NEJM publishes MSD's VICTRELIS two pivotal Phase III studies against HCV

MSD (NYSE: MRK), known as Merck in the United States and Canada, announced today that final results from the two pivotal Phase III studies of VICTRELIS^™ (boceprevir), its investigational oral hepatitis C protease inhibitor, will be published in the March 31^st edition of The New England Journal of Medicine (NEJM). In the studies, the addition of boceprevir to peginterferon alfa-2b and ribavirin (PR) significantly improved sustained virologic response (SVR) - the goal of treatment - for adult patients who failed previous treatment (treatment-failure) and those who were new to treatment (treatment-naïve) for chronic hepatitis C virus (HCV) genotype 1, compared to standard therapy (PR) alone. In these studies, nearly half of all patients receiving response-guided therapy with boceprevir were eligible for a shorter course of treatment that was 12 to 20 weeks less than the standard 48 weeks of therapy.

These data formed the basis of Merck's New Drug Application (NDA) for boceprevir, which has been granted priority review status by the U.S. Food and Drug Administration (FDA). The FDA advisory committee meeting to review the application is scheduled to occur on April 27, 2011. In the European Union, Merck's Marketing Authorization Application for boceprevir has been accepted for accelerated assessment.

"We initially presented the results of these two landmark studies at The Liver Meeting^® late last year, and their publication in this prestigious journal further underscores the importance of these data to the medical community," said Bruce Bacon, M.D., professor of internal medicine, Saint Louis University School of Medicine, and lead author for the HCV RESPOND-2 study in patients who failed previous treatment.

"Evaluating response-guided therapy with boceprevir was an important component of these pivotal studies. Using this approach enabled many patients in the studies - both those who failed previous treatment and those who were new to treatment - to achieve success with a shorter duration of therapy compared to current therapy," said Fred Poordad, M.D., chief of hepatology and liver transplantation, Cedars-Sinai Medical Center, Los Angeles, and lead author for the HCV SPRINT-2 study in treatment-naïve patients. "Using response-guided therapy in these studies provided physicians flexibility in the management of their patients' HCV therapy, which enabled them to adapt treatment duration based on individual patient response."

The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir added to PEGINTRON^® (peginterferon alfa-2b) and ribavirin (PR) to assess the ability of boceprevir to improve SVR rates and potentially shorten overall treatment duration compared to the use of PR alone for 48 weeks, which is the current standard duration of therapy. In both studies, all patients receiving boceprevir were treated with a 4-week lead-in of PEGINTRON (1.5 mcg/kg/week) and an investigational dose of ribavirin (600-1,400 mg/day), followed by the addition of boceprevir (800 mg three times a day). In each study, patients were randomized to three groups:

• Response-guided therapy (RGT), in which total treatment duration was based on certain early response criteria. Treatment-failure patients with undetectable virus (HCV-RNA) at week 8 were eligible to stop all treatment at 36 weeks. Treatment-naïve patients who had undetectable virus (HCV-RNA) during weeks 8 through 24 were eligible to stop all treatment at 28 weeks.
• 48 weeks of treatment, in which patients received a 4-week lead-in with PR followed by the addition of boceprevir for 44 weeks.
• Control, in which patients received PR for 48 weeks.

Primary results: Adding Boceprevir significantly increased SVR compared to control

The HCV RESPOND-2 study was conducted at U.S. and international sites, and included 403 adult patients who had failed prior therapy, including patients who relapsed or were non-responders to prior treatment with peginterferon and ribavirin. The HCV SPRINT-2 study was conducted at U.S. and international sites in 1,097 adult patients who were new to treatment.ⁱ Primary results from these two studies, which each achieved statistical significance of p<0.0001 based on intent-to-treat analyses, were:

In treatment-failure patients: the addition of boceprevir to PR resulted in approximately a three-fold increase in SVR rates to 59 percent for the RGT arm (95/162) and 66 percent for the 48-week treatment arm (107/161) compared to 21 percent for control (17/80).

In treatment-naïve patients: the addition of boceprevir to PR resulted in an increase in SVR rates to 63 percent for the RGT arm (233/368) and 66 percent for the 48-week treatment arm (242/366), compared to 38 percent for control (137/363).

Boceprevir in response-guided therapy: nearly half of all patients were eligible to receive a shorter duration of therapy than current standard treatment duration

Study authors reported that nearly half of all patients receiving boceprevir in the response-guided therapy arms of these studies met early response criteria, and received a shorter total duration of therapy. Key secondary analyses for the two studies were reported in NEJM as follows:

• Boceprevir in RGT:
  • Treatment-failure study: 46 percent (74/162) of patients met the early response criteria and were eligible to stop all treatment at 36 weeks, which is 12 weeks shorter than current standard therapy. In these patients, the SVR rate was 86 percent (64/74).
  • Treatment-naïve study: 44 percent of patients met the early response criteria and were eligible to stop all treatment at 28 weeks  which is 20 weeks shorter than current standard therapy. In these patients, the SVR rate was 96 percent (156/162).
• Corresponding results for patients receiving boceprevir who met early response criteria in the 48-week treatment arms:
  • Treatment-failure study: the SVR rate was 88 percent (74/84).
  • Treatment-naïve study: the SVR rate was 96 percent (155/161).

Tolerability profile in treatment-failure patients

The five most common treatment-related adverse events in the HCV RESPOND-2 study reported for patients receiving boceprevir in RGT and in a 48-week treatment regimen and control, respectively, were: fatigue (54, 57, and 50 percent), headache (41, 39 and 48 percent), nausea (44, 39 and 38 percent), anemia (43, 46 and 20) and chills (35, 30 and 30 percent). Serious adverse events were reported in 10, 14 and 5 percent of patients in the study arms, respectively. There was one death in the study, a suicide in the group receiving RGT, which occurred 18 weeks after the end of the study treatment and was considered to be unrelated to the study treatment.

Treatment discontinuations due to adverse events over the total course of all treatment were 8 percent and 12 percent for patients receiving RGT and a 48-week treatment regimen, respectively, compared to 2 percent for control. Treatment discontinuations due to anemia were 0 percent and 3 percent for the treatment groups, respectively, compared to 0 percent for control. Erythropoietin (EPO) for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 41 and 46 percent of patients receiving RGT and a 48-week treatment regimen, respectively, compared to 21 percent for control.

Tolerability profile in treatment-naïve patients

The five most common treatment-related adverse events in the HCV SPRINT-2 study reported for patients receiving RGT, a 48-week treatment regimen and control, respectively, were: fatigue (53, 57 and 60 percent), headache (46, 46 and 42 percent), nausea (48, 43 and 42 percent), anemia (49, 49 and 29 percent) and dysgeusia (bad taste) (37, 43 and 18 percent). Serious adverse events were reported in 11, 12 and 9 percent of patients in the study arms, respectively. There were six deaths during the study: four patients in the control group died, as did two patients in the boceprevir groups. Two suicides (one patient in the control group and one patient receiving RGT) were judged to have possibly been related to peginterferon. No other deaths were considered to be drug-related.

Treatment discontinuations due to adverse events over the total course of all treatment were 12 percent and 16 percent for patients receiving RGT and a 48-week treatment regimen, respectively, compared to 16 percent for control. Treatment discontinuations due to anemia were 2 percent for each of the treatment groups receiving boceprevir compared to 1 percent for control. EPO for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 43 percent of patients in each of the treatment groups receiving boceprevir compared to 24 percent for control.

The HCV RESPOND-2 and HCV SPRINT-2 studies each employed futility or "stopping" rules, whereby patients in any treatment group who had detectable virus at week 12 in the HCV RESPOND-2 study or at week 24 in the HCV SPRINT-2 study were considered treatment failures and discontinued all treatment. These stopping rules allowed for patients in the studies who did not respond to treatment to have their therapy stopped early, thereby avoiding ineffective treatment.

Merck's global commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. 2011 marks the 10-year anniversary of the introduction of PEGINTRON and ribavirin in combination therapy, a current standard therapy for chronic HCV worldwide. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis care.