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[DewDiligence]

This is SGP’s EASL PR on Boceprevir and SCH 900518.
(Please see the actual PR for footnote references.)

http://finance.yahoo.com/news/Final-Results-of-Boceprevir-prnews-15011615.html

›Final Results of Boceprevir Phase II HCV SPRINT-1 Study Showed Significantly Higher SVR Rates Compared to Standard of Care in Treatment-Naive Genotype 1 Hepatitis C Patients

Thursday April 23, 2009, 10:30 am EDT

48-week investigational regimen yielded nearly double SVR rate compared to standard of care

Update on next-generation HCV protease inhibitor SCH 900518 presented at EASL annual meeting

COPENHAGEN, Denmark, April 23 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE: SGP ) today reported that final results of the HCV SPRINT-1 study showed boceprevir, its investigational oral hepatitis C protease inhibitor, in combination with peginterferon alfa-2b and ribavirin, significantly increased sustained virologic response (SVR)(1) rates with 28 and 48 weeks of therapy compared to current standard of care, peginterferon and ribavirin for 48 weeks (control group). The results from this Phase II study in 595 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 were presented at the 44th European Association for the Study of the Liver (EASL) 2009 Annual Meeting.(2) Genotype 1 is the most common and hardest to treat form of hepatitis C.

In Part I of the study, a 48-week boceprevir regimen achieved a 75 percent SVR rate (n=77/103) in patients who received 4 weeks of PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL® (ribavirin, USP) (P/R) followed by the addition of boceprevir (800 mg TID) for 44 weeks (boceprevir P/R lead-in regimen). This represents a near doubling of the 38 percent SVR rate (n=39/104) for patients in the control group (p<0.0001). In a 28-week boceprevir P/R lead-in regimen 56 percent of patients (n=58/103) achieved SVR (p=0.005).(3)

Importantly, the likelihood (predictability) of attaining SVR was greater for patients who received the boceprevir P/R lead-in regimens compared to the no lead-in arms. Of patients in the boceprevir P/R lead-in arms who achieved a rapid virologic response (RVR), 94 percent in the 48-week regimen and 82 percent in the 28-week regimen achieved SVR. RVR is defined as undetectable virus (HCV RNA) in plasma at 4 weeks after the addition of boceprevir. In the lead-in arms, 64 percent of patients achieved RVR. Fewer patients in the lead-in arms discontinued treatment due to viral breakthrough.

"These results are very exciting and provide important insights to help further define response guided therapy using a P/R lead-in boceprevir regimen with peginterferon and ribavirin backbone treatment," 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 lead investigator of the study. "Building on these results, the boceprevir Phase III clinical program individualizes treatment based on response, utilizing RVR criteria at week 4 of boceprevir treatment to determine overall duration of therapy. Based on the RVR rate seen in this Phase II study, we are hopeful that the majority of patients can be treated with 28 weeks of therapy."

Part II of the HCV SPRINT-1 study explored a low-dose ribavirin strategy in which boceprevir was given in combination with PEGINTRON and low-dose REBETOL for 48 weeks. SVR for the low-dose REBETOL arm was 36 percent (n=21/59) compared to 50 percent for a 48-week control arm with PEGINTRON and standard-dose REBETOL plus boceprevir (n=8/16). In contrast to the results seen in Part I, the low-dose REBETOL regimen was associated with increased viral breakthrough during treatment, higher relapse rates after the end of treatment and lower SVR, strongly indicating that standard-dose ribavirin is required to optimize response.

Another key finding of the HCV SPRINT-1 study is that treatment-emergent anemia appeared to be associated with higher SVR, with anemic patients (hemoglobin decreasing to less than 10 g/dL) having higher SVR rates than those without anemia (hemoglobin did not decrease to less than 10 g/dL). Anemia is a known adverse event with combination therapy for hepatitis C and this association with higher SVR has been seen in other clinical studies with peginterferon and ribavirin, including the IDEAL study.(4) Boceprevir is associated with about a 1 g/dL incremental decrease in hemoglobin. In the HCV SPRINT-1 study, anemia occurred in approximately half of the patients in the boceprevir arms and over a third of patients in the control arm. Erythropoietin (EPO) supplementation was allowed in the study at the discretion of the investigator and was used by 26 percent of patients in the control arm and 39-51 percent of patients in the boceprevir arms with standard-dose REBETOL.

Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. The incidence of skin adverse events (rash or pruritus) observed in the boceprevir arms was similar to that seen in the PEGINTRON and REBETOL control arm.

Treatment discontinuations due to adverse events in Part I of the study were between 9 and 19 percent for patients in the boceprevir arms, compared to 8 percent for the control arm. Treatment discontinuations for boceprevir patients due to viral breakthrough were fewer in the 28- and 48-week lead-in arms (4 and 5 percent, respectively) compared to the no lead-in arms (7 and 12 percent, respectively).

SCH 900518 (Next-Generation HCV Protease Inhibitor) Data at EASL

Researchers at EASL also presented early phase clinical data for SCH 900518, Schering-Plough's investigational next-generation HCV protease inhibitor.(5) This proof-of-concept study explored the safety and antiviral activity of two different dosing regimens for SCH 900518 administered as monotherapy and in combination therapy with PEGINTRON with or without ritonavir in treatment-naive and treatment-experienced patients with HCV genotype 1. In this study, low doses of ritonavir were used for metabolic inhibition to enhance the levels of SCH 900518 within the body and reduce the frequency of SCH 900518 dosing (BID vs. TID).

In the study, SCH 900518 administered as monotherapy exhibited potent antiviral activity, achieving 4.0-4.5 log10 decreases in viral load (HCV RNA) from baseline at day 8. SCH 900518 was well tolerated, with no drug related serious adverse events. Pharmacokinetic and pharmacodynamic modeling from this study was used to design the ongoing Phase IIa dose-finding study of SCH 900518 with ritonavir in combination with PEGINTRON and REBETOL. This study, known as NEXT-1, explores SCH 900518 in 200 mg, 400 mg or 600 mg once daily (QD) doses with low-dose ritonavir (100 mg) in combination with PEGINTRON and REBETOL (with and without a 4-week P/R lead-in period) in treatment-naive patients with HCV genotype 1.

About the HCV SPRINT-1 Study

In this Phase II study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir (800 mg TID) was evaluated in three treatment regimens: 4 weeks of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) therapy followed by the addition of boceprevir to the combination for 24 or 44 weeks (totaling 28 or 48 weeks of treatment), boceprevir in combination with PEGINTRON and REBETOL at the doses described above for 28 or 48 weeks, and, in Part II of the study, boceprevir in combination with PEGINTRON and low-dose REBETOL (400-1000 mg daily based on patient weight) for 48 weeks. In Part I of the study, the boceprevir regimens were compared to a control of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) alone for 48 weeks (an approved treatment regimen). In Part II of the study, boceprevir in combination with PEGINTRON and low-dose REBETOL for 48 weeks was compared to a contemporaneous control of PEGINTRON, full-dose REBETOL and boceprevir for 48 weeks. The primary endpoint of the study was SVR after 24 weeks of follow up. In the study, the 28-week and 48-week boceprevir no lead-in arms had SVR rates of 54 percent (n=58/107) and 67 percent (n=69/103), respectively.

The HCV SPRINT-1 study was conducted at sites across the United States, Canada and Europe. Overall, 77 percent of the 595 patients in the study were enrolled in the United States. African-Americans represented 16 percent of the patients enrolled and 7 percent of the patients in the study were cirrhotic.

Rationale for Lead-In Regimen

The use of the P/R lead-in prior to the addition of boceprevir was shown in the HCV SPRINT-1 study to reduce the incidence of viral breakthrough regardless of treatment duration. The rationale for the lead-in treatment regimen is based on the fact that both PEGINTRON and REBETOL reach steady-state concentrations by week 4, therefore patients have the protease inhibitor added at a time when the backbone drug levels have been optimized and viral load (HCV RNA) has been reduced. 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 agent, potentially reducing the likelihood for the development of resistance.

About Ongoing Boceprevir Phase III Registration Studies

Patient enrollment has been completed in two ongoing randomized, double-blind, placebo-controlled registration studies evaluating boceprevir in combination with PEGINTRON and REBETOL compared to standard of care with PEGINTRON and REBETOL alone. More than 1,500 patients were enrolled in these studies at U.S. and international sites.

The HCV SPRINT-2 study evaluates the efficacy of 28- and 48-week lead-in 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 treatment-naive adult patients with chronic HCV genotype 1. The study enrolled a total of 1,099 patients, including 158 African-American/Black patients.

The HCV RESPOND-2 study evaluates 36- and 48-week lead-in regimens of boceprevir in combination with PEGINTRON and REBETOL at the same doses as described above compared to a control of PEGINTRON and REBETOL alone for 48 weeks in adult patients with chronic HCV genotype 1 who failed prior treatment (relapsers and nonresponders) with peginterferon and ribavirin combination therapy. The study enrolled a total of 404 patients.

In both registration studies, RVR criteria at 4 weeks of boceprevir treatment (treatment week 8) is used to determine which boceprevir patients can stop all treatment at 28 weeks (HCV SPRINT-2) or 36 weeks (HCV RESPOND-2).

For more information about ongoing studies, please visit www.clinicaltrials.gov, search term boceprevir or SCH 900518.‹