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

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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