At the recent EASL 2008 conference in Milan (April 23-27, 2008), researchers presented data on Schering-Plough's experimental oral HCV NS3 serine protease inhibitor boceprever. "Four weeks of treatment with [pegylated interferon/ribavirin] prior to boceprevir administration markedly increased rapid virological response (RVR) and early virological response (EVR) and reduced viral breakthrough by 50%," concluded the study authors.

In addition, they noted, "This new treatment paradigm has the potential to maximize efficacy of multi-drug combinations and minimize the risk of resistance by identifying responders to [pegylated interferon/ribavirin]. Finally, they wrote, "Interim results also demonstrate that full dose ribavirin is optimal."

Based on the promising results from this and other early studies of boceprevir, Schering announced this week that the company is initiating two Phase 3 studies of boceprevir. Following are edited excerpts form the announcement:
Schering-Plough Corporation today [May 22, 2008)] announced that the company is initiating two large Phase 3 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 (naïve) 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 (peginterferon alfa-2b) and Rebetol( ribavirin) 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 naïve 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 (Naïve) 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 (600-1400mg/day) compared to a control of PegIntron and Rebetol alone for 48 weeks in previously untreated (naïve) 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 beconsidered 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 PegIntrol (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 reatment (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 byresponse 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-naïve patients with chronic HCV genotype 1 werepresented at the 43rd Annual Meeting of the European Association for the Study of the Liver [EASL 2008] (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 RebetolBETOL 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.

References

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 and others. EASL 2008. 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.

5/23/08

Source
Schering Plough. SCHERING-PLOUGH TO INITIATE PHASE III STUDIES WITH HCV PROTEASE INHIBITOR BOCEPREVIR IN PREVIOUSLY UNTREATED HEPATITIS C PATIENTS AND THOSE WHO FAILED PRIOR TREATMENT. Press Release. May 22. 2008.