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Biopharmaceuticals Regulatory

 News Release - April 30, 2007

European Union's CHMP Issues Positive Opinion on PEGINTRON(Tm) and REBETOL(R) Combination Therapy for Hepatitis C in Patients Coinfected With HIV

KENILWORTH, N.J., April 30 (HSMN NewsFeed) -- Schering-Plough Corporation (NYSE: SGP ) today reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) has issued a positive opinion recommending approval of combination therapy with PEGINTRON(TM) (peginterferon alfa-2b, 1.5 mcg/kg once weekly) and REBETOLĀ® (ribavirin, 800 - 1,200 mg daily) for the treatment of previously untreated adult patients with chronic hepatitis C who are coinfected with clinically stable HIV. Approximately 40 percent of the estimated 2.5 million people living with HIV in Europe are coinfected with the hepatitis C virus (HCV), according to the World Health Organization (WHO).

The CHMP recommendation serves as the basis for a European Commission approval of this expanded indication for PEGINTRON and REBETOL combination therapy, which is currently approved in the European Union (EU) for treating chronic hepatitis C in previously untreated adult patients. Upon approval, this new coinfection indication will result in Marketing Authorization with unified labeling that will be valid in the current EU 27 member states as well as in Iceland and Norway.

In two clinical studies, HCV/HIV coinfected patients treated with PEGINTRON combination therapy achieved higher statistically significant sustained virological response (SVR) rates overall compared to conventional interferon alfa-2b and ribavirin.(1,2) SVR is defined as undetectable HCV-RNA six months following the end of treatment and is the standard measure of treatment success for hepatitis C.

Importantly, PEGINTRON combination therapy demonstrated a predictable response in HCV/HIV coinfected patients. Early virological response by treatment week 12, defined as a 2 log viral load decrease or undetectable levels of HCV-RNA, has been shown to be predictive for SVR. The negative predictive value for SVR in HCV/HIV coinfected patients treated with PEGINTRON combination therapy was 99 percent.(1) This means patients with hepatitis C who fail to achieve an early virological response are highly unlikely to become sustained virological responders and can stop therapy with confidence. This can be critical to the effective management of coinfected patients, who are at greater risk for treatment-related adverse events.

Liver disease caused by chronic hepatitis C virus is now a leading cause of morbidity and mortality among HIV patients in the developed world, where deaths due to AIDS-related diseases have declined dramatically as a result of the widespread use of highly active antiretroviral therapy (HAART) for HIV.

"HCV/HIV coinfection represents a complex treatment challenge and a major concern for patients, as hepatitis C in coinfected individuals appears to have a more aggressive course," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "As a result, effective treatment of HCV is critically important for people living with HIV. The CHMP recommendation for approval of weight-based PEGINTRON combination therapy further underscores the benefits of PEGINTRON HCV treatment."

Clinical Studies

The CHMP recommendation for approval of PEGINTRON and REBETOL combination therapy for HCV/HIV coinfection is based on the results of two published clinical studies in previously untreated adult patients with chronic hepatitis C who were coinfected with HIV. RIBAVIC(1) was a multicenter study that randomized 412 patients to receive either PEGINTRON or conventional interferon alfa-2b (3 MIU three times weekly) in combination with flat-dosed ribavirin (800 mg daily) for 48 weeks. The second study(2) was a randomized, single- centre study in which 95 patients were randomized to receive either PEGINTRON or conventional interferon alfa-2b in combination with weight-based REBETOL (800-1,200 mg daily) for 48 weeks, except for patients infected with HCV genotypes 2 or 3 and HCV viral load less than 800,000 IU/ml (Amplicor) who were treated for 24 weeks.

Based on the results of these studies, the CHMP recommended duration of dosing with PEGINTRON and REBETOL combination therapy for HCV/HIV coinfected patients is 48 weeks, regardless of HCV genotype.

PEGINTRON in the European Union

PEGINTRON and REBETOL combination therapy for chronic hepatitis C was approved in the EU in March 2001. The recommended dose in the EU for combination therapy is PEGINTRON 1.5 mcg/kg once weekly plus REBETOL 800-1,200 mg daily, adjusted to body weight. The recommended duration of treatment is 24 weeks for patients with HCV genotype 1 and low viral load, or HCV genotype 2 or 3. For patients with HCV genotype 1 and high viral load or HCV genotype 4, the recommended duration of treatment is 48 weeks. PEGINTRON had previously received centralized marketing authorization in the EU and is marketed as a monotherapy in cases of intolerance or contraindication to ribavirin for the treatment of adult patients with chronic hepatitis C.

Chronic hepatitis C is estimated to affect more than 10 million people in major world markets, including 5 million in Europe. It is a leading cause of chronic liver disease and one of the most common reasons for liver transplant in Europe.

PEGINTRON in the United States

PEGINTRON is not approved in the United States for treatment of HCV/HIV coinfected patients. In the United States, PEGINTRON is indicated for use alone or with ribavirin for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and who are at least 18 years of age.

Important Safety Information Regarding U.S. Labeling for PEGINTRON and REBETOL


Alpha interferons, including PEGINTRON, 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 PEGINTRON 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/PEGINTRON 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/PEGINTRON 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.


There are no new adverse events specific to PEGINTRON as compared to INTRONĀ® 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 PEGINTRON were "flu- like" symptoms, occurring in approximately 50 percent of patients, which may decrease in severity as treatment continues. Application site disorders were common (47 percent), but all were mild (44 percent) or

moderate (4 percent) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation). Injection site pain was reported in 2 percent of patients receiving PEGINTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEGINTRON.

Psychiatric adverse events, which include insomnia, were common (57 percent) with PEGINTRON but similar to INTRON A (58 percent). Depression was most common at 29 percent. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1 percent of patients during or shortly after completing treatment with PEGINTRON.

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

REBETOL should not be used in patients with creatinine clearance less than 50 mL/min. Schering-Plough is 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 approximately 33,500 people around the world. The company is based in Kenilworth, N.J., and its Web site is

SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the potential of PEGINTRON and REBETOL. Forward-looking statements relate to expectations or forecasts of future events. Schering- Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering- Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details of these and other risks and uncertainties that may impact forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Item 1A, "Risk Factors" in the company's first quarter 2007 10-Q.


1. Carrato F, Bani-Sadir F, Pol S et al. JAMA 2004; 292(23): 2839-2848.

2. Laguno M, Murillas J, Blanco J et al. AIDS 2004; 18(13): F27-F36.

Source: Schering-Plough

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