HCV Polymerase Inhibitor R7128 Demonstrates Antiviral Activity in Prior Non-responders

R7128 (a pro-drug of PSI-6130) is an oral cytidine nucleoside analog HCV polymerase inhibitor being developed by Pharmasset, Inc., in collaboration with Roche Laboratories. As previously reported, the U.S. Food and Drug Administration (FDA) granted R7128 "fast track" designation in late October.

At the Frontiers in Drug Development in Viral Hepatitis (HEP-DART) conference this week in Lahaina, Hawaii, researchers reported data from a study of R7128 in prior non-responders to interferon-based therapy.

In Part 1, single doses of R7128 were tested in 46 healthy HCV negative volunteers; 6 subjects received active drug and 2 received placebo in each of 5 sequential dose groups (500 mg, 1500 mg, 4500 mg, 6000 mg, and 9000 mg), as well as a 1500 mg food effect group.

In Part 2, multiple oral doses of R7128 were administered for 14 days to 40 chronic hepatitis C patients who did not achieve sustained response with prior treatment. Three-quarters had HCV genotype 1a, while the rest had 1b; none had liver cirrhosis at baseline. In each cohort, 8 received active drug and 2 receive placebo. The doses tested were 750 mg or 1500 mg either once or twice daily.

Results

•	In Part 1, following single doses, 19 adverse events (AEs) were reported; all were mild to moderate, none were dose-dependent, and no gastrointestinal AEs were reported.
•	In Part 2, the 14-day study demonstrated that R7128 monotherapy delivered sufficient antiviral potency to suppress HCV below the limit of detection (<15 IU/mL) in prior non-responders.
•	The mean reduction in HCV RNA using the 1500 mg twice-daily dose was 2.7 log₁₀ IU/mL (range 1.2 to 4.2 log₁₀) at Day 15.
•	Twice-daily administration was superior to once-daily administration for viral suppression.
•	The pharmacokinetic profile following single and multiple doses indicated good exposure to PSI-6130, with no dose-related adverse events or laboratory abnormalities.
•	The terminal half-life for PSI-6130 was about 5 hours; Cmax occurred 2-3 hours after dosing.
•	The lack of virological rebound suggests a high genetic barrier for nucleoside NS5B polymerase inhibitors.
•	No serious AEs were reported, and no AEs required dose modification.
•	No clinically significant changes in vital signs, ECGs, hematology, renal, or other laboratory parameters were observed.
•	The most frequently reported AEs in patients receiving R7128 were headache (n=13) and dry mouth (n=3).

Conclusion

Based on these findings the researchers concluded, �The safety and efficacy of this monotherapy study support further development of R7128 in combination with pegylated interferon and ribavirin.�

Duke Clinical Research Institute, Durham, NC; University of Pennsylvania, Philadelphia, PA; Fundacion de Investigacion de Diego, Santurce, PR; Auckland Clinical Studies Limited, Auckland, New Zealand; Quest Clinical Research, SanFrancisco, CA; University of Colorado, Aurora, CO; Orlando Immunology Center,Orlando, FL; Mayo Clinic, Phoenix, AZ; Pharmasset, Durham, NC;Roche, Palo Alto, CA.

12/14/07

References

JG McHutchison, R Reddy, M Rodriguez-Torres, and others. Potent Antiviral Activity of the Nucleoside HCV Inhibitor, R7128, in Prior IFN Non-Responders. Frontiers in Drug Development in Viral Hepatitis (HEP-DART). Lahaina, Hawaii. December 9-13, 2007.

Pharmasset Inc. Pharmasset Announces Clevudine and R7128 Presentations at HEP-DART. Press release. December 11, 2007.