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FDA Approves Expanded Indication for Peginterferon-Based Combination Therapy for Chronic HCV

March 12, 2009 — Schering-Plough Corporation announced yesterday that the US Food and Drug Administration (FDA) has approved an expanded indication for peginterferon-based combination therapy for chronic hepatitis C virus (HCV) infection. Peginterferon alfa-2b (PegIntron) and ribavirin, USP (Rebetol) combination therapy is no longer restricted to treatment-naive patients and may be used to treat chronic HCV infection in patients 3 years of age and older with compensated liver disease.

"With the FDA approval of Pegintron and Rebetol combination therapy for this new indication, U.S. physicians now have a treatment option that offers a second chance for success to certain patients who failed prior therapy," Robert J. Spiegel, MD, chief medical officer and senior vice president, Schering-Plough Research Institute, said in a news release.

In the United States, this pegylated interferon combination therapy is now the first and only such therapy available that is not restricted to treatment-naive patients, offering an important therapeutic option for selected patients refractory to previous HCV treatment. The numbers of such patients are increasing and currently exceed 100,000 patients.

Factors associated with lower probability of success from retreatment after failing a course of therapy include previous nonresponse, previous use of pegylated interferon, significant bridging fibrosis or cirrhosis, and infection with HCV genotype 1.

"Based on a patient's treatment history, physicians can identify which patients may be right for retreatment with Pegintron combination therapy and may have the best chance to achieve a sustained response," Eugene R. Schiff, MD, director of the Center for Liver Diseases, University of Miami Miller School of Medicine, Florida, and a lead investigator for the pivotal clinical trial, said in a news release. "Conversely, patients with certain treatment characteristics who are unlikely to respond to this regimen can be advised accordingly."

FDA approval of the expanded indication was based on findings from 1 of the clinical trials in Evaluation of PEG-INTRON in Control of Hepatitis C Cirrhosis study (EPIC3), in which achievement of undetectable HCV RNA at treatment week 12 strongly predicted sustained virologic response (SVR).

"Patients with undetectable virus at week 12 have a better chance for success and can be motivated to continue treatment, and those patients who fail to achieve an early response can have their therapy stopped with confidence, thus avoiding unnecessary treatment and potential adverse events," Dr. Schiff said.

In this noncomparative trial, 2293 adults with moderate to severe fibrosis or cirrhosis who failed previous treatment for at least 12 weeks with combination interferon alfa/ribavirin received peginterferon alfa-2b (1.5 μg/kg once weekly) plus weight-adjusted ribavirin (800 – 1400 mg daily). Prior nonresponders (who had detectable levels of HCV RNA after ≥12 weeks of treatment) and prior relapsers (who did not have detectable levels of HCV RNA at the end of treatment and later relapsed) were included.

Response rate, defined as undetectable HCV RNA at 24 weeks posttreatment, was 22% overall. At treatment week 12, 64% of patients did not achieve undetectable HCV RNA and were offered enrollment into long-term treatment trials. Among patients with undetectable HCV RNA at treatment week 12, those infected with HCV genotype 1 had an SVR rate of 48% vs 70% for those with HCV genotype 2 or 3. For all HCV genotypes, patients with higher fibrosis scores were less likely to achieve SVR.

Regardless of HCV genotype, the recommended treatment duration with peginterferon alfa-2b combination therapy is 48 weeks. Retreated patients with detectable HCV RNA at week 12 or 24 are highly unlikely to achieve SVR, and discontinuing treatment should therefore be considered.

Adverse events associated with peginterferon alfa-2b and ribavirin as retreatment are similar to those reported during clinical trials of treatment-naive patients. Interferon alfa therapy requires close monitoring with periodic clinical and laboratory evaluations, because it may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.

Ribavirin may cause birth defects and fetal death, so pregnancy must be avoided in female patients and in female partners of male patients. Ribavirin also causes hemolytic anemia and should be considered a potential carcinogen.