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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

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Thursday October 18, 8:30 am ET

Top Line Results of Phase II Study in Previous Nonresponders also Reported

KENILWORTH, N.J., Oct. 18 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE: SGP ) 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® (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.
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