 |
|
|
| |
Data Supporting Boceprevir Response Guided Therapy Presented at American
Association for the Study of Liver Diseases (AASLD) Annual Meeting - Schering Plough press release
|
| |
| |
Sun Nov 1, 2009 5:00pm EST
BOSTON, Nov. 1 -- Schering-Plough Corporation (NYSE:
SGP) today reported two data presentations supporting response guided therapy with boceprevir combination therapy in patients with chronic hepatitis C virus (HCV) genotype 1. These retrospective analyses were presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting in Boston, Oct. 30-Nov. 3.
Boceprevir is an investigational HCV protease inhibitor. Phase III registration studies with boceprevir in treatment-naïve HCV patients and patients who failed prior treatment have been fully enrolled and are expected to be completed in mid-2010.
Boceprevir response guided therapy utilizes a unique 4-week lead-in of PEGINTRON(R) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) prior to the addition of boceprevir (800 mg TID) for an additional 24-44 weeks.
Response guided therapy is intended to enable the physician to determine the duration of boceprevir combination therapy based on a patient's viral response during treatment. Although baseline characteristics cannot predict which
patients may benefit from longer therapy, on-treatment virologic responses appear likely to do so. The lead-in strategy allows for an assessment to define a patient's response to peginterferon and ribavirin alone in this
initial 4-week treatment period.
Boceprevir Response Guided Therapy in Null Responder Patients
The boceprevir Phase II HCV SPRINT-1 study in treatment-naïve patients with HCV genotype 1 had two treatment arms in which patients received a 4-week lead-in followed by the addition of boceprevir for an additional 24 or 44
weeks (n=206). In an oral presentation at AASLD,(1) researchers analyzed results from these two arms to determine SVR rates in patients who had a null
response to peginterferon and ribavirin therapy (defined as <1 log decrease in HCV viral load) after the 4-week lead-in period. Overall, 38 percent of null responders achieved SVR (19/50), with 25 percent (7/28) of patients who received 28 weeks of therapy and 55 percent (12/22) of patients who received 48 weeks of therapy achieving SVR. Patients with null response to peginterferon and ribavirin are considered to be among the most difficult to treat successfully and historically achieve a low rate of SVR.
"Although the numbers are small, this analysis of the HCV SPRINT-1 study data showed that it was possible to achieve SVR in a proportion of null responders to peginterferon and ribavirin when boceprevir was added to their backbone
regimen," 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. "However, the risk of developing viral resistance to protease inhibitors in patients who do not achieve SVR must be carefully weighed against the potential benefits of
treatment with this new class of direct antiviral agents. With the lead-in strategy, initial peginterferon and ribavirin responsiveness is determined prior to the addition of a protease inhibitor, thus allowing the physician to take into account the potential for the development of resistance."
The ongoing Phase III boceprevir registration studies employ the lead-in strategy for all patients and will provide greater insight into the relationship between peginterferon and ribavirin responsiveness and the
likelihood of achieving SVR in a diverse patient population. These Phase III studies, in treatment-naïve patients (HCV SPRINT-2) and patients who failed
prior treatment (HCV RESPOND-2), prospectively evaluate the use of rapid viral response (RVR) to determine which boceprevir patients can stop all treatment at 28 weeks or 36 weeks, respectively. Patients without RVR receive a 48-week boceprevir-based regimen. RVR in these studies is defined as undetectable virus (HCV RNA) in plasma at 4 weeks after the addition of boceprevir (treatment week 8).
Boceprevir Response Guided Therapy to Determine Treatment Duration
In a poster presentation at AASLD,(2) researchers reported that patients in the lead-in arms (4 weeks of PEGINTRON and REBETOL followed by the addition of boceprevir) of the Phase II HCV SPRINT-1 study who had RVR and were treated
for 28 weeks achieved an 82 percent SVR (54/66). Patients in the lead-in arms who did not have RVR, but had undetectable virus by treatment week 16, and were treated for 48 weeks achieved a 79 percent SVR (15/19). These results doubled the 38 percent SVR (39/104) achieved by patients in the control group receiving 48 weeks of peginterferon and ribavirin alone. Overall, 64 percent
of patients in the lead-in arms achieved RVR (132/206).
"These results are very exciting and provide important insights to help further define response guided therapy with boceprevir using a peginterferon and ribavirin lead-in strategy," Kwo said. "Building on the RVR rate seen in
this Phase II study, the boceprevir Phase III study in treatment-naïve patients is designed to confirm whether the majority of patients can be treated with a 28-week boceprevir-based regimen."
SVR was the primary efficacy endpoint of the HCV SPRINT-1 study. Based on an intent-to-treat analysis (ITT), the 28-week and 48-week lead-in boceprevir arms had SVR rates of 56 percent (58/103) and 75 percent (77/103), respectively, and the no lead-in boceprevir arms had SVR rates of 54 percent (58/107) and 67 percent (69/103), respectively, compared to 38 percent SVR for the control group.(3-5)
In the HCV SPRINT-1 study, 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. 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 with concomitant ribavirin dose reduction and was used for 26 percent of patients in the control arm and 39-51 percent of patients in the boceprevir arms with
standard-dose REBETOL.
Treatment discontinuations due to adverse events were between 9 and 19 percent for patients in the boceprevir arms, compared to 8 percent for the control arm. Treatment discontinuations in the boceprevir arms 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).
About the HCV SPRINT-1 Study
In the Phase II HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1) study, 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 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 peginterferon and ribavirin 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 the patient's immune system will have been activated and primed by PEGINTRON. With the lead-in strategy, initial peginterferon and ribavirin responsiveness is determined prior to the addition of a protease inhibitor, thus allowing the physician to take into account the potential for the development of resistance.
|
| |
|
|
|
|
|
