Schering-Plough To Initiate Phase III Studies With HCV Protease Inhibitor Boceprevir in Previously Untreated Hepatitis C Patients and Those Who Failed Prior Treatment

KENILWORTH, N.J., May 21 /PRNewswire-FirstCall/ -- Schering-Plough Corporation , a leader in hepatitis research, today announced that it is initiating two large Phase III studies of boceprevir, its investigational oral hepatitis C protease inhibitor, in patients chronically infected with hepatitis C virus (HCV) genotype 1. One study will be in previously untreated (naive) patients and the other in patients who failed prior treatment (relapsers and nonresponders), an area of great unmet medical need. The two randomized, double-blind, placebo-controlled studies will evaluate the efficacy of boceprevir in combination with PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) compared to standard of care with PEGINTRON and REBETOL alone. The Company said the two pivotal studies will run concurrently and are projected to enroll a total of more than 1,400 patients at U.S. and international sites.

"We are excited to advance to Phase III clinical studies with boceprevir in combination with PEGINTRON and REBETOL," said Fred Poordad, M.D., chief of hepatology in the division of gastroenterology at Cedars-Sinai Medical Center, associate professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles (UCLA), and co-principal investigator of the Phase III study in naive patients. "These studies are designed to demonstrate that this combination therapy has the potential to benefit a broad range of patients by significantly increasing sustained response rates with a potentially shorter course of treatment."

In both Phase III clinical studies, patients will receive 4 weeks of treatment with PEGINTRON and REBETOL prior to the addition of boceprevir. The rationale for this novel treatment paradigm 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, and may help reduce the likelihood for the development of resistance by identifying patients who are responders to interferon and ribavirin prior to their receiving a protease inhibitor.

Pivotal Study in Previously Untreated (Naive) Patients

The primary objective of this pivotal study, known as HCV SPRINT-2 (HCV Serine Protease Inhibitor Therapy-2), is to evaluate the efficacy of 28- and 48-week regimens of boceprevir (800 mg TID) in combination with PEGINTRON (1.5 mcg/kg/week) and REBETOL (600-1400 mg/day) compared to a control of PEGINTRON and REBETOL alone for 48 weeks in previously untreated (naive) adult patients with chronic HCV genotype 1. The study is projected to enroll a total of more than 1,000 patients, including a minimum of 150 African-American/Black patients.

In this study, in the 28-week treatment arm, rapid viral response (RVR) criteria at 4 weeks of boceprevir treatment (treatment week 8) will be used to determine which boceprevir patients can stop all treatment at 28 weeks. Patients in the 28-week boceprevir arm who achieve RVR, defined as undetectable virus (HCV-RNA) in plasma at week 4 of boceprevir treatment, will stop all treatment at week 28. Patients who do not meet the RVR criteria will stop boceprevir treatment at week 28 and continue PEGINTRON and REBETOL alone for an additional 20 weeks, for a total treatment duration of 48 weeks. In the 48-week treatment arm, patients will receive PEGINTRON and REBETOL plus boceprevir for a total treatment duration of 48 weeks. Patients in any arm of this study with detectable virus at week 24 will be considered treatment failures and will discontinue treatment.

The primary efficacy endpoint of the study is sustained virologic response (SVR).(1) Secondary efficacy endpoints include early virologic response in patients who achieve SVR. The study will be stratified by HCV genotype 1 subtype 1a versus 1b, and baseline viral load.

Professor Jean-Pierre Bronowicki, M.D., Ph.D., department of hepato-gastroenterology, University Hospital of Nancy, France, and Jonathan McCone, M.D., director, Mount Vernon Endoscopy Center, Alexandria, Va., are the other co-principal investigators of this study.

Pivotal Study in Patients Who Failed Prior Treatment

The primary objective of this pivotal study, known as HCV RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PEGINTRON/REBETOL) is to evaluate the efficacy of 36- and 48-week regimens of boceprevir (800 mg TID) in combination with PEGINTRON (1.5 mcg/kg/week) and REBETOL (600-1400 mg/day) compared to a control of PEGINTRON and REBETOL alone for 48 weeks in adult patients with chronic HCV genotype 1 who failed prior treatment with peginterferon and ribavirin combination therapy. The study is projected to enroll a total of 375 patients.

This study will enroll treatment-failure patients who have documented previous interferon responsiveness by achieving at least a 2 log decrease in viral load by week 12 of peginterferon and ribavirin therapy (nonresponders) or who were viral negative at end of peginterferon and ribavirin therapy, but did not obtain a sustained virologic response (relapsers). 'Null' responders -- those patients who do not meet the aforementioned criteria -- will not be enrolled in this study.

In this study, in the 36-week treatment arm, RVR criteria at 4 weeks of boceprevir treatment (treatment week 8) will be used to determine which boceprevir patients can stop all treatment at 36 weeks. Patients in the 36-week boceprevir arm who achieve RVR, defined as undetectable virus (HCV-RNA) in plasma at week 4 of boceprevir treatment, will stop all treatment at week 36. Patients who do not meet the RVR criteria will stop boceprevir treatment at week 36 and continue on PEGINTRON and REBETOL alone for an additional 12 weeks, for a total treatment duration of 48 weeks. In the 48-week treatment arm, patients will receive PEGINTRON and REBETOL plus boceprevir for a total treatment duration of 48 weeks. Patients in any arm of the study with detectable virus at week 12 will be considered treatment failures and will discontinue treatment.

The primary efficacy endpoint of the study is SVR.(1) Secondary efficacy endpoints include early virologic response in patients who achieve SVR. The study will be stratified by response to prior peginterferon and ribavirin therapy -- patients who achieved undetectable HCV-RNA (relapsers) versus those who did not (nonresponders) -- and by HCV genotype 1 subtype 1a versus 1b.

Bruce R. Bacon, M.D., James F. King M.D. Endowed Chair in Gastroenterology, professor of internal medicine, and director, gastroenterology and hepatology, Saint Louis University School of Medicine, and Professor Rafael Esteban-Mur, M.D., head of internal medicine and liver unit, Hospital Universitario Val D'Hebron, Barcelona, Spain, are the co-principal investigators of this study.

Boceprevir Clinical Development

Schering-Plough recently reported that results from a planned interim analysis of an ongoing Phase II study of boceprevir in 595 treatment-naive patients with chronic HCV genotype 1 were presented at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL).(2) The ongoing study, known as HCV SPRINT-1, evaluates boceprevir in 28- and 48-week treatment regimens.

In a 28-week treatment regimen in which patients received 4 weeks of PEGINTRON and REBETOL prior to the addition of boceprevir (800 mg TID), the rate of sustained virologic response at 12 weeks after the end of treatment (SVR 12) was 57 percent (ITT).(3-5) 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. SVR 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.

In boceprevir clinical studies reported to date, the most common adverse events have been the same as those seen with PEGINTRON and REBETOL alone: fatigue, anemia, nausea and headache. Patients have been exposed to up to 56 weeks of boceprevir combination therapy. No increase in skin adverse events (rash or pruritus) beyond what was seen in the PEGINTRON and REBETOL control arm was observed.

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 http://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 http://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 IA. "Risk Factors" in Schering-Plough's 2008 Q1 10-Q.

Endnotes: (1) SVR, the protocol specified primary efficacy endpoint, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment. Per protocol, if a patient does not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment will be utilized. (2) Kwo et al., EASL 2008, p. 372; Oral Presentation. (3) 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 HCV SPRINT-1 study is SVR as defined above. (4) Intention-To-Treat (ITT) analysis includes any patient who has taken at least one dose of any study drug. (5) Roche Cobas Taqman 1.0 assay; lower limit of detection is 15 IU/mL.