SCHERING-PLOUGH ANNOUNCES FDA APPROVAL OF REBETRON™ COMBINATION THERAPY FOR PREVIOUSLY UNTREATED HEPATITIS C PATIENTS

REBETRON COMBINATION THERAPY NOW APPROVED FOR USE IN
BOTH NAÏVE AND RELAPSE HEPATITIS C PATIENTS

On December 9, 1998, the U.S. Food and Drug Administration (FDA) approved REBETRON™ Combination Therapy containing REBETOL^® (Ribavirin, USP) Capsules and INTRON^® A (Interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon therapy (naïve patients).

The FDA decision was based in part on clinical data from two pivotal multicenter Phase III studies involving naïve patients. Results of these studies showed that REBETRON Combination Therapy resulted in a significant increase in the number of patients showing a sustained loss of detectable¹ hepatitis C virus as compared to patients receiving INTRON^® A alone.

This FDA action is the second time in 1998 that the agency has granted marketing approval to REBETRON Combination Therapy for the treatment of chronic hepatitis C. On June 3, 1998, the FDA approved REBETRON Combination Therapy for the treatment of chronic hepatitis C in patients with compensated liver disease who have relapsed following alpha interferon therapy. Prior to REBETRON Combination Therapy, the only drugs approved in the United States for treating hepatitis C had been alpha interferon monotherapy.

"REBETRON Combination Therapy is changing the course of treatment for chronic hepatitis C, one of the most prevalent public health problems of the 1990s," said Richard W. Zahn, president of Schering Laboratories. "This combination therapy brings new hope to this large and growing patient population," Zahn said.

"Research into the treatment of many viral diseases has demonstrated that combination therapies often offer considerable potential for more effective treatment," commented Willis C. Maddrey, M.D., professor of internal medicine at the University of Texas Southwestern Medical Center at Dallas and world-renowned hepatologist.

Some 4 million Americans are chronically infected with the hepatitis C virus and approximately 70 percent of infected patients go on to develop chronic liver disease, according to the Centers for Disease Control and Prevention (CDC). Hepatitis C infection contributes to the deaths of 8,000 to 10,000 Americans each year. This toll is expected to triple by the year 2010 and exceed the number of annual deaths due to AIDS, according to the CDC. The American Liver Foundation has reported that liver failure due to hepatitis C infection is the leading cause of liver transplants in the United States.

In Europe, 1 to 2 percent of the general population is chronically infected with the hepatitis C virus. According to a study conducted by the World Health Organization (WHO), as many as 5 million Europeans have been chronically infected with the disease. Schering Corporation has submitted a Marketing Authorization for REBETRON Combination Therapy to the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of relapse hepatitis C patients.


Clinical Trials
The safety and efficacy of REBETRON™ Combination Therapy containing REBETOL^® (Ribavirin, USP) Capsules and INTRON^® A (Interferon alfa-2b, recombinant) Injection were evaluated in two multicenter, double-blind clinical trials involving 1,711 patients with compensated chronic hepatitis C and detectable HCV RNA who were previously untreated with alpha interferon therapy.

Patients were randomized to receive subcutaneous injections of INTRON^® A 3 million international units (MIU) three times per week and either oral REBETOL^® 1,000-1,200 mg daily or a matched placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up.

Results of these studies showed that patients treated with REBETRON Combination Therapy had a significant improved virologic and histologic response compared to patients treated with INTRON^® A and placebo. Six months after therapy was completed, 198 of 496 patients (40 percent) who were treated with 48 weeks of REBETRON Combination Therapy had undetectable virus levels² as compared to 73 of the 491 patients (15 percent) who were treated with 48 weeks of INTRON^® A and placebo.¹

Contraindications and Warnings
Anemia associated with therapy may exacerbate symptoms of coronary disease or deteriorate cardiac function. It is advised that complete blood counts (CBC) should be obtained at baseline and at weeks 2 and 4 of therapy or more frequently if clinically indicated.

The most common adverse experiences associated with REBETRON Combination Therapy are "flu-like" symptoms, such as headache, fatigue, myalgia, and fever, which appear to decrease in severity as treatment continues. Severe psychiatric adverse events may manifest in patients receiving therapy with interferons, including INTRON A therapy. DEPRESSION AND SUICIDAL BEHAVIOR, INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, MAY OCCUR.

Dosage
The recommended dosage of REBETRON Combination Therapy containing REBETOL^® (Ribavirin, USP) Capsules and INTRON^® A (Interferon alfa-2b, recombinant) Injection is 3 MIU of INTRON^® A injected subcutaneously three times per week and 1,000-1,200 mg of REBETOL capsules administered orally in a divided daily (morning and evening) dose. Patients weighing 75 kg (165 pounds) or less should receive 1,000 mg of REBETOL^® daily, while patients weighing more than 75 kg should receive 1,200 mg of REBETOL^® daily.

The recommended duration of REBETRON Combination Therapy for patients previously untreated with interferon is 24 to 48 weeks. At the end of 24 weeks of treatment, virologic response should be assessed. Treatment should be discontinued in patients who have not achieved an HCV RNA/qPCR³ below the limit of detection of the assay used by 24 weeks.

For patients who relapse following interferon therapy, the recommended duration of REBETRON Combination Therapy is 24 weeks. There are no data on treatment for longer than 24 weeks in this patient population.

INTRON^® A is a recombinant version of naturally occurring alpha interferon, which has been shown to exert both antiviral and immunomodulatory effects. Schering Corporation markets INTRON^® A, the world's largest-selling alpha interferon, for 16 major antiviral and anticancer indications worldwide.

REBETOL^® is an oral formulation of ribavirin, a synthetic nucleoside analog with broad-spectrum antiviral activity. Schering Corporation has exclusive rights to market oral ribavirin for hepatitis C in all major world markets through a licensing agreement with ICN Pharmaceuticals, Inc. (NYSE: ICN) of Costa Mesa, California.

Schering Laboratories is the U.S. prescription pharmaceutical marketing arm of Schering-Plough Corporation, a research-based company engaged in the discovery, development, manufacturing, and marketing of pharmaceutical and healthcare products worldwide.

References
1. Defined as HCV RNA below limits of detection using a research-based RT-PCR assay at 24 weeks posttreatment.

2. Combined results from two multicenter, randomized, double-blind studies of 1,711 previously untreated chronic hepatitis C patients. Dosing regimen: INTRON^® A 3 MIU tiw plus either placebo or REBETOL^® 1200 mg daily (1000 mg daily for patients weighing < 75 kg) for 48 weeks with 24 weeks of off-therapy follow-up. Results: Study 1 (n=912): Sustained virologic response in 85/228 REBETRON Combination Therapy patients vs. 27/225 INTRON A/placebo patients. Study 2 (n=799): Sustained virologic response in 113/268 REBETRON Combination Therapy patients vs. 46/266 INTRON A/placebo patients.

3. HCV-RNA (qPCR)-negative is defined as <100 copies/mL of hepatitis C viral RNA as measured by the National Genetics Institute assay.