KENILWORTH, N.J., Sept. 24 /PRNewswire-FirstCall/ -- Schering-Plough Corporation 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 REBETOL(R) (ribavirin, 800 - 1,400 mg daily) for retreating adult patients with chronic hepatitis C whose previous treatment with interferon alpha (pegylated or non- pegylated) and ribavirin combination therapy or interferon alpha monotherapy did not result in a sustained response. Upon European Commission approval, PEGINTRON and REBETOL will be the only available hepatitis C therapy in the European Union (EU) indicated for retreatment of prior treatment failures.
“A large and growing number of patients whose previous hepatitis C therapy did not result in a sustained response are in need of viable treatment options today,” said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. “Upon EU approval of this new indication, PEG-INTRON combination therapy will help address this serious unmet medical need.”
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 naive (previously untreated) adult patients, including naive patients with clinically stable HIV coinfection. Upon approval, this new retreatment 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.
The CHMP positive opinion is based on results from an ongoing non-comparative clinical study (EPIC3)(1) in which 1,336 patients with moderate to severe fibrosis or cirrhosis who failed previous treatment with combination alpha interferon/ribavirin therapy were retreated with PEGINTRON combination therapy.
In this study, virological response at week 12 of treatment was shown to be an important predictor for achieving a sustained virological response (SVR), with 57 percent (282/499) of patients who had undetectable virus (HCV-RNA) at week 12 going on to achieve SVR with a 48-week course of therapy. Within this subgroup, the SVR rates were 59 percent and 47 percent for patients who failed prior therapy with non-pegylated or pegylated interferon, respectively. Approximately 37 percent of patients in the study overall had undetectable virus at week 12. Importantly, patients who achieved a significant reduction in virus (greater than 2 log decreased) but did not have undetectable virus at week 12, had little chance of achieving SVR (6 percent). Overall, 23 percent of patients in the study achieved SVR. SVR is defined as undetectable HCV-RNA at 24 weeks post-treatment.
“The ability with PEGINTRON to help predict efficacy of retreatment early in the course of therapy would assist physicians in managing this hard-to- treat patient population,” said Thierry Poynard, M.D., professor of medicine, University of Paris VI, Hopital Pitie-Salpetriere, Paris, and a lead investigator of the clinical trial. “Patients with undetectable virus at week 12 have an even chance of success regardless of whether they failed previous therapy with pegylated or non-pegylated interferon and are motivated to continue treatment, and those patients who fail to achieve an early response can have their therapy stopped with confidence.”
In the study, failure to prior therapy was defined as relapse or non- response to one or more courses of interferon alpha plus ribavirin combination therapy (HCV-RNA positive at the end of a minimum of 12 weeks of treatment). Patients who were HCV-RNA negative at treatment week 12 continued treatment for a total of 48 weeks and were followed for 24 weeks post-treatment.
Based on results from this clinical study, the recommended duration of dosing with PEGINTRON combination therapy for retreating patients who failed previous therapy and who have undetectable virus at week 12 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 800-1,400 mg daily, adjusted to body weight. The recommended duration of treatment is 24 weeks for naive patients with HCV genotype 1 and low viral load, or HCV genotype 2 or 3. The recommended duration of treatment is 48 weeks for naive patients with HCV genotype 1 and high viral load, HCV genotype 4 or HIV coinfection regardless of HCV genotype. 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
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. PEGINTRON is not indicated in the United States for retreatment of patients who failed previous interferon therapy.
Important Safety Information Regarding U.S. Labeling for PEGINTRON and REBETOL
Alpha interferons, including PEGINTRON and INTRON(R) 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 PEGINTRON and/or INTRON A therapy.
Use with Ribavirin: Ribavirin may cause birth defects and/or death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen
Contraindications
PEGINTRON is contraindicated in patients with hypersensitivity to PEGINTRON or any other component of the product, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic CHC patients before or during treatment. INTRON A (Interferon alfa- 2b, recombinant) for Injection is contraindicated in patients with hypersensitivity to INTRON A or any component of the product, autoimmune hepatitis, and decompensated liver disease. PEGINTRON or INTRON A in combination with REBETOL therapy is additionally contraindicated in patients with hypersensitivity to ribavirin or any other component of the product, women who are pregnant, men whose female partners are pregnant, patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia), and patients with creatinine clearance less than 50 mL/min.
Avoid Pregnancy
REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients during therapy and 6 months post-treatment. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for 6 months after completion of therapy. A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment, and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.
Incidence of Adverse Events
There are no new adverse events specific to PEGINTRON 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 PEGINTRON 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 PEGINTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEGINTRON.
Psychiatric adverse events, which include insomnia, were common (57%) with PEGINTRON 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 PEGINTRON.
The following serious or clinically significant adverse events have been reported at a frequency less than 1% 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% in the PEGINTRON/REBETOL groups compared to 14% in the INTRON A/ REBETOL group. The incidence of severe adverse events in the PEGINTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEGINTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEGINTRON (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL.
Additional Safety Information
Relapse of drug addiction/overdose has occurred in patients on PEGINTRON therapy. Aggressive behavior sometimes directed towards others has occurred in patients with and without a previous psychiatric disorder during PEGINTRON and/or INTRON A treatment and follow-up. If patients develop psychiatric problems, including clinical depression, it is recommended that patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior towards others is identified, it is recommended that treatment with PEGINTRON and/or INTRON A be discontinued, and the patient be carefully followed with psychiatric intervention, as appropriate. Cases of encephalopathy have been observed in some patients, usually elderly, treated with higher doses of PEGINTRON and/or INTRON A. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha therapies, including PEGINTRON and INTRON A. Dental and periodontal disorders have been reported in patients receiving PEGINTRON or INTRON A in combination with REBETOL therapy.
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 www.schering-plough.com.
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 second quarter 2007 10-Q.
Reference (1) EPIC3 (Evaluation of PEGINTRON in Control of Hepatitis C Cirrhosis) is a large multicenter global clinical study evaluating the benefits of PEGINTRON in the fibrotic and cirrhotic patient at approximately 140 sites worldwide.
Schering-Plough Corporation
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