FOOD AND DRUG ADMINISTRATION
Center for Drug Evaluation and Research
ANTIVIRAL DRUGS ADVISORY COMMITTEE (AVAC) MEETING
QUESTIONS TO THE COMMITTEE
November 14, 2002
Holiday Inn, 8120 Wisconsin Avenue, Bethesda, MD
BLA 125061, peginterferon alfa-2a in combination with ribavirin, NDA 21-511, Hoffmann-La
Roche, Inc., proposed for treatment of chronic hepatitis C
PEGINTERFERON AND RIBAVIRIN DOSE OPTIMIZATION
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.
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.
4. Should a separate study of patients with genotype 4 be undertaken to determine the optimal dosing regimen? What should be recommended at the present time?
OUTCOMES BY GEOGRAPHIC REGION
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.
5. Please discuss the implications of these geographical differences; in particular, the implications if cross study comparisons are attempted. What additional factors (other than stated above) might help explain these differences?
PATIENTS WITH CIRRHOSIS
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.
RECOMMENDATIONS FOR DISCONTINUATION OF TREATMENT FOR INADEQUATE EARLY VIRAL RESPONSE
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.
7. Please discuss what advice should be provided regarding early discontinuation of treatment for lack of efficacy.
Compared to Interferon combination therapy, Peginterferon combination therapy was associated with a higher incidence of serious adverse events (12% vs. 9%) including serious infections (4% vs 2%) and a higher incidence of grade 4 neutropenia (5% vs 1%) and grade 3 thrombocytopenia (5% vs. 0.2%). There is the suggestion that some patients had a blunted ability to respond to infections. PEGASYS combination treatment resulted in a high incidence of reversible lymphopenia. Interferon treatment in general appears to result in higher triglyceride levels, but this parameter was not rigorously assessed in clinical studies.
OVERALL Safety and Efficacy
9. Do these data demonstrate the safety and efficacy of PEGASYS/COPEGUS for the treatment of patients with chronic hepatitis C infection?