The dose of the pegylated interferon (PEGASYS) used in the combination therapy studies, 180 mcg fixed dose administered once weekly SC, was selected based on the monotherapy studies. No dose ranging studies of PEGASYS in combination with ribavirin (COPEGUS) were carried out.

The selection of the ribavirin (COPEGUS) dose was based in part on its similarity to the ‘Schering ribavirin’ (Rebetol). In study 1 (#15801), the COPEGUS dose was crudely weight adjusted (1000 mg for body weight <75 kg and 1200mg for body weight > 75 kg administered in split dose once daily with food ). In study 2 (#15942), two doses of ribavirin were compared, a "low" fixed dose (800 mg) and the "standard" or crudely weight adjusted dose(1000-1200mg).

Exploratory analyses suggested that individuals treated with the combination therapy who were > 85 kg had a lower sustained viral response (SVR) than those < 85 kg, and experienced less toxicity, particularly hematologic toxicity, compared to patients with a lower body weight.

1. Should the sponsor evaluate lower doses (e.g. 135 : g) and/or weight-based dosing (vs. fixed dosing) of PEGASYS in combination with COPEGUS?
2. Should the sponsor evaluate additional dosages of COPEGUS? If so, please discuss, in light of the dose comparison performed in study #2, what additional doses should be studied.

Note that if licensed, such studies could be performed in the post-marketing period

DOSE AND Treatment Duration

In study 2, in addition to the two doses of COPEGUS, two intervals of combination therapy, 24 weeks and 48 weeks, were evaluated. Because of the unequal randomization, with higher risk patients preferentially placed in the higher dose of COPEGUS and longer treatment duration, it is not possible to directly compare total SVRs across all four treatments. Based on comparisons across randomization strata, patients with HCV genotype 1 achieved higher SVRs with the higher COPEGUS dose and longer duration of treatment. For patients with HCV genotype non- 1, neither more COPEGUS nor a longer duration of treatment appear to improve the SVR. However, the SVR data in the small subset of patients infected with HCV genotype 4 suggest a possible benefit for higher COPEGUS dose and longer duration of treatment.

3. If licensed, please discuss what dose of COPEGUS and what duration of treatment should be recommended based on viral factors that predict treatment response. Are there sufficient data in genotype 2 and 3 patients, regardless of viral load, to recommend shorter treatment duration and or 800 mg COPEGUS? If not, what additional studies should be conducted?

US patients achieved lower SVRs than non-US patients, regardless of treatment arm. For example, in study 1, response rates were in US patients and non-US patients were 42% and 61%, respectively. The US patients had a greater preponderance of higher risk factors, including genotype 1, cirrhosis, older age, and higher body weight. In the multivariate analysis, these factors had more of an impact on ultimate treatment response, while geographic region contributed less.

Assuming the differences across regions are real, regardless of causative factors, studies conducted predominantly in the US will yield lower SVRs than studies conducted predominantly outside the US.

The overall reported incidence of adverse events per patient was higher in US patients compared to non-US patients.

Of the three efficacy studies conducted in the PEGASYS monotherapy program, one specifically targeted patients with cirrhosis. Approximately 80% of the patients in that study had cirrhosis or bridging fibrosis. In contrast, approximately 20% of patients enrolled in the other two trials had cirrhosis, a percentage more representative of studies in chronic hepatitis C. The monotherapy label specifically identifies the cirrhotic population as one in which efficacy had been demonstrated.

In the PEGASYS/COPEGUS combination studies, patients with cirrhosis comprised 13 and 25% of the patients.

6. Please discuss the implications of cirrhosis. Should clinical development programs for products intended for treatment of patients with chronic hepatitis C infection include separate studies for patients with cirrhosis? Should presence of cirrhosis be a stratification variable?

In both studies, study subjects who did not demonstrate either an early virologic response (HCV negative or ³ 2 log₁₀ decrease) or an early biochemical response (normal ALT) could be withdrawn from the study by 12 weeks of therapy and were to be withdrawn from study if unresponsiveness persisted by 24 weeks. Ninety-six percent of patients who showed no early virologic response by week 12 failed to achieve a SVR.

8. Please discuss how best to further evaluate, characterize, and minimize the toxicity of PEGASYS/COPEGUS, specifically with regard to the hematologic and infectious events. Note that some of these assessments could be incorporated into the design of ongoing studies conducted in other clinical settings.