Merck's two pivotal boceprevir Phase III registration studies for chronic HCV meet primary endpoint

Merck reported that two pivotal Phase III registration studies for boceprevir, its investigational oral hepatitis C protease inhibitor, have been completed and met the primary endpoints: in both studies in patients with chronic hepatitis C virus (HCV) genotype 1 infection, the addition of boceprevir to treatment with PEGINTRON^® (peginterferon alfa-2b) and REBETOL^® (ribavirin, USP) (Peg/riba) significantly increased the number of patients who achieved sustained virologic response (SVR; defined as undetectable virus levels 24 weeks after the end of treatment), compared to control groups that received Peg/riba plus placebo.

“There is a clear need for new treatment strategies for chronic hepatitis C”

Boceprevir, in combination with Peg/riba, is being studied for the treatment of patients with chronic hepatitis C genotype I who have previously been treated (treatment-failure; HCV RESPOND-2) and in patients who are new to treatment (treatment-naïve; HCV SPRINT-2). Abstracts for boceprevir studies have already been submitted for presentation at a medical meeting later this year, and additional abstracts are being submitted this week. Merck plans to submit a New Drug Application (NDA) for boceprevir to the U.S. Food and Drug Administration on a rolling basis, and expects to complete regulatory submissions in the U. S. and E.U. in 2010.

"There is a clear need for new treatment strategies for chronic hepatitis C," said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. "We look forward to seeking regulatory approvals to bring boceprevir forward to help treat people living with chronic hepatitis C."

The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir: 48 weeks of treatment for all patients (4-week lead-in with 1.5 mcg/kg/week of PEGINTRON and an investigational dose of 600-1,400 mg/day of REBETOL, followed by the addition of boceprevir 800 mg three times a day for 44 weeks), and response-guided therapy, in which patients with undetectable virus at week 8 and again at certain points later in the studies were able to stop all treatment at 36 weeks in HCV RESPOND-2 and at 28 weeks in HCV SPRINT-2. Patients who did not meet these criteria continued treatment with Peg/riba alone for a total treatment duration of 48 weeks. Control groups in the studies received Peg/riba at the doses described above plus placebo for 48 weeks.

The HCV RESPOND-2 study was conducted in 403 patients who failed prior therapy at U.S. and international sites, and patients were randomized into the three groups (48 weeks control; 48 weeks control plus boceprevir; control plus boceprevir using response-guided therapy) at a 1:1:1 ratio. In the boceprevir 48-week treatment group, 66 percent of patients achieved SVR, and in the boceprevir response-guided therapy group, 59 percent of patients achieved SVR, compared to 21 percent of patients in the control group (p<0.0001 for both, intent-to-treat analysis).

"These results are very exciting," said Bruce R. Bacon, M.D., professor of internal medicine, Saint Louis University School of Medicine, and co-principal investigator of the HCV RESPOND-2 study. "Patients who failed prior hepatitis C therapy are among the hardest to treat, and the use of boceprevir in this study helped significantly more of these patients achieve undetectable levels of the virus at 24 weeks after the end of therapy than treatment with Peg/riba alone."

In the HCV SPRINT-2 study, 1,097 treatment-naïve patients at U.S. and international sites were enrolled in two separate cohorts, one with 938 non-African-American/Black patients and the other with 159 African-American/Black patients. Patients were randomized into the three treatment groups (48 weeks control; 48 weeks control plus boceprevir; control plus boceprevir using response-guided therapy) at a ratio of 1:2:2. In the study overall, 66 percent of patients in the boceprevir 48-week treatment group achieved SVR, and 63 percent of patients in the response-guided therapy group achieved SVR, compared to 38 percent of patients in the control group (p<0.0001 for both, intent-to-treat analysis).

As specified by the HCV SPRINT-2 study protocol, results for the non-African-American/Black and African-American/Black patient cohorts were analyzed separately. Several previous studies have shown that African-American/Black patients have a lower response to HCV treatment than non-African-American/Black patients. Among the non-African-American/Black patients in the boceprevir 48-week treatment group, 69 percent achieved SVR, and in the response-guided therapy group, 67 percent of patients achieved SVR, compared to 40 percent in the control group (p<0.0001 for both, intent-to-treat analysis). Among the African-American/Black patients, 53 percent of patients in the 48-week treatment group and 42 percent of patients in the response-guided therapy group achieved SVR, compared to 23 percent in the control group.

"The response-guided therapy approach used in these studies enabled those patients - both treatment-failure patients and treatment-naïve patients - who had undetectable virus at certain points of the study to achieve SVR with a shorter total treatment duration than current standard therapy," 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 HCV SPRINT-2 study.

In the HCV RESPOND-2 study, the five most common treatment-emergent adverse events reported for the boceprevir 48-week treatment group, boceprevir response-guided therapy group and control group, respectively, were: fatigue (57, 54, and 50 percent), headache (40, 43 and 49 percent), nausea (42, 44 and 38 percent), anemia (47, 43 and 20 percent) and dysgeusia (bad taste) (45, 43 and 11 percent). Treatment discontinuations due to anemia were 3 percent and 0 percent for the boceprevir groups, respectively, compared to 0 percent for the control group. Treatment discontinuations due to adverse events overall were 12 percent and 8 percent for the boceprevir groups, respectively, compared to 3 percent for the control group.

In the HCV SPRINT-2 study, the five most common treatment-emergent adverse events reported for the boceprevir 48-week treatment group, boceprevir response-guided therapy group and control group, respectively, were: fatigue (57, 53 and 60 percent), headache (46, 46 and 42 percent), nausea (43, 48 and 42 percent), anemia (49, 49 and 29 percent) and pyrexia (fever) (32, 33 and 33 percent). Treatment discontinuations due to anemia were 2 percent for each of the boceprevir groups compared to 1 percent for the control group. Treatment discontinuations due to adverse events overall were 16 percent and 12 percent for the boceprevir groups, respectively, compared to 16 percent for the control group.