By Liz Highleyman

Researchers are currently studying several directly targeted antiviral agents that attack various stages of the HCV lifecycle, in an attempt to improve upon current standard treatment with pegylated interferon plus ribavirin.

Investigators presented data on Roche's experimental HCV polymerase inhibitor, R1626, in a late-breaker session at the 43rd annual meeting of the European Association for the Study of the Liver (EASL) last week in Milan.

Prior studies demonstrated that R1626 monotherapy decreased HCV RNA levels in a dose-dependent fashion. The current Phase 2a study was designed to evaluate the safety and efficacy of R1626 in combination with pegylated interferon plus ribavirin in treatment-naive adults with genotype 1 chronic hepatitis C.

A total of 104 participants were randomly assigned to an initial 4 weeks of dual therapy with R1626 at doses of 1500 mg or 3000 mg twice-daily (BID) plus 180 mcg/week pegylated interferon alfa-2a (Pegasys), or else triple therapy with 1500 mg BID R1626 plus both pegylated interferon and 1000-1200 mg/day ribavirin, or else standard therapy with only pegylated interferon plus ribavirin. After week 4, all patients received pegylated interferon plus ribavirin for a further 44 weeks, for a total of 48 weeks of treatment.

Serum HCV RNA was measured using the Roche COBAS TaqMan assay with a limit of detection of 15 IU/mL. The investigators used 2 measures of rapid virological response (RVR): RVR-2 was defined as undetectable HCV RNA at week 2, while RVR-4 was defined as undetectable virus at week 4.

Results

• At Week 48, end-of-treatment response rates (HCV RNA < 15 IU/mL) were as follows:

• 84% in the triple therapy 1500 mg R1626 arm;
• 66% in the dual therapy 3000 mg R1626 arm;
• 52% in the dual therapy 1500 mg R1626 arm;
• 65% in the standard therapy control arm.

• HCV RNA fell by a mean 5.2 log10 from baseline in the triple therapy 1500 mg R1626 arm.

• Response rates were similar in patients with HCV genotypes 1a and 1b.

• Rates of undetectable HCV RNA at week 4 remained stable or increased by the end of treatment, despite early pegylated interferon dose modifications.

• RVR-2 and RVR-4 in the triple therapy 1500 mg R1626 arm positively correlated with end-of-treatment responses (100% and 91%, respectively).

• Dose-dependent Grade 4 neutropenia was more frequent in the R1626-containing arms.

• However, laboratory hematological abnormalities improved promptly after completion of R1626 dosing, falling to levels comparable to those of the control arm.

Conclusion

"RVR-2 and RVR-4 among patients receiving R1626, [pegylated interferon] and ribavirin positively correlated with end-of-treatment (week 48) response," the investigators concluded. "R1626-associated hematological abnormalities were reversible."

"These results demonstrate that R1626 holds significant promise to potentially increase the number of hepatitis C patients who can be successfully treated," said Dr. David Nelson of the University of Florida in a press release issued by Roche. "It is particularly interesting that R1626, a polymerase inhibitor, is demonstrating a higher end-of-treatment response rate than current HCV protease inhibitors in development, together with a high barrier to the development of resistance. Since most patients responded very early in treatment with R1626, we expect excellent SVR rates that improve significantly on those achieved with the current standard of care."

The company announced last week that a large Phase IIb study called POLI1 that was initiated in November 2007 to determine the optimal dose of R1626 in combination with pegylated interferon and ribavirin is now fully enrolled with approximately 500 patients.

In a related presentation, Roche researchers looked at development of resistance to R1479, the active version of R1626 in the body (i.e., R1626 is a pro-drug of R1479). In vitro studies previously identified S96T and S96T/N142T as mutations in the HCV NS5B polymerase that reduce sensitivity to R1479.

In a laboratory study, the investigators examined the level of resistance and the replication capacity of R1479-resistant HCV replicons carrying S96T and S96T/N142T mutations in the NS5B of the reference strain Con 1 and of clinical isolates to estimate viral fitness. They also assessed the frequency of S96T, N142T, and S96T/N142T by looking at a total of 2724 NS5B variants (1786 at baseline and 938 after R1626 treatment) in the HCV quasispecies from 21 treated patients.

They found that R1479 resistance mutations conferred a 4- to 5-fold reduced sensitivity to the drug and reduced the replication capacity of HCV replicons by about 95%.

None of the 1786 baseline NS5B baseline sequences contained the S96T, N142T, or S96T/N142T mutations. Clonal analysis of the 938 post-treatment NS5B variants showed a lack of selection of R1626 resistance, even as a minority of all circulating HCV during treatment with R1626.

The researchers concluded that, "These results suggest that the high barrier to the development of resistance to R1626 in vivo may be related to low level of resistance, low replication capacity, and lack of pre-existence in the viral quasispecies of R1626-resistance mutations."

4/29/08

References

D Nelson, PJ Pockros, E Godofsky, and others. High End-of-Treatment Response (84%) After 4 Weeks of R1626, Peginterferon Alfa-2a (40kd) and Ribavirin Followed By a Further 44 Weeks of Peginterferon Alfa-2a and Ribavirin. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

S Le Pogam, A Seshaadri, H Kang, and others. Low Level of Resistance, Low Viral Fitness and Absence of Resistance Mutations in Baseline Quasispecies May Contribute to High Barrier to R1626 Resistance in Vivo. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

Additional Sources

Roche. Roche's R1626, First-in-Class Hepatitis C Polymerase Inhibitor, Demonstrates Impressive End-of-Treatment Response in Phase IIa Study. Press release. April 26, 2008.

European Association for the Study of the Liver. Important Progress Toward Control of Hepatitis B and C. Press release. April 25, 2008.