HCV with moderately variable PK. VX-950 administration resulted in a significant dose/regimen dependent inhibition of viral production with a consequent rapid clearance of the virus over 14 days.

· A steep decline in HCV RNA levels was seen in the first two days which closely correlated with total blood concentrations during the first dosing.

· Due to the rapid viral decline it was speculated that it may be possible to eradicate hepatitis C within approximately 12 weeks of treatment.