Study Shows Molecular Size and Structure of PEG Interferon Molecules, As Used...

Study Shows Molecular Size and Structure of PEG Interferon Molecules, As Used in Peg-Intron(R), Affect Antiviral Activity in Vitro



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BOSTON, MA–(HISPANIC PR WIRE)–Oct. 28, 2003–The molecular size and structure of pegylated interferon molecules, as used in PEG-INTRON(R) (peginterferon alfa-2b) Powder for Injection, have an effect on antiviral activity in vitro, according to a new study(1) presented here at the 54th annual meeting of the American Association for the Study of Liver Diseases (AASLD). In all, there were 54 PEG-INTRON study abstracts presented at the AASLD meeting.

“This is one of the first studies to relate antiviral activity in vitro to pegylated interferon molecular size and structure, and provides valuable insights into the mechanism of action of these compounds,” said Ira M. Jacobson, M.D., chief, division of gastroenterology and hepatology, Weill Medical College of Cornell University, New York.

PEG-INTRON in combination with REBETOL(R) (ribavirin, USP) Capsules is the most-prescribed treatment for hepatitis C worldwide. More than 300,000 hepatitis C patients worldwide, including 175,000 U.S. patients, have received this combination therapy since its introduction in 2001.

Study and Findings

Interferon is pegylated to prolong its activity, a process that involves the attachment of polyethylene glycol (PEG) polymer “strings” to the interferon molecule. To understand how the site of pegylation and the size of the PEG molecule affect antiviral specific activity, researchers at Schering-Plough Research Institute prepared for biological analysis purified positional pegylation isomers of interferon alfa-2b pegylated at various sites with PEG polymers ranging from 5 to 30 kilodaltons (kD) in size.

Using a variety of specialized test-tube assays, researchers found that pegylated interferon alfa-2b with relatively small PEG polymers (12 kD) attached at one particular site on the interferon molecule (His34) had the highest antiviral activity. Pegylated interferon alfa-2b molecules with larger PEG polymers attached at other positions (Lys and Cys1) had significantly lower activity. For example, the 30 kD Lys31 form had only 6 percent of the activity of the 12 kD His34 form. PEG-INTRON consists entirely of 12 kD polymers, with about 50 percent being pegylated at the His34 position.

PEG-INTRON and REBETOL

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(R) 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.

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 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.)

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 <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.

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.

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.

(1) Grace MJ, Cannon-Carlson S, Bradshaw S, Cullen C, Chapman J, Spond J, Lee S, Wylie D, Indelicato S, Voloch M, Bordens R. Site of Pegylation and peg molecule size directly attenuates interferon-alpha antiviral specific activity through the JAK/STAT signaling pathway. Abstract 1188, poster presentation: 54th annual meeting of the American Association for the Study of Liver Diseases (AASLD), Boston, MA, Oct. 24-28, 2003.

SOURCE Schering-Plough Corporation Web Site: http://www.schering-plough.com

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Contact:

Robert J. Consalvo

(908) 298-7409

Study Shows Molecular Size and Structure of PEG Interferon Molecules, As Used in Peg-Intron(R), Affect Antiviral Activity in Vitro