Interim Results from Boceprevir Phase II Study in Genotype 1 Treatment-Naive Hepatitis C Patients Presented At EASL

Update: Victrelis (boceprevir) Now FDA Approved - May 13, 2011

MILAN, Italy, April 26, 2008 /PRNewswire/ -- Schering-Plough Corporation today reported that results from a planned interim analysis of an ongoing Phase II study of boceprevir, its investigational oral hepatitis C protease inhibitor, in 595 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 were presented at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL). The ongoing study evaluates boceprevir in 28-week and 48-week treatment regimens.

In a 28-week treatment regimen in which patients received 4 weeks of PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) prior to the addition of boceprevir (800 mg TID), the rate of sustained virological response at 12 weeks after the end of treatment (SVR 12) was 57 percent (ITT).(1-3) Importantly, this treatment regimen provided an indication of early predictability of response, with patients who had undetectable virus (HCV-RNA) in plasma after 4 weeks of boceprevir treatment achieving an SVR 12 rate of 86 percent.

"These interim results are very encouraging, especially given the response seen with a shorter course of therapy in a difficult-to-treat patient population," said principal investigator Paul Kwo, M.D., associate professor of medicine and medical director, liver transplantation, Department of Medicine, Division of Gastroenterology/Hepatology, , Indianapolis, who presented the data. "Boceprevir has been well tolerated by patients in this study, including in the longer duration treatment arms, and we look forward to further results from this ongoing study."

Overall, 77 percent of the 595 patients in the study were enrolled in the United States. African-Americans represent 16 percent of the patients enrolled and 7 percent of patients in the study are cirrhotic.

In the ongoing study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir (800 mg TID) is being evaluated in three treatment regimens: 4 weeks of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) therapy followed by the addition of boceprevir to the combination for 24 or 44 weeks (totaling 28 or 48 weeks of treatment); boceprevir in combination with PEGINTRON and REBETOL at the doses described above for 28 or 48 weeks (triple combination); and boceprevir in combination with PEGINTRON and low-dose REBETOL (400-1000 mg daily) for 48 weeks, compared to a control of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) alone for 48 weeks (an approved treatment regimen). The primary endpoint of the study is sustained virologic response after 24 weeks of follow up.

During a late-breaker oral presentation at EASL, Dr. Kwo presented interim results for the two 28-week boceprevir arms of the study. For patients receiving 4 weeks of PEGINTRON and REBETOL therapy prior to the addition of boceprevir, SVR 12 was 57 percent (59/103), compared to 55 percent (59/107) for patients in the boceprevir triple combination arm. For patients in these two boceprevir arms who had undetectable virus (HCV-RNA) after 4 weeks of boceprevir treatment (RVR), the SVR 12 rates were 86 percent (53/62) and 74 percent (31/42), respectively. SVR 12 rates are not yet available for patients in the 48-week boceprevir arms or the 48-week control arm, as treatment of these patients is ongoing.

Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. No increase in skin adverse events (rash or pruritus) beyond what was seen in the PEGINTRON and REBETOL control arm was observed. Treatment discontinuations due to adverse events were between 11 and 15 percent for patients in the boceprevir arms, compared to 8 percent for the control arm.

Early response rates at week 4 (RVR) and week 12 (EVR) of boceprevir treatment were increased for patients who received 4 weeks of PEGINTRON and REBETOL therapy prior to the administration of boceprevir (62 and 79 percent, respectively), compared to patients in the triple combination (38 and 69 percent) and control (8 and 34 percent) arms, respectively. In the 28-week boceprevir arms, these patients also had a reduction in viral breakthrough compared to patients in the triple combination arm (4 vs. 7 percent, respectively).

"The results seen with this novel treatment paradigm will influence the design of our future clinical studies, as we plan to consider RVR at week 4 of boceprevir treatment as the criterion for determining which patients can receive a shorter course of boceprevir therapy and which patients should continue treatment for 48 weeks," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "Additionally, this strategy has the potential to reduce the likelihood of the development of resistance by identifying patients who are responders to interferon and ribavirin prior to their receiving a protease inhibitor."

The rationale for this novel treatment regimen is based on the fact that both PEGINTRON and REBETOL reach steady-state concentrations by week 4, so patients have the protease inhibitor added at a time when the backbone drug levels have been optimized. In addition, the patient's immune system will have been activated and primed by PEGINTRON at the time that boceprevir is added to the regimen. This approach may minimize the period of time when there is a "functional monotherapy" with a direct antiviral, potentially reducing the likelihood for the development of resistance.

The HCV SPRINT-1 study is currently ongoing at sites across the United States, Canada and Europe. Final results from the study are anticipated to be available in early 2009, and will be submitted for presentation at an appropriate medical meeting.

About Hepatitis C

Hepatitis C is a serious and potentially life-threatening disease. It is the most common blood-borne infection in America and Europe, and the most common form of liver disease, affecting nearly 5 million people in the United States, 5 million in Europe and some 200 million people worldwide. It is the leading cause of cirrhosis and liver cancer, and the number one reason for liver transplants in the United States and Europe.

About PEGINTRON

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 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.

In a study with weight-based ribavirin, there was a higher rate of anemia among patients in the weight-based dosing group (29%) compared to the flat-dosing group (19%). The majority of these cases were mild and responded to dose reductions. Serious adverse events were similar between the two groups (12%), and discontinuations for adverse events (15% in weight-based dosing and 14% in flat dosing) were also similar. Dose modifications due to adverse events occurred more frequently in the weight-based dosing group (29%) compared to the flat-dosing (23%) group.

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.

Please see important full U.S. prescribing information and the Medication Guide for PEGINTRON at www.schering-plough.com.

About Schering-Plough

Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription and consumer products as well as to animal health products. Schering-Plough's vision is to "Earn Trust, Every Day" with the doctors, patients, customers and other stakeholders served by its colleagues 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 company's clinical development plans and the potential for boceprevir. 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 about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Part I, Item 1A. "Risk Factors" in Schering-Plough's 2007 10-K/A.

    Endnotes:


    1 SVR 12 is defined as undetectable HCV-RNA in plasma at 12 weeks after

      the end of treatment.  The protocol specified primary efficacy endpoint

      of the study is SVR 24, defined as undetectable HCV-RNA in plasma at 24

      weeks after the end of treatment.

    2 Intention-To-Treat (ITT) analysis includes any patient who has taken at

      least one dose of any study drug.

    3 Roche Cobas Taqman 1.0 assay; lower limit of detect

CONTACT: Media, Robert J. Consalvo, +1-908-298-7409; or Investors, AlexKelly, +1-908-298-7436, or Joseph Romanelli, +1-908-298-7904

Web site: http://www.schering-plough.com/

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Posted: April 2008

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