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Results of Peginterferon Alfa-2b and Ribavirin Study in Retreating Hepatitis C Patients Who Failed Previous Combination Therapy Presented at AASLD

BOSTON, MA -- October 30, 2006 -- Schering-Plough today reported data from EPIC3, a large ongoing clinical study, showing that retreatment with PEG-Intron(R) (peginterferon alfa-2b) and Rebetol(R) (ribavirin, USP) combination therapy can result in sustained virologic response(1) (SVR) in patients with chronic hepatitis C who failed previous treatment with any alpha interferon-based combination therapy, including peginterferon regimens.

In this study, 56% of patients who had undetectable virus (HCV-RNA) after 12 weeks went on to achieve SVR with a 48-week course of therapy. Of the first 1,354 patients retreated, approximately 38% had undetectable virus at week 12. Importantly, patients who did not have undetectable virus at 12 weeks had little chance of achieving SVR. Overall, 23% of patients achieved SVR.

"The ability to predict efficacy of retreatment early in the course of therapy would assist physicians in managing this hard-to-treat patient population," said Eugene R. Schiff, M.D., chief, division of hepatology and director, Center for Liver Disease, University of Miami Miller School of Medicine, and co-lead investigator of the EPIC3 study. "These results suggest undetectable viral load at week 12 defines an early virologic response that predicts SVR for patients who failed previous combination therapies and are retreated with PEG-Intron and Rebetol."

Data from the EPIC3 retreatment study are being presented here at the 57^th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).(2)

"A large and growing number of patients who failed previous HCV therapy are in need of viable treatment options," said Robert J. Spiegel, MD, chief medical officer and senior vice president, Schering-Plough Research Institute. "The results of this study demonstrate that retreatment with PEG-Intron and Rebetol combination therapy may help address this unmet medical need in this difficult-to-treat patient population."

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and is a significant healthcare problem worldwide. The current standard of care for treating chronic HCV is the combination of peginterferon and ribavirin, which achieves SVR in approximately 50 to 60% of patients overall.(3,4)

EPIC3 Data Presented at AASLD
EPIC3 (Evaluation of PEG-Intron in Control of Hepatitis C Cirrhosis) is a large multicenter global clinical study program involving a total of more than 2,200 patients at approximately 140 sites worldwide. The program includes a global, multicenter, open-label, single-arm prospective study designed to assess the safety and efficacy of retreatment with PEG-Intron and Rebetol combination therapy in patients with moderate-to-severe fibrosis (METAVIR F2- F4) who failed previous treatment with any interferon-alfa plus ribavirin combination therapy, including peginterferon-based regimens (peginterferon alfa-2a or peginterferon alfa-2b).

In this non-comparative study, patients were retreated with PEG-Intron (1.5 mcg/kg once weekly) in combination with weight-based dosed Rebetol (800-1,400 mg/daily) for up to 48 weeks. The primary end point of the study was SVR, defined as undetectable plasma HCV-RNA 24 weeks after the end of treatment. An aim of the study was to further characterize early viral response at week 12 as a predictor of SVR in these patients.

The data presented at AASLD included safety and efficacy results for the first 1,354 patients retreated in the study. Of these, 77% of patients failed previous interferon-alfa plus ribavirin therapy and 23% failed previous peginterferon plus ribavirin therapy; 64% were characterized as nonresponders, 24% as relapsers and 12% were uncategorized treatment failures.

Overall, 23% of retreated patients achieved SVR. Of those who attained a greater than or equal to 2 log decrease in viral load at week 12, 37% achieved SVR. Among patients who had undetectable HCV-RNA at week 12, 56% achieved SVR. However, only 6% of those who attained a 2 log decrease in HCV-RNA but had detectable virus at week 12 achieved SVR. Of this latter group, 17% of patients with very low viral load at week 12 (less than or equal to 100 IU) achieved SVR compared to 5% of those with residual viral load (greater than 100-250 IU) and no patients with HCV- RNA greater than 750 IU.

About PEG-Intron
PEG-Intron is approved in the United States as monotherapy and for use in combination therapy with Rebetol (800 mg/day) for the treatment of chronic hepatitis C in patients with compensated liver disease who are at least 18 years of age.

Important Safety Information Regarding U.S. Labeling for PEG-Intron and Rebetol

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(R) 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 or equal to 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.


REFERENCES:
1 Sustained virologic response (SVR) is defined as undetectable virus (HCV-RNA) levels in the blood at 6 months after the end of therapy.
2 HCV-RNA Negativity After 12 Weeks of Therapy Is the Best Predictor of Sustained Viral Response (SVR) in the Retreatment of Previous Interferon alfa/Ribavirin Nonresponders (NR): Results From the EPIC3 Program; T. Poynard et al.; Poster No. 1123; American Association for the Study of Liver Diseases (AASLD) 2006.
3 Manns et al. Lancet 2001;358:958-65.
4 Fried et al. N Engl J Med 2002;347:975-82.


SOURCE: Schering-Plough Corporation

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