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Schering-Plough Reports Comparative Pharmacokinetics and Pharmacodynamics Data for PEG-Intron(R) and PEGASYS(R) in Hepatitis C Virus Infection

Posted on: Monday, 1 November 2004, 12:00 CST

Schering-Plough today reported that important new scientific data characterizing the different pharmacokinetic profiles and biological properties of PEG-INTRON (peginterferon alfa-2b / Schering Corp.) and PEGASYS (peginterferon alfa-2a / Hoffmann-La Roche, Inc.), the two leading drugs currently available to treat chronic hepatitis C infection, will be presented at the 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

Results of the study,(i) Comparison of Peginterferon alfa-2a and Peginterferon alfa-2b Pharmacokinetics and Pharmacodynamics in COMPARE, a Randomized, Prospective, Blinded Trial, Silva M, et al., will be presented as part of AASLD's "Hot Topics in Clinical Hepatology" Session on Sunday, Oct. 31, and will be highlighted in the AASLD press conference on Saturday, Oct. 30.

"This study is designed to explore the relationship between antiviral activity in patients and the chemical, structural and biological properties of the peginterferon molecule," said Marcelo O. Silva, M.D., associate professor of medicine, Favaloro University School of Medicine; medical coordinator, liver transplant unit, Hospital Universitario Austral, Pilar, Argentina, and lead investigator of the study. "In this eight-week study, we found that PEG-INTRON was associated with greater viral load reductions in patients."

PEG-INTRON and PEGASYS differ substantially in terms of their chemical and structural characteristics, pharmacokinetic and pharmacodynamic properties. The COMPARE study investigated the effect of these differences on interferon gene expression and initial viral load reduction in patients.

COMPARE Study and Results

The COMPARE study was a randomized, double blind, parallel group trial in 36 patients with chronic hepatitis C genotype 1 who had not been previously treated. Genotype 1 is the most common type of hepatitis C worldwide and the most difficult to treat. Patients received PEG-INTRON (1.5 mcg/kg/wk) or PEGASYS (180 mcg/wk) monotherapy for four weeks, followed by four weeks with the addition of ribavirin (13/mg/kg/day).

In the COMPARE study, PEG-INTRON demonstrated significantly greater antiviral activity vs. PEGASYS at week one, with greater maximum antiviral activity (P < 0.001) and greater cumulative antiviral activity (P=0.017); and at week 4, with greater maximum antiviral activity (P < 0.001) and greater cumulative antiviral activity (P < 0.001). The slope of the viral load reduction for PEG-INTRON was greater over the eight-week study duration (P < 0.002). In addition, 72 percent of patients in the PEG-INTRON arm achieved at least a 2.0 Log10 reduction in viral load as compared to 44 percent of patients in the PEGASYS arm during the study (p=0.09).

Patients in the study were evenly matched for age, gender, race, study site and weight, as well as for baseline viral load, white blood cell, neutrophil and platelet counts, and liver function laboratory values (AST and ALT).

Great care was taken in the study blinding method to maintain scientific rigor and minimize the potential for bias. Trial medication was prepared and administered by staff not otherwise involved in the trial. Intensive pharmacokinetic assays were performed throughout weeks one and four. Pharmacodynamic markers included viral load decline and interferon response gene mRNA levels. Routine safety laboratory tests were carried out.

"The results of the COMPARE study provide important insights into how these two drugs work in the body and shed new light on the relationship between interferon activity, gene activation and viral load decline," said Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute. "The clinical relevance of these findings can only be determined in a large, randomized, controlled study evaluating the comparative efficacy of these two drugs. Schering-Plough's ongoing IDEAL study is designed specifically to answer that question."

The IDEAL Study

Schering-Plough Research Institute is sponsoring the IDEAL study, a large head-to-head clinical study involving 2,880 patients that for the first time directly compares PEG-INTRON in combination with REBETOL(R) (Ribavirin, USP) versus PEGASYS in combination with COPEGUS(R) (Ribavirin, USP / Hoffmann-La Roche, Inc) in U.S. patients with chronic hepatitis C genotype 1.

The IDEAL study (Individualized Dosing Efficacy vs. flat dosing to Assess optimaL pegylated interferon therapy) will involve up to 100 sites nationwide. Most of the planned study centers have already been initiated and are actively screening patients. To date, over a thousand patients are in screening or have been randomized. This rapid enrollment is on target with the study projections and plans. For more information about the IDEAL study or to locate study centers, please visit www.idealstudy.com.

PEG-INTRON and REBETOL Combination Therapy

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.

The recommended dose of PEG-INTRON is 1.5 mcg/kg weekly in combination with REBETOL 800 mg daily for 48 weeks.

PEG-INTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy dosed according to patient body weight that is designed to achieve an effective balance between antiviral activity and elimination half-life. PEG-INTRON is a longer-acting form of INTRONO A (interferon alfa-2b, recombinant) Injection.

REBETOL is an oral formulation of ribavirin, a synthetic nucleoside analog with broad-spectrum antiviral activity.

WARNING

Alpha interferons, including PEG-INTRON, 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 PEG-INTRON therapy.

Ribavirin causes hemolytic anemia. Anemia associated with REBETOL therapy may exacerbate 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. It is advised that complete blood counts (CBC) be obtained at baseline and at weeks 2 and 4 of therapy or more frequently if clinically indicated.

REBETOL and combination REBETOL/PEG-INTRON therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and during the 6 months after stopping therapy. REBETOL and combination REBETOL/PEG-INTRON therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (at least two reliable forms) during treatment and during the 6-month post-treatment follow-up period. Significant teratogenic and/or embryocidal 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 6 months after treatment stops, physicians are encouraged to report such cases by calling (800) 727-7064.

PEG-INTRON

There are no new adverse events specific to PEG-INTRON as compared to INTRON A (interferon alfa-2b, recombinant) for Injection, 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/REBETOL is contraindicated in patients with autoimmune hepatitis, decompensated liver disease, and in patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia).

The following serious or clinically significant adverse events have been reported at a frequency less than 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.

In the PEG-INTRON/REBETOL combination trial the incidence of serious adverse events was 17% in the PEG-INTRON/REBETOL groups compared to 14% in the INTRON A/REBETOL group. The incidence of severe adverse events in the PEG-INTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEG-INTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-INTRON (1.5 mcg/kg)/ REBETOL and in 34% of those receiving INTRON A/REBETOL.

REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.

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.

Please see full prescribing information available at www.schering-plough.com.

Schering-Plough Corporation, a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its more than 30,000 people around the world. The company is based in Kenilworth, N.J., USA, and its Web site is www.schering-plough.com.

DISCLOSURE NOTICE: The information in this press release contains "forward-looking statements" within the meaning of the Securities Litigation Reform Act of 1995, including the market for PEG-INTRON, REBETOL and combination therapy using both drugs ("Products") and the market for drugs to treat hepatitis C. Forward-looking statements relate to expectations or forecasts of future events and not to historical information. Schering-Plough does not assume the obligation to update any forward-looking statement. There are no guarantees about the market performance of the Products, Schering-Plough stock or Schering-Plough's business. Actual results may vary materially from forward-looking statements made here or in other Schering-Plough written or spoken communications due to many factors and uncertainties, which include the market acceptance of the Products, trade buying patterns, the introduction and performance of competitive products in the market, legislation that may impact the pricing/availability of the Products and other items discussed in Schering-Plough's Securities and Exchange Commission filings, including the 10-Q filed October 28, 2004.

PEGASYS and COPEGUS are trademarks of Hoffman-La Roche Inc. See the PEGASYS and COPEGUS product inserts for information on these products.

Reference

(i)Silva M, Poo-Ramirez J-L, Wagner F, Jackson M, Laughlin M. Comparison of peginterferon-a2a and peginterferon-a2b pharmacokinetics and pharmacodynamic in COMPARE, a randomized, prospective, blinded trial. Abstract 68, oral presentation at: 55th annual meeting of the American Association for the Study of Liver Diseases (AASLD), Boston, MA, October 29-Nov 2, 2004.

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 Contact: Robert J. Consalvo (908) 298-7409  Schering-Plough Corporation 2000 Galloping Hill Road Kenilworth, New Jersey 07033-0530  

SOURCE: Schering Plough

Source: MARKET WIRE

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