Roche and Pharmasset start phase IIb clinical trial of R7128 nucleoside polymerase inhibitor for chronic hepatitis C

Pharmasset, Inc. and Roche have announced that the first patient has been dosed in a Phase IIb study of R7128, the nucleoside polymerase inhibitor most advanced in development for the treatment of chronic hepatitis C (HCV).

The trial will evaluate the dose and duration of treatment of R7128 in combination with Roche's PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin) - in HCV patients who have not been treated previously. The goal of adding R7128 to the existing standard therapy is to improve rates of sustained virological response (SVR) and to shorten the length of treatment for patients.

R7128 is being developed by Roche and Pharmasset under a partnership agreement entered into in 2004. The first patient dosed in this study triggered a $10 million payment to Pharmasset from Roche.

A Phase I/IIa trial demonstrated the ability of R7128 to generate high rapid virologic response rates (RVR) in combination with PEGASYS and COPEGUS. Unlike protease inhibitors in development, R7128 is active against multiple HCV genotypes and presents a high barrier to the development of resistance.

"We look for the Phase IIb study to further support the efficacy and safety of R7128, and nucleoside polymerase inhibitors as a class," said Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We believe nucleoside inhibitors have a number of advantages over other classes of HCV drugs, including a higher barrier to resistance and activity across multiple genotypes, as well as a high level of potency."

"The collaboration with Pharmasset underscores Roche's commitment to develop new therapies that will meet the needs of a growing population of patients with hepatitis C," said Rob Mitchell, Global Head of Roche's Virology business. "We are hopeful that a combination of R7128 and the current gold standard of PEGASYS and COPEGUS can provide a more potent - and potentially shorter - treatment regimen."

These collaborations position Roche as a leader, and they underscore Roche's role as a pioneer, in the next evolution of hepatology treatments.

The Phase IIb trial is anticipated to enroll about 400 HCV-infected patients with genotypes 1 or 4 who have not been treated previously. The primary efficacy endpoint of the trial will be the proportion of patients who achieve an SVR, defined as undetectable levels of HCV (measured by Roche TaqMan assay) 24 weeks after completion of treatment. The trial will be conducted in North America, Europe and Australia. Patients will be enrolled into one of 5 arms:

• 24 weeks of total treatment, with R7128 500mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by 12 weeks of PEGASYS and COPEGUS ("12+12")
• 24 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by 12 weeks of PEGASYS and COPEGUS ("12+12")
• 24 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 8 weeks, followed by a further 16 weeks of PEGASYS and COPEGUS ("8+16")
• 48 weeks of total treatment, with R7128 1000mg bid in combination with PEGASYS and COPEGUS for 12 weeks, followed by a further 36 weeks of PEGASYS and COPEGUS ("12+36")
• A control arm with PEGASYS and COPEGUS for 48 weeks.    

Patients in the 24-week arms will discontinue all treatment at week 24 if they have achieved RVR, defined as undetectable levels of HCV at week 4 (a strategy known as "RVR-guided" treatment), and maintain undetectable levels of HCV until week 22. Patients who do not achieve an RVR at week 4 will continue on the standard of care until week 48.

According to the study design, 100 patients will be initially enrolled, equally across all five arms. The remaining 300 will be enrolled following a review of the 12-week data by the data safety monitoring board.

R7128, a cytidine nucleoside analog inhibitor, is being developed for the treatment of chronic HCV infection. R7128 has shown in vitro activity against all of the most common HCV genotypes.

In a 4-week Phase I combination study conducted in 81 treatment-naive patients with chronic HCV, R7128 demonstrated significant short-term antiviral activity with safety and tolerability comparable to placebo with standard of care. Up to 88 percent of patients achieved undetectable levels of HCV (<15 IU/ml) after only 4 weeks of treatment with R7128 1000mg bid and the standard of care, compared to 18.75 percent treated with the standard of care alone.   -- In the harder to treat populations of genotype 2 or 3 patients who had not responded to previous therapy, results with R7127 1500mg twice-daily in combination with the standard of care showed that 90 percent of patients achieved undetectable levels of HCV(<15 IU/ml) after 4 weeks, compared to 60 percent in the standard of care arm.    

In November 2008, Roche, Pharmasset and InterMune initiated the INFORM-1 trial to investigate the combination of R7128 with InterMune's R7227, a protease inhibitor, in HCV patients. This is the first-ever clinical study to investigate the combination of two oral antiviral medicines in the absence of weekly injections of interferon, or ribavirin. Interim results of this trial will be presented this weekend at the European Association of Liver Disease (EASL) meeting being held in Copenhagen, Denmark.