PRNewswire - November 12, 2001

PEG-INTRON and REBETOL combination therapy received U.S. Food and Drug Administration (FDA) approval in August 2001 for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and are at least 18 years of age. The combination therapy was approved for hepatitis C in the European Union (EU) in March 2001.

In an oral presentation, investigators reviewed clinical data indicating that PEG-INTRON and REBETOL combination therapy reduces the rate of fibrosis progression in patients with chronic hepatitis C. The extent of liver fibrosis is known to be an important prognostic factor in patients infected with the hepatitis C virus (HCV). Researchers pooled data from four randomized studies involving 3,010 previously untreated patients with pre- and post-treatment biopsies who received one of 10 different regimens utilizing either standard or pegylated alpha interferon and ribavirin. The histological impact of each regimen was estimated by the percentage of patients with at least one grade improvement in liver necrosis and inflammation, the percentage of patients with at least one stage worsening in fibrosis and by the fibrosis progression rate per year. While all regimens reviewed in this study reduced fibrosis progression rates in comparison to rates before treatment, PEG-INTRON and REBETOL combination therapy showed the greatest improvement in liver necrosis and inflammation and the lowest rate of fibrosis worsening among these treatment regimens.

"The development of pegylated interferon is a significant advance in the treatment of hepatitis C, especially when used in combination with oral ribavirin," said Ira Jacobson, M.D., chief, division of gastroenterology and hepatology, Weill Medical College of Cornell University, New York. "It is imperative for us now to better define optimal treatment regimens using these therapies and further explore their use in treating specific patient populations," he said. Jacobson is the lead investigator for the largest prospective hepatitis C study undertaken to date, which is expected to enroll more than 4,000 U.S. patients. Schering-Plough is supporting this study.

"Schering-Plough's ongoing commitment to developing improved treatments for hepatitis C is evidenced by the more than 125 clinical studies with PEG- INTRON, INTRON A and REBETOL as well as new research leads reported at this year's AASLD meeting," said Robert J. Spiegel, M.D., senior vice president of medical affairs and chief medical officer, Schering-Plough Research Institute. "Through this clinical research, physicians are gaining a better understanding of how to optimize the use of available therapies to more effectively treat hepatitis C."

PEG-INTRON Studies Presented at AASLD

In a study designed to evaluate the effect of adherence to therapy on treatment outcome for HCV patients receiving PEG-INTRON and REBETOL, researchers performed an analysis on data from the pivotal clinical study involving 1,530 patients that served as the basis for U.S. and EU regulatory approval of the combination therapy. Analysis of sustained viral response(1) (SVR) rates according to patient compliance during therapy showed that patients receiving greater than or equal to 80% of their total interferon dose and greater than or equal to 80% of their ribavirin dose for greater than or equal to 80% of the expected duration of therapy had enhanced SVR rates compared to patients who were not adherent to therapy.

New treatment strategies are needed to maximize HCV viral clearance in the growing number of patients with chronic hepatitis C who did not respond to, or had relapsed following, previous interferon-based therapy. Researchers at AASLD presented interim data from eight separate ongoing prospective studies evaluating the safety and efficacy of PEG-INTRON and REBETOL combination therapy in this treatment setting.

A large randomized study is ongoing to evaluate two different dosing regimens of PEG-INTRON and REBETOL in nonresponders to interferon monotherapy or combination therapy with ribavirin, or in patients who relapsed following combination therapy. Of the 330 patients enrolled in this study to date, 152 have completed 24 weeks of treatment (half way through therapy). Combined results of the two dosing regimens for the subset of patients who did not respond to prior combination therapy showed that 26% of these patients (29/112) had a virologic response after 24 weeks of treatment, including patients with genotype 1 (22/98), the predominant genotype worldwide and the most difficult to treat.

In another large ongoing study involving patients who failed to clear the hepatitis C virus following interferon-based therapy, the first 250 patients enrolled are being treated with PEG-INTRON (1.5 mcg/kg/week) and REBETOL (800 mg/kg/day) for 48 weeks. The next 250 patients enrolled will receive the same dose of PEG-INTRON, but in combination with a weight-based dose of REBETOL. Of the 132 patients to date who have received at least 24 weeks of treatment with PEG-INTRON (1.5 mcg/kg/week) and REBETOL (800 mg/kg/day), 41% are HCV negative. Of these patients, 31% with genotype 1a and 49% with genotype 1b, as well as 22% of previous nonresponders and 25% of African Americans, are HCV negative.

Treatment of chronic hepatitis C in patients co-infected with HIV has become a major issue in the last few years as the prognosis of HIV disease has improved dramatically with the development of highly active antiretroviral therapy (HAART). As a consequence, an increasing number of co-infected patients are prone to develop cirrhosis and end-stage liver disease. Investigators reported interim results of an ongoing open-label study evaluating the safety and efficacy of PEG-INTRON (150 mcg/week) and REBETOL (800 mg/day) in 31 co-infected patients previously untreated with interferon, many of whom are receiving antiretroviral drugs for HIV. After 12 weeks of treatment, serum HCV-RNA was undetectable in 22 patients (75%) and liver enzyme levels normalized in 27 patients (85%), with three patients stopping therapy due to adverse effects. These interim results indicate that longer follow up is warranted.

In a study comparing the public health burden of chronic hepatitis C and HIV infection in France, researchers using mortality data and natural history estimates applied the back-calculation method to make projections about incidence and mortality from HCV and HIV up to 1997. The HCV model applied natural history and hepatocellular carcinoma mortality data from French national statistics. The HIV model used AIDS cases reported to the French National Institute for Public Health Surveillance and HIV/AIDS deaths reported to the French Institute of Health and Medical Research. These data indicate that the public health burden of HCV is on the rise in France, while the burden of HIV may be on the decline.

Hepatitis C virus recurrence after liver transplantation is common and poses one of the greatest challenges to transplantation for this indication. In a small study, PEG-INTRON and REBETOL combination therapy was evaluated in six patients who developed aggressive recurrent HCV after receiving transplants for HCV-related cirrhosis. Researchers noted that additional clinical studies are necessary to define duration of therapy and whether treatment will lead to improved overall patient and graft survival.

A significant number of patients chronically infected with hepatitis C have cirrhosis or transition to cirrhosis at the time of diagnosis. In order to define the impact of severe liver disease on the pharmacokinetics and pharmacodynamics of PEG-INTRON and REBETOL combination therapy, pharmacokinetic data for REBETOL (1,367 patients) and pharmacodynamic data for PEG-INTRON in combination with REBETOL (627 patients) were collected from the pivotal clinical study involving 1,530 patients that served as the basis for U.S. and EU regulatory approval of the combination therapy. Additionally, pharmacokinetic data for PEG-INTRON (894 patients) were collected from the pivotal clinical study involving 1,219 patients that served as the basis for U.S. and EU regulatory approval of PEG-INTRON monotherapy. The population models for PEG-INTRON and REBETOL were developed separately and the severity of hepatic fibrosis was determined by Knodell HAI score. Results of this analysis suggest that baseline fibrosis score had no effect on the apparent clearance of REBETOL. For PEG-INTRON, the baseline fibrosis score had no effect on week 4 clearance. Furthermore, the baseline fibrosis score had no effect on other pharmacokinetic parameters, including the baseline clearance, the ratio of clearance at treatment week 4 relative to week 48 (end of treatment) and the time that the clearance of PEG-INTRON declines to half of the baseline clearance (T50).

Researchers also presented results of a cost-effectiveness study of PEG- INTRON and REBETOL combination therapy in the initial treatment of hepatitis C. For this analysis, summary data from the pivotal clinical study involving 1,530 patients that served as the basis for U.S. and EU regulatory approval of the combination therapy was applied to a previously published and validated computer cohort simulation to project lifelong clinical outcomes. Their analysis suggested that PEG-INTRON and REBETOL combination therapy should be considered cost effective, providing good economic value for its clinical benefit.

Schering-Plough HCV Products

PEG-INTRON, which is approved for dosing according to patient body weight, is the first and only pegylated interferon product approved for marketing in the United States. PEG-INTRON is a longer-acting form of INTRON(R) A (interferon alfa-2b, recombinant) Injection that uses proprietary PEG technology developed by Enzon, Inc. (Nasdaq: ENZN) of Piscataway, N.J. PEG-INTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy designed to optimize the balance between antiviral activity and elimination half-life. Schering-Plough holds an exclusive worldwide license to PEG-INTRON.

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. Schering-Plough has exclusive worldwide rights to market oral ribavirin for hepatitis C through a licensing agreement with ICN Pharmaceuticals, Inc. (NYSE: ICN) of Costa Mesa, Calif.

WARNING

-- REBETOL monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. (See WARNINGS.)

-- The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with REBETOL therapy may result in worsening of cardiac disease that has lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL. (See WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.)

-- Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking REBETOL therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month post-treatment follow-up period. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS-Information for Patients and Pregnancy Category X.)

-- Alpha interferons, including PEG-INTRON and INTRON A, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping therapy with PEG-INTRON or INTRON A. (See WARNINGS, ADVERSE REACTIONS.)

PEG-INTRON

There are no new adverse events specific to PEG-INTRON as compared to INTRON A, however, the incidence of some (e.g., injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEG-INTRON were "flu-like" symptoms, occurring in approximately 50% of patients, which may decrease in severity as treatment continues. Application site disorders were common (47%), but all were mild (44%) or moderate (4%) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation). Injection site pain was reported in 2% of patients receiving PEG-INTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEG-INTRON.

Psychiatric adverse events, which include insomnia, were common (57%) with PEG-INTRON, but similar to INTRON A (58%). Depression was most common at 29%. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1% of patients during or shortly after completing treatment with PEG-INTRON. PEG-INTRON is contraindicated in patients with autoimmune hepatitis and decompensated liver disease.

The following serious or clinically significant adverse events have been reported at a frequency less than or equal to 1% with PEG-INTRON or interferon alpha: Severe decreases in neutrophil or platelet counts, hypothyroidism, hyperglycemia, hypotension, arrhythmia, ulcerative and hemorrhagic colitis, development or exacerbation of autoimmune disorders including thyroiditis, RA, systemic lupus erythematosus, psoriasis, pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, some resulting in patient deaths), urticaria, angioedema, bronchoconstriction, anaphylaxis, retinal hemorrhages and cotton wool spots.

Renal failure patients should be closely monitored for signs and symptoms of interferon toxicity and PEG-INTRON should be used with caution in patients with creatinine clearance less than or equal to 50 mL/min. Patients on PEG- INTRON therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter.

INTRON A

All patients receiving INTRON A therapy experienced mild-to-moderate side effects. Some patients experienced more severe side effects, including neutropenia, fatigue, myalgia, headache, fever, chills and increased SGOT. Other frequently occurring side effects were nausea, vomiting, depression, alopecia, diarrhea and thrombocytopenia. DEPRESSION AND SUICIDAL BEHAVIOR, INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HAVE BEEN REPORTED IN ASSOCIATION WITH TREATMENT WITH ALFA INTERFERONS, INCLUDING INTRON A THERAPY.

Hepatitis C

Some 4 million Americans are infected with the hepatitis C virus (HCV) 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 an estimated 8,000 to 10,000 Americans each year and this toll is expected to triple by the year 2010, according to the CDC. The CDC has reported that HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults. It is predicted that direct U.S. medical costs to treat HCV-related disease will exceed $13 billion for the years 2010 through 2019, according to a study published in the American Journal of Public Health.

Schering-Plough Research Institute is the pharmaceutical research and development arm of Schering-Plough Corporation of Kenilworth, N.J., a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

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

SOURCE Schering-Plough Corporation Web Site: http://www.schering-plough.com Company News On Call: Company News On-Call: http://www.PRNewswire.com/comp/777050.html

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