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Combination Therapy with Investigational HCV Polymerase Inhibitor R7128 Produces Rapid Response in Patients with Genotype 2/3 HCV

Due to the limited efficacy and side effects of standard hepatitis C therapy using pegylated interferon (Pegasys or PegIntron) plus ribavirin, researchers are studying several oral agents that directly target various steps of the hepatitis C virus (HCV) lifecycle. One such agent, Pharmasset's R7128 (a prodrug of the nucleoside analog HCV polymerase inhibitor PSI-6130) is currently in Phase 1 clinical trials, in combination with Pegasys plus ribavirin. In August, the company reported preliminary data from a cohort of patients with hard-to-treat HCV genotype 1. This week, Pharmasset reported early results from a subgroup of participants with easier-to-treat genotypes 2 or 3.

Below is an excerpt from the company's recent press release describing the latest findings:

Princeton, NJ, September 8, 2008 -- Pharmasset, Inc. (Nasdaq: VRUS) announces the preliminary results of the fourth cohort of a 4-week Phase 1 proof-of-concept clinical trial evaluating R7128 1500 mg twice daily (BID) in combination with the standard of care (SOC), Pegasys (pegylated interferon [alfa-2a]) plus Copegus (ribavirin) in 20 patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 who had not achieved a Sustained Viral Response (SVR) with prior SOC therapy. R7128, a prodrug of PSI-6130, is a nucleoside analogue polymerase inhibitor of HCV that is being developed through Pharmasset's collaboration with Roche.

In this study, preliminary results indicated that R7128 demonstrated significant short-term antiviral activity in patients who were previous non-responders or relapsers to treatment and was generally safe and well tolerated. Of the 25 patients enrolled, 20 patients received R7128 1500 mg BID and 5 received placebo.

Patients receiving R7128 1500 mg BID with SOC for 4 weeks achieved a mean 5.0 log10 HCV RNA decline and 90% (18 of 20) achieved undetectable (<15 IU/ml) HCV RNA levels (RVR). Patients receiving placebo with SOC for 4 weeks achieved a mean 3.7 log10 HCV RNA decline and 60% (3 of 5) achieved an RVR. These viral load reductions for patients with genotype 2 or 3 are similar to those reported earlier for patients with genotype 1 treated with 1000 mg BID and 1500 mg BID and are consistent with the in vitro data demonstrating equal potency by R7128 against HCV genotypes 1, 2, 3 and 4.

The preliminary safety and tolerability of R7128 1500 mg BID with SOC was comparable to placebo with SOC in Cohort 4.

Dr. Michelle Berrey, Pharmasset's Chief Medical Officer stated, "In this study, R7128, in combination with SOC, has demonstrated significant antiviral activity in genotype 2 or 3 patients who had failed prior interferon-based therapy. R7128, an HCV nucleoside polymerase inhibitor, may provide better antiviral activity in these patients where the protease inhibitors and non-nucleoside polymerase inhibitors have not yet shown success. Longer-term studies of R7128 with SOC are needed to provide additional information about its potential to improve SVR rates and possibly shorten the treatment duration for genotype 2 or 3 HCV patients."

"Patients with genotype 2 or 3 represent 20-30% of the worldwide chronically infected HCV population. Up to 40% of these patients, using SOC in first line therapy for 24 weeks, do not achieve an SVR, which represents an unmet medical need that R7128 has the potential to address," stated Patrick Higgins, Pharmasset's Executive Vice President of Sales and Marketing. "R7128 is the first small molecule to demonstrate significant antiviral activity in humans against a broad spectrum of HCV genotypes. If this early evidence of competitive advantage is sustained in future development, this potentially means that R7128 could become the preferred direct-acting antiviral to be added to the SOC because it is equally active across all of the most common genotypes and has a high barrier to drug resistance."

R7128 4-week Combination Study Overview

The 4-week Phase 1 combination clinical trial was a multiple center, observer-blinded, randomized and placebo-controlled study that was conducted in 81 treatment-naive patients chronically infected with HCV genotype 1 and 25 prior treatment non-responder patients chronically infected with HCV genotype 2 or 3. The primary objective was to assess the safety, tolerability, pharmacokinetics and antiviral activity of R7128 in the clinically-relevant setting of combination therapy for chronic HCV infection. Cohort 1 administered R7128 500 mg BID, Cohort 2 administered R7128 1500 mg BID, and Cohort 3 administered an intermediate dose of 1000 mg BID, all given in combination with pegylated interferon and ribavirin for 28 days. All subjects then went on to receive a total of 48 weeks of the standard-of-care regimen. In Cohort 4, patients with HCV genotype 2 or 3 who did not achieve an SVR with previous interferon-based therapy were administered R7128 1500 mg BID in combination with SOC for 4 weeks, and subsequently treated with an additional 20 weeks of SOC.

About R7128

R7128 is being developed for the treatment of chronic HCV infection. R7128 is a prodrug of PSI-6130, a cytidine nucleoside analog inhibitor of HCV RNA polymerase. A prodrug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. R7128 has shown in vitro activity against all of the most common HCV genotypes (1, 2, 3 and 4).

Results from an oral single ascending dose study of PSI-6130 in 24 healthy male volunteers showed that PSI-6130 was generally well tolerated with no serious adverse events in doses up to 3000 mg.

R7128 demonstrated significant, dose-dependent antiviral activity across four prior treatment-failure patient cohorts (n=40) receiving 750 mg or 1500 mg administered either once-daily or twice-daily for 14 days as monotherapy. The greatest mean decrease in HCV RNA from baseline was demonstrated in the patient cohort that received 1500 mg twice-daily, the highest dose of R7128 administered in the study. These patients demonstrated a mean 2.7 log10 IU/mL (> 99%) decrease in HCV RNA. There was no evidence of the development of viral resistance in any dose cohort after 14 days of dosing.

In a 4-week Phase 1 combination study that was conducted in 81 treatment-naive patients chronically infected with HCV genotype 1, R7128 demonstrated significant short-term antiviral activity with safety and tolerability comparable to placebo with SOC. Results from the 500 mg, 1500 mg and 1000 mg dose cohorts (cohorts 1, 2 and 3) in 81 treatment-naive patients chronically infected with HCV genotype 1 indicated.

Preliminary results with R7128 1000 mg BID with SOC indicated patients achieved a mean 5.0 log10 IU/mL decrease in HCV RNA and 88% (22 of 25) patients achieved RVR.

Results with R7128 1500 mg BID with SOC indicated patients achieved a mean 5.1 log10 IU/mL decrease in HCV RNA and 85% (17 of 20) patients achieved RVR

Results with R7128 500 mg BID with SOC indicated patients achieved a mean 3.8 log10 IU/mL decrease in HCV RNA and 30% (6 of 20) patients achieved RVR.

Results with placebo with SOC indicated patients achieved a mean 2.9 log10 IU/mL decrease in HCV RNA and 18.75% (3 of 16) patients achieved RVR

About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV).

Pharmasset is currently developing three product candidates. Clevudine, for the treatment of chronic HBV infection, is enrolling Phase 3 clinical trials for registration in North, Central and South America and Europe. Clevudine is already approved for HBV in South Korea and marketed by Bukwang Pharmaceuticals in South Korea under the brand name Levovir. R7128, an oral treatment for chronic HCV infection, is in a 4-week Phase 1 clinical trial in combination with Pegasys plus Copegus through a strategic collaboration with Roche. Racivir, which is being developed for the treatment of HIV in combination with other approved HIV drugs, has completed a Phase 2 clinical trial.

For more information, visit www.pharmasset.com.

9/12/08

Source

Pharmasset, Inc. Pharmasset reports preliminary results of a 4-week proof-of-concept combination study of R7128 for the treatment of chronic hepatitis C in genotype 2 or 3 non-responders. Press release. September 8, 2008.