Experimental Roche Polymerase Inhibitor R1626 Shows Robust Synergistic Effect in Combination with Pegylated Interferon with or without Ribavirin

By Ronald Baker, PhD

The experimental nucleoside polymerase inhibitor R1626 from Roche has demonstrated dose-dependent potent inhibition of HCV when administered as monotherapy to patients with chronic hepatitis C. As previously reported, the U.S. Food and Drug Administration (FDA) has granted "fast track" status to the drug.

In the present Phase 2a study, presented in a Presidential Plenary session at the 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007) in Boston (November 2-6, 2007), researchers assessed the efficacy and safety of R1626 given to treatment-naive genotype 1 patients for 4 weeks in combination with 180 mcg/week peginterferon alfa-2a (Pegasys) with or without ribavirin (abstract 167).

• 104 patients were randomized as follows:

• Dual Low: 1500 mg bid + pegylated interferon (n=21);

• Dual High: 3000 mg bid + pegylated interferon (n=32);

• Triple Low: 1500 mg bid + pegylated interferon + ribavirin (n=31);

• Standard of care: pegylated interferon + ribavirin (n=20).

Results

• At 4 weeks, HCV RNA was undetectable in 81% of patients treated with the Triple Low regimen (mean reduction of 5.2 log10 IU/mL), 69% treated with the Dual High regimen (mean reduction of 4.5 log10 IU/mL), and 33% treated with the Dual Low regimen (mean reduction of 3.6 log10 IU/mL), compared to only 5% of patients treated with the standard of care regimen (mean reduction of 2.4 log10 IU/mL).

• Synergy was observed between R1626 and standard of care therapy (additional 2.8 log10 IU/mL reduction, Triple Low vs standard of care), and between R1626 and ribavirin (additional 1.6 log10 IU/mL, Triple Low vs Dual Low).

• ALT normalized in approximately 50% of patients in the R1626 treatment groups.

• Most adverse events (AEs) were mild or moderate.

• 6 patients had 8 serious AEs during the 4-week period: 4 in the Dual High, 1 in the Triple Low and 1 in the sandard of care groups.

• The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in the Dual Low, Dual High, Triple Low, and standard of care groups, respectively, and was the main reason for dose reductions.

Based on these results, the authors concluded, "A robust synergistic antiviral effect was observed when R1626 is combined with pegylated interferon alfa-2a ± ribavirin, with up to 81% of patients undetectable by week 4."

Furthermore, they wrote, "Dosing of R1626 may be limited mainly by neutropenia; additional studies of different dosages of R1626 in combination with pegylated interferon alfa-2a and ribavirin are underway."

Scripps Clinic, La Jolla, CA; University of Florida, Gainsville, FL; University Hepatitis Center, Bradenton, FL; Fundacion de Investigacion de Diego, Santurce, PR; University of Colorado Health Sciences Center, Denver, CO; University of North Carolina at Chapel Hill, Chapel Hill, NC; Liver Institute at Dallas Methodist Hospital, Dallas, TX; Brooke Army Medical Center, Houston, TX; Kaiser Permanente Medical Center, San Diego, CA; McGuire VA Medical Center, Richmond, VA. Roche, Palo Alto, CA; Roche, Nutley, NJ.

High Barrier to the Development of
Resistance to R1626 in Vivo

In a Phase 2a study, R1626 produced maximum mean and median HCV RNA reductions of up to 3.7 log10 and 4.1 log10, respectively, following 2 weeks of monotherapy study, and 5.2 log10 following 4 weeks in combination with peginterferon alfa-2a (Pegasys) with or without ribavirin in patients infected with genotype 1 HCV.

In vitro replicon studies have identified NS5B polymerase amino acid substitutions -- S96T or S96T/N142T -- that result in 4- to 5-fold reduced sensitivity to R1479 (of which R1626 is a pro-drug). These mutations also resulted in about a 95% reduction in HCV replication capacity compared with the wild-type replicon.

To study resistance development in vivo, phenotypic and genotypic analyses were performed on multiple serum samples from 11 HCV patients treated with R1626 (3 from a monotherapy study and 8 from a combination therapy study) who experienced viral rebound before the end of treatment. Viral rebound was defined as a sustained ? 0.5 log10 increase of viral load above the nadir (lowest-ever point), where nadir is a ? 0.5 log10 decrease from baseline. Results were presented in a poster session at AASLD 2007 (abstract 1298).

All samples tested in the HCV NS5B phenotypic assay were sensitive to inhibition by R1479 to a similar extent compared with the baseline samples and the 2 reference strains, Con1 and H77. Sequence analysis of the entire NS5B coding region revealed no known R1479 resistance mutations (S96T or S96T/N142T) or any other common amino acid substitutions.

Three patients who failed to respond to R1626 (defined as < 0.5 log10 viral load decrease from baseline) had all received 500 mg R1626 as monotherapy. NS5B population sequence analysis and clonal sequence analysis of between 40-106 NS5B polymerase molecular clones for baseline samples from these 3 patients did not reveal pre-existing amino acid substitutions among the quasispecies that could be responsible for resistance to R1479.

These findings are consistent with the sensitivity of these samples to inhibition by R1479 as observed in the phenotypic assay. In addition, sequence analysis demonstrated the absence of known R1479-resistance mutations in baseline samples of all patients who participated in both studies.

According to the study authors, "There was no evidence for resistance selection to R1626 after 2 weeks of monotherapy or after 4 weeks in combination with pegylated interferon alfa-2a ± ribavirin."

In addition, they noted, "These findings suggest that there is a high barrier to the development of resistance to R1626 in vivo that may contribute to the robust antiviral effect of this drug that has been observed in randomized clinical trials."

Roche Palo Alto LLC, Palo Alto, CA, USA.

11/06/07

References

PJ Pockros, D Nelson, E Godofsky, and others. Robust Synergistic Antiviral Effect of R1626 in Combination with Peginterferon alfa-2a (40KD), with or without Ribavirin - Interim Analysis Results of Phase 2a Study (Presidential Plenary III). 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007). Boston, MA. November 2-6, 2007. Abstract (oral) 167.

S Le Pogam, A Seshaadri, A Kosaka, and others. A high barrier to resistance may contribute to the robust antiviral effect demonstrated by R1626 in HCV genotype 1-infected treatment-naive patients. AASLD 2007. Abstract (poster) 1298.

Following are excerpts from a Roche press announcement about 2 presentations on R1626 at AASLD 2007 in Boston:

Roche's Investigational Polymerase Inhibitor, Combined with Pegasys and Copegus, Shows Potent Antiviral Activity in Treatment of Chronic Hepatitis C at Four Weeks

(Boston - November 2, 2007) - R1626, one of Roche's new investigational drugs for chronic hepatitis C virus (HCV) infection, has shown promising antiviral activity when given in combination with Pegasys (peginterferon alfa-2a) and Copegus (ribavirin), according to results being presented at the American Association for the Study of the Liver Disease (AASLD) meeting, being held in Boston, Nov. 2-6.

After four weeks of treatment with this triple combination, the virus could no longer be detected in up to 81 percent of patients, with a mean decrease in viral load of 5.2 log10 from baseline. This is indicative of a robust virological response, and R1626 is being progressed into Phase IIb study as a result of these findings.

R1626 belongs to a class of antivirals called polymerase inhibitors, which are being investigated in combination with the current standard of care, pegylated interferon, and ribavirin. The hope is that this combination will increase the number of patients who are able to be successfully treated for hepatitis C.

"The results from this Phase 2a study show that R1626 has a profound antiviral effect when used in combination with Pegasys plus Copegus," said Dr. Paul Pockros, Scripps Clinic, San Diego, California, the lead investigator of the study. "This effect of R1626 in combination therapy, along with the lack of resistance observed to date, means that R1626 could be an exciting drug for patients with hepatitis C, if a safe and acceptable dosing regimen can be determined in future studies."

Antiviral Activity and Safety Results Presented at AASLD

The multicenter Phase 2a study enrolled patients with genotype 1 chronic HCV who have not previously received treatment. The objectives were to evaluate the four-week activity and safety of combining R1626 with Pegasys alone or R1626 with Pegasys plus Copegus in comparison to Pegasys/Copegus, the standard of care. The study found:

Lack of Resistance

According to a second presentation at the conference, resistance to R1626 was not identified following intensive testing for either two weeks of treatment with R1626 as monotherapy, or in patients treated with R1626 for four weeks in combination with the standard of care. These findings suggest that there is a high barrier to the development of resistance to R1626 in vivo.

Start of Phase IIb Trial

R1626 is being progressed into Phase IIb study, called POLI 1, to further investigate the new treatment regimens of R1626, in combination with standard or lower dose of Pegasys and standard dose of Copegus. This Phase IIb trial is now open and enrolling patients in eight countries, including the United States. More information about R1626 and the clinical studies can be found on www.roche-trials.com.

"As a clinician, I am excited by the high rates of viral negativity that were observed after four weeks of treatment with R1626 in combination with the standard of care. The design of the Phase IIb study should enable us to find the doses of R1626, Pegasys and Copegus that achieve the appropriate balance between safety and efficacy," said Dr. David Nelson, Director of Hepatology and Liver Transplantation at the University of Florida, Gainesville, and a lead investigator in this Phase IIb study.

11/06/07

Source
Roche Laboratories. Roche's Investigational Polymerase Inhibitor, Combined with Pegasys and Copegus, Shows Potent Antiviral Activity in Treatment of Chronic Hepatitis C at Four Weeks. Press Release. November 2, 2007.