Initial Results of Phase II Study with HCV Protease Inhibitor Boceprevir in Treatment-Naive Hepatitis C Patients Show a High Rate of Early Virologic Response

Update: Victrelis (boceprevir) Now FDA Approved - May 13, 2011
Top Line Results of Phase II Study in Previous Nonresponders also Reported

KENILWORTH, N.J., October 18, 2007 /PRNewswire-FirstCall/ -- Schering-Plough Corporation today provided an update on the clinical development program for boceprevir, its investigational oral hepatitis C protease inhibitor. Initial results from an ongoing Phase II study in treatment-naive (previously untreated) hepatitis C patients showed boceprevir (800 mg TID) in combination with PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) achieved a high rate of early virologic response, with up to 79 percent of patients having undetectable virus (HCV-RNA) at week 12 of boceprevir treatment compared to 34 percent of patients receiving PEGINTRON and REBETOL alone.

"These initial results, while preliminary, are very encouraging, and showed that boceprevir is a potent antiviral agent for hepatitis C," said Paul Kwo, M.D., associate professor of medicine and medical director, liver transplantation, Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, and the lead investigator of the study. "In this study, boceprevir improved viral clearance rates at week 12 in genotype 1 hepatitis C infection compared to the control group. We look forward to further results from this ongoing study."

Boceprevir is being evaluated in combination with PEGINTRON and REBETOL for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1 in two large Phase II clinical studies, in which more than 800 patients have received boceprevir. One study involves treatment-naive patients and the other involves patients who were nonresponders to previous peginterferon and ribavirin combination therapy. In these boceprevir studies, the most common adverse events have been fatigue, headache, nausea and anemia. No increase in skin adverse events (rash) beyond what was seen in the PEGINTRON and REBETOL control was observed. Gastrointestinal events were the most common adverse events leading to discontinuation in the boceprevir arms.

In the treatment-naive study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir (800 mg TID) is being evaluated in three treatment regimens: in combination with PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily) for 28 or 48 weeks; 4 weeks of PEGINTRON and REBETOL combination therapy at the doses described above followed by adding boceprevir to the combination for 24 or 44 weeks; and boceprevir in combination with PEGINTRON and low-dose REBETOL (400-1000 mg daily) for 48 weeks, compared to a control of PEGINTRON and REBETOL alone for 48 weeks (a standard of care). The primary endpoint of this study is sustained virologic response. Patients receiving these boceprevir regimens achieved a high rate of early virologic response, with 70, 79 and 54 percent of patients, respectively, having undetectable virus (HCV-RNA) at week 12 of boceprevir therapy compared to 34 percent of patients in the control arm (Roche Cobas Taqman 1.0 assay; lower limit of detection is 15 IU/mL). Treatment discontinuations due to adverse events were 12, 9, and 8 percent for patients in the boceprevir regimens, respectively, compared to 5 percent for the control arm.

A total of 595 patients have been treated in the HCV SPRINT-1 study at sites across the United States, Canada and Europe, including 491 patients treated with boceprevir. Overall, 77 percent of patients in the study were enrolled in the United States. African-Americans represent 16 percent of the patients enrolled in the study and 7 percent of patients in the study are cirrhotic.

Boceprevir in "Null" Nonresponder HCV Patients

Schering-Plough also reported top line results from a completed Phase II study evaluating boceprevir dose response and the need for ribavirin in patients chronically infected with HCV genotype 1 who were nonresponders to previous peginterferon and ribavirin combination therapy (i.e., patients who did not have undetectable HCV-RNA or who did not achieve a 2 log decline in viral load with a minimum of 12 weeks of peginterferon and ribavirin combination therapy). These "null" nonresponders to peginterferon and ribavirin combination therapy represent the most difficult-to-treat patient population. Patients who relapsed following previous HCV therapy (relapsers) were not included in this study.

This study was complex, involving seven different treatment arms. Patients were initially randomized to low doses of boceprevir (100, 200, 400 mg TID) before initiating an 800 mg TID boceprevir arm. Under the study protocol, patients received these boceprevir doses in combination with PEGINTRON (1.5 mcg/kg weekly) with or without REBETOL (800-1400 mg daily) for 24 or 48 weeks, or received PEGINTRON and REBETOL alone as a control. During the ongoing review of the study by the Data Safety Monitoring Board (DSMB), it was recommended that patients in the lower-dose boceprevir arms who demonstrated a substantial antiviral response during treatment cross over to boceprevir 800 mg TID in combination with PEGINTRON and REBETOL for an additional 24 weeks. Patients who did not demonstrate a substantial antiviral response during treatment were discontinued from the study. In addition, patients in the control arm who did not respond to PEGINTRON and REBETOL alone were allowed to cross over to boceprevir 800 mg TID in combination with PEGINTRON and REBETOL. Patients received a maximum of 24 weeks of the optimized regimen (boceprevir 800 mg TID in combination with PEGINTRON and REBETOL). In all, 357 patients were enrolled at centers in the United States and Europe, including 348 patients who received boceprevir at some point in the study.

In this study of well-documented null nonresponders, some patients achieved a sustained virologic response (SVR). Overall, 7-14 percent of patients in the boceprevir crossover arms achieved SVR compared to 2 percent in the control arm. SVR was associated with early virologic response and a longer course of therapy (more than 36 weeks). While potent antiviral activity with boceprevir was seen in the study, with viral loads in some patients decreasing below the limit of detection, viral loads for other patients decreased and then rebounded to baseline levels while on therapy and some patients relapsed following the end of treatment. Several resistant variants were observed in these patients. These HCV variants are similar to those reported after treatment with other HCV protease inhibitors and those previously observed in boceprevir in vitro studies. Whether the results of this study would have been different had all patients been started with the optimized regimen of boceprevir 800 mg TID in combination with PEGINTRON and REBETOL -- and with treatment extending to 48 weeks -- is not known.

"Although interferon nonresponders appear to respond to HCV protease inhibition, it seems that some significant element of interferon response is needed to achieve a sustained virologic response in the majority of these patients," said Eugene R. Schiff, M.D., chief, division of hepatology and director, Center for Liver Disease, University of Miami Miller School of Medicine, and the lead investigator of the study.

Schering-Plough said that in patients with little to no interferon response, alternative treatment strategies are required, and the company will continue to explore regimens containing boceprevir, PEGINTRON and REBETOL in the Phase II setting, using the insights gained in this initial study.

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. PEGINTRON is indicated for 48 weeks of treatment in the United States.

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.

About Schering-Plough

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 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 and a discussion of risks and uncertainties that may impact forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Part II, Item 1A, "Risk Factors" in the company's second quarter 2007 10-Q.

CONTACT: Media, Robert J. Consalvo, +1-908-298-7409, or Investors, AlexKelly, +1-908-298-7436, or Robyn Brown, +1-908-298-7436

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

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Posted: October 2007

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