SAN FRANCISCO, Nov. 14 /PRNewswire-FirstCall/ -- Schering-Plough’s investigational oral hepatitis C protease inhibitor (SCH 503034) capsules demonstrated potent antiviral activity and was well-tolerated, both as monotherapy and in combination with PEG-INTRON(R) (peginterferon alfa-2b), in Phase I clinical studies in patients chronically infected with hepatitis C virus (HCV) genotype 1 who were nonresponders to previous therapy, including peginterferon combination therapy. HCV genotype 1 is the most common form of the virus worldwide and is considered the most difficult to treat successfully. Currently, there are no products approved for treating HCV patients who failed previous therapies, representing an area of great unmet medical need. Chronic hepatitis C affects more than 10 million people in major world markets and is the leading cause of chronic liver disease.
The results of the studies were presented for the first time at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
“These early results are important because they show protease inhibitor SCH 503034 exhibits a potent and direct antiviral effect on HCV genotype 1,” said Professor Stefan Zeuzem, M.D., Saarland University, Homburg, Germany, who presented the data. “This promising oral antiviral agent may point the way to future HCV treatment regimens that are more effective, less toxic and shorter in duration.”
SCH 503034 is an oral HCV NS3 protease inhibitor and one of the most advanced investigational agents in a potential new class of HCV drugs. The NS3 protease is part of the HCV replication complex and its activity is essential for viral replication. It has long been a key target for HCV drug development.
In the Phase I studies, SCH 503034 capsules exhibited potent and rapid dose-related reductions in HCV viral load and ALT levels. Elevated ALT levels are considered to be a marker of liver injury due to HCV infection. In the combination study, SCH 503034 showed an additive effect to PEG-INTRON, with 4 of 10 patients in the SCH 503034 400 mg TID combination group achieving undetectable virus during the 14-day treatment vs. 0 of 22 patients receiving PEG-INTRON alone.
Based on the results of the Phase I program, Schering-Plough has initiated a large, Phase II study of SCH 503034 in combination with PEG-INTRON in nonresponders with HCV genotype 1.
“As a leader in the development of novel hepatitis therapies for more than decade, Schering-Plough is uniquely positioned to develop innovative products and improved treatment regimens for HCV infection,” said Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute. “The development of SCH 503034, as well as our ongoing research with PEG-INTRON, underscores our long-term commitment to this therapeutic area and to finding better therapies to benefit patients with hepatitis C infection.”
Phase I Studies and Results
In the Phase I rising multiple dose monotherapy study, 61 patients (45 active, 16 placebo) with HCV genotype 1 who failed previous peginterferon- based therapy (<2 log reduction in HCV RNA after 12 wks) were randomized 3:1 to receive SCH 503034 capsules or placebo: 100 mg BID, 200 mg BID, 400 mg BID, 400 mg TID, for 14 days. SCH 503034 was rapidly absorbed and exhibited potent dose-related antiviral activity that was first detectable 24 hours post-dose. Reductions in mean viral load positively correlated with SCH 503034 exposure. Mean maximum viral load reduction in the 400 mg TID group was 2.06 log10 from baseline (1.1 to 2.7 log10). A dose-related decline in ALT occurred during treatment and correlated with viral load reductions.
In the Phase I open-label combination study, SCH 503034 was evaluated in combination with PEG-INTRON vs. either agent alone in a crossover design in adult patients with HCV genotype 1 who were previous nonresponders to PEG- INTRON-based therapy. Patients were randomized to receive in random sequence, A) SCH 503034 (200 mg or 400 mg TID) as a monotherapy for 7 days, B) PEG- INTRON (1.5 mcg/kg weekly) as monotherapy for 14 days, and C) A + B combination therapy for 14 days, in a three-period crossover design with a three-week washout between treatments.
Viral load was substantially reduced by SCH 503034 plus PEG-INTRON, with 4 of 10 patients in the 400 mg TID combination group achieving undetectable virus during the 14-day treatment vs. 0 of 22 patients receiving PEG-INTRON alone. Mean maximum viral load reductions were 2.4 log10 (1.0-4.5 log10) and 2.9 log10 (2.3-4.1 log10) for SCH 503034 200 mg TID and 400 mg TID plus PEG- INTRON, respectively, vs. 1.1 log10 for PEG-INTRON alone.
Safety and Tolerability
In the Phase I program, SCH 503034 was shown to be safe and well tolerated at all dose levels evaluated, with no dose-related increase in the frequency of adverse events. In the monotherapy study, adverse events were mild or moderate and similar to placebo. The most frequently reported adverse event was headache. In the combination study, adverse events also were mild or moderate, with the adverse events for SCH 503034 being similar to those for PEG-INTRON alone, except for a slight increase in the incidence of headache. Clinical laboratory values such as bilirubin, creatinine and PPT were similar to placebo in the monotherapy study and to PEG-INTRON in the combination study. Both Phase I clinical studies included ECG monitoring and no clinically significant changes in ECG were seen. No phenotypic resistance was observed in either study.
Phase II Study Ongoing
Based on the results of the Phase I clinical program and extensive preclinical safety and pharmacology studies, Schering-Plough has initiated a large, randomized Phase II dose-finding study involving 300 patients worldwide. This study is designed to evaluate the safety and efficacy of SCH 503034 in combination with PEG-INTRON, with and without added ribavirin, for 24 or 48 weeks in patients with chronic HCV genotype 1 who were nonresponders to previous peginterferon and ribavirin combination therapy. The primary objective of this study is to determine the safe and effective dose range of SCH 503034 in combination with PEG-INTRON in this patient population. A secondary objective is to explore whether or not ribavirin provides an additional benefit when combined with SCH 503034 plus PEG-INTRON.
Important 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 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.
Schering-Plough Corporation 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 more than 30,000 people around the world. The company’s Web site is http://www.schering-plough.com.
SCHERING-PLOUGH DISCLOSURE NOTICE: This press release contains certain “forward-looking statements” within the meaning of the Securities Litigation Reform Act of 1995, including statements related to the company’s strategy and the market for SCH 503034, as monotherapy and in combination with PEG-INTRON. 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, current and future branded, generic or over-the-counter competition and the regulatory process, 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 the company’s third quarter 2005 10-Q.
Schering-Plough Corporation
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