icon-folder.gif   Conference Reports for NATAP  
  American Association for the Study of Liver Diseases 2003 Conference
Boston, MA
Oct 24-28, 2003
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  Press release from Schering Plough
BOSTON, Oct. 24, 2003 — Schering-Plough Corporation (NYSE: SGP) today reported that a novel investigational protease inhibitor developed by Schering-Plough Research Institute (SPRI) was shown to be a potent inhibitor of hepatitis C virus (HCV) replication in vitro, according to data provided by researchers in an oral presentation here at the 54th annual meeting of the American Association for the Study of Liver Diseases (AASLD).
The hepatitis C protease is a viral enzyme complex that is essential to the replication of the hepatitis C virus. By interfering with viral replication, HCV protease inhibitors may represent a new antiviral approach to treating hepatitis C patients.
“The development of protease inhibitors has been a major milestone in the treatment of HIV infection. Now companies such as Schering-Plough are beginning to test the first of similar drugs to treat the hepatitis C virus, which can cause fatal liver disease and has infected millions of people worldwide,” said Francesco Negro, M.D., divisions of gastroenterology and hepatology, and of clinical pathology, University Hospital, Geneva, Switzerland, who presented the data. “Hepatitis C protease inhibitors have the potential to have the same impact on HCV therapy that the HIV drugs have had,” he said.
“These encouraging findings suggest this class of drugs is a promising area of research in the treatment of hepatitis C,” said Cecil B. Pickett, Ph.D., president of Schering-Plough Research Institute. “Once developed, these protease inhibitors, either alone or in combination with existing therapies, may help in eradicating the hepatitis C virus in patients chronically infected with the disease. Our lead compound in this area has just begun clinical testing.”
Schering-Plough has a dedicated HCV protease inhibitor development program. Its researchers, leaders in the structural biology of HCV, are using their expertise to design potent antiviral agents that can inhibit the enzyme activities required for HCV maturation and replication. As the worldwide leader in developing new and more effective treatments for hepatitis C, Schering-Plough is well positioned to develop and market innovative therapies that target HCV replication. The company in 1991 introduced the first product approved in the United States for treating chronic hepatitis C and in 1998 launched the first combination therapy. In 2001, Schering-Plough introduced the first pegylated interferon therapy.
Study Results
Dr. Negro, along with fellow scientists from University Hospital and working with a team of SPRI researchers, used multiple procedures to assess the antiviral activity of a novel protease inhibitor in the Schering-Plough portfolio known as SCH6 in a standard cell line (Huh-7 hepatoma cells) that was infected with HCV. After a 72-hour incubation period with varying concentrations of SCH6, viral transcription and protein expression were measured by real-time polymerase chain reaction, or PCR (by TaqMan), quantitative in situ hybridization, immunoblot and indirect immunofluorescence.
HCV replication and expression were effectively inhibited by SCH6, which reached its peak activity at 100 nM, as consistently shown by all procedures used. At these concentrations and for these lengths of incubation, SCH6 did not appear to induce cytotoxic morphological changes or apoptosis (cell death).
Researchers noted that while HCV protease inhibitors show promise in early stage development, much additional work will be required before this class of compounds becomes available to patients.
The company on Oct. 13, 2003, announced U.S. marketing approval of PEG-INTRON REDIPEN, the first and only pen delivery system approved for administering pegylated interferon therapy. The pre-filled, disposable REDIPEN is designed to be simpler to use than a traditional vial and syringe, thus enhancing patient confidence with dosing of their PEG-INTRON regimen and making treatment administration easier for some patients.
PEG-INTRON and REBETOL combination therapy is indicated 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.
PEG-INTRON, a long-acting, pegylated form of INTRON A (interferon alfa-2b, recombinant) Injection, is the only interferon product for hepatitis C approved for dosing according to body weight. It uses proprietary PEG technology developed by Enzon, Inc. (NASDAQ: ENZN) of Bridgewater, N.J.
PEG-INTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy that is designed to achieve an effective balance between antiviral activity and elimination half-life. Schering-Plough holds an exclusive worldwide license to PEG-INTRON. REBETOL is an oral formulation of the antiviral agent ribavirin, a synthetic nucleoside analog.
  • 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 led 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.)
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 <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 <50 mL/min. Patients on PEG-INTRON therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter.
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.
DISCLOSURE NOTICE: The information in this press release includes certain “forward-looking” statements concerning, among other things, the future prospects of the company and its products, which the reader of this release should understand are subject to substantial risks and uncertainties. The company’s business prospects and the prospects of its products may be adversely affected by general market and economic factors, competitive product development, product availability, current and future branded, generic and OTC competition, market acceptance of new products, federal and state regulations and legislation, the regulatory review process in the United States and foreign countries for new products and indications, existing manufacturing issues and new manufacturing issues that may arise, timing of trade buying, patent positions, litigation and investigations, and instability or destruction in a geographic area important to the company due to reasons such as war or SARS. For further details and a discussion of these and other risks and uncertainties, see the company’s Securities and Exchange Commission filings, including the company’s 8-K filed Oct. 22, 2003.
Schering-Plough Research Institute is the pharmaceutical research and development arm of Schering-Plough Corporation, a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.