Report from AASLD Meeting About Rebatron Therapy

AASLD: Rebetron Shows Promise In Combination Therapy For Hepatitis C
DALLAS,TX -- November 9, 1999 -- Schering-Plough Corporation reported that results of several clinical studies, presented at the 50th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) demonstrated the utility of Rebetron(TM) Combination Therapy containing Rebetol(R) (ribavirin, USP) Capsules and Intron(R) A (Interferon alfa-2b, recombinant) Injection in the treatment of patients with chronic hepatitis C. In all, Rebetron Combination Therapy was the subject of four oral presentations by study investigators as well as eight poster presentations and 98 study abstracts. Intron A was the subject of 34 study abstracts.

"Schering-Plough's commitment to developing improved treatments for hepatitis C is evidenced by the large number of studies with Rebetron Combination Therapy and Intron A as well as new research leads reported at this year's meeting," said Dr. Robert J. Spiegel, senior vice president of medical affairs and chief medical officer, Schering-Plough Research Institute.

In addition to studies involving Rebetron Combination Therapy, results of two Phase I studies with PEG- Intron(R), a longer-acting pegylated version of Intron A, were presented here for the first time by study investigators. PEG- Intron is a modified form of Intron A that uses proprietary PEG technology developed by Enzon, Inc. of Piscataway, N.J. Schering-Plough holds an exclusive worldwide license to PEG- Intron.

In a dose-ranging study designed to assess the biologic activities, pharmacokinetics, pharmacodynamics and tolerance of PEG- Intron, previously untreated patients chronically infected with the hepatitis C virus (HCV) received the drug subcutaneously once weekly for 24 weeks. Intron A 3 MIU administered subcutaneously three times a week was used as a comparator. In vitro activity was assessed using an HCV-surrogate cell-based assay. In this study, PEG- Intron was shown to be a biologically active molecule and demonstrated antiviral activity in vitro. PEG- Intron also demonstrated delayed clearance characteristics consistent with once weekly dosing.

In an oral presentation of results of a dose-ranging study of PEG- Intron in combination with Rebetol, investigators assessed the tolerance, pharmacokinetics and efficacy of the combination therapy in patients with chronic hepatitis C and evaluated its antiviral activity. In this study, the tolerance profile of PEG- Intron / Rebetol was comparable to the known tolerance profile of Rebetron Combination Therapy.

Schering-Plough has submitted a centralized Marketing Authorization Application to the European Union's (EU) European Agency for the Evaluation of Medicinal Products (EMEA) seeking clearance to market PEG- Intron (peginterferon alfa-2b) powder for solution for injection for the treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease. The application, which proposes administration of PEG- Intron subcutaneously once weekly for one year, is currently under CPMP review.

Other oral presentations at AASLD included a study showing that a decline in serum HCV RNA level during treatment with Rebetron Combination Therapy or Intron A in chronic hepatitis C patients who are virologic nonresponders is associated with an improvement in hepatic histology. In a study designed to assess durability of viral response to Rebetron Combination Therapy or Intron A in patients with chronic hepatitis C, results suggested that few patients who still have undetectable levels of HCV RNA* six months after completing treatment (sustained response) with either therapy will subsequently relapse. In this study, late relapse was less common following treatment with Rebetron Combination Therapy than with Intron A.

Investigators presented results of a study designed to compare the efficacy and tolerance of long-term continuous treatment with Intron A versus 24-week intermittent courses of the drug in maintaining sustained virologic response and in inducing histologic improvement in patients with chronic hepatitis C who had previously responded to alpha interferon therapy but relapsed. Other oral presentations included results of a study assessing the impact of race and another study assessing the impact of baseline livervhistology on virologic response in chronic hepatitis C patients treated with Rebetron Combination Therapy or Intron A. Researchers also gave presentations on experimental therapies for hepatitis C, research in viral hepatitis replication systems and basic HCV virology and immunology.

In a study of the health impact of HCV in Japan versus the United States as estimated by molecular evolutionary analysis, researchers noted that the incidence of HCV infection in Japan is approximately the same as in the United States, yet the incidence of HCV-related hepatocellular carcinoma is eight times greater in Japan. Researchers estimated that in Japan the divergence of genotype 1b infection, the most prevalent genotype in that country, started between 1943-1949. In the United States, the divergence of genotype 1a infection, the most prevalent genotype in the United States, started between 1966-1970. The incidence of hepatocellular carcinoma in Japan was observed to increase in 1975, approximately three decades after the spread of HCV infection there. Projecting from these dates, researchers estimated that the incidence of hepatocellular carcinoma in the United States may start to increase soon (three decades after 1966-1970).

Also presented at AASLD were a number of posters and abstracts reporting on additional studies involving Rebetron Combination Therapy. In a study to determine whether treatment with Rebetron Combination Therapy is justified in patients with mild chronic hepatitis C based on virologic response and improvement in quality of life, patients with mild disease responded equally as well to Rebetron Combination Therapy as patients with non-mild disease in terms of virology and quality-of-life burden. Investigators concluded that given the unpredictable natural history of chronic hepatitis C in individual patients, the combination therapy should be offered to informed patients regardless of disease activity.

In a study assessing the accuracy of testing serum HCV RNA levels at various time points during Rebetron Combination Therapy to predict eventual nonresponse or sustained response in chronic hepatitis C patients, testing at week 24 of therapy was shown to be most accurate and correctly identified 98 percent of nonresponders to combination therapy.

In a study to determine whether ribavirin and its triphosphate metabolite (RTP) have any direct antiviral effect against HCV, RTP was shown to inhibit HCV polymerases derived from all HCV genotypes. Researchers concluded that in addition to its reported immunomodulatory effect, ribavirin also has a direct antiviral effect against HCV, possibly through its misincorporation into viral RNA products as a result of its inhibition of the HCV polymerase enzyme.

Schering-Plough markets 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 or who have relapsed following alpha interferon therapy.

Hemolytic anemia associated with the use of Rebetol in combination with interferon alfa-2b (Rebetron Combination Therapy) may exacerbate symptoms of coronary disease or deteriorate cardiac function. It is advised that complete blood counts (CBC) be obtained at baseline and at week 2 and week 4 of therapy or more frequently if clinically indicated. The most common adverse experiences associated with combination Rebetol /interferon alfa-2b (Intron A) 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.

Combination Rebetol / Intron A therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and the six months after stopping therapy. Combination Rebetol / Intron A therapy should not be initiated until a report of a negative pregnancy has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (two reliable forms) during treatment and during the 6-month post-treatment follow-up period. Significant teratogenic and/or embriocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one-twentieth of the recommended human dose of Rebetol. If pregnancy occurs in a patient or partner of a patient during treatment or during the six months after treatment stops, physicians are encouraged to report such cases by calling (800) 727-7064.

Some 4 million Americans are infected with the hepatitis C virus, according to the Centers for Disease Control and Prevention (CDCP). As many as 5 million Europeans (1 percent to 2 percent of the general population) are chronically infected with the hepatitis C virus, according to a study conducted by the World Health Organization (WHO). Chronic hepatitis C is the leading cause of chronic liver disease and the most common reason for liver transplant, according to WHO.

Intron A is a recombinant version of naturally occurring alpha interferon, which has been shown to exert both antiviral and immunomodulatory effects. Schering-Plough 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-Plough has exclusive rights to market oral ribavirin for hepatitis C in all major world markets through a licensing agreement with ICN Pharmaceuticals, Inc.

*Defined as HCV RNA below limit of detection using a research-based RT-PCR assay at 24 weeks post-treatment.

SOURCE: Doctor's Guide to Medical News <http://www.pslgroup.com/dg/1440c2.htm>

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