August 04, 2010 08:09 AM Eastern Daylight Time
Merck Expects to Submit NDA by Year-End
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck today 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.
“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”
.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.1-3 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 (p=0.004 and p=0.044, respectively, intent-to-treat analysis).
“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.
About the studies
The HCV RESPOND-2 study was conducted in patients chronically infected with hepatitis C genotype 1 who failed prior therapy with peginterferon and ribavirin, including those who had experienced prior relapse or who were prior non-responders, and the HCV SPRINT-2 study was conducted in previously untreated (treatment-naïve) patients chronically infected with hepatitis C genotype 1. Approximately 25 percent of patients in each of the studies had less than a 1 log decrease in viral load after the 4-week Peg/riba lead-in period.
Sustained virologic response (SVR), the protocol-specified primary efficacy endpoint, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication (Roche TaqMan LLD=9.3 IU/mL). Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient’s 12-week post-treatment assessment was utilized.
In the HCV RESPOND-2 study, patients in the response-guided therapy arm who had undetectable virus at treatment week 8 and week 12 received a total of 36 weeks of therapy (lead-in with Peg/riba followed by the addition of boceprevir for 32 weeks); patients with detectable virus at week 8, but undetectable virus at week 12, stopped boceprevir treatment at week 36 and continued on Peg/riba alone for an additional 12 weeks, for a total treatment duration of 48 weeks. Patients in any arm of the study who had detectable virus at week 12 were considered treatment failures and discontinued treatment.
In the HCV SPRINT-2 study, patients in the response-guided therapy group of the study who had undetectable virus at treatment week 8 through week 24 received a total of 28 weeks of therapy (lead-in with Peg/riba followed by the addition of boceprevir for 24 weeks); patients with detectable virus at week 8, but undetectable virus at week 24, stopped boceprevir treatment at week 28 and continued on Peg/riba alone for a total treatment duration of 48 weeks. Patients in any arm of the study who had detectable virus at week 24 were considered treatment failures and discontinued treatment.
Merck's commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the hepatitis field by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to hepatitis care.
Conference call
Investors are invited to a live webcast of Merck's conference call today at 9:00 a.m. EDT by visiting Merck's Web site, www.merck.com/investors/events-and-presentations/home.html. Institutional investors and analysts can participate in the call by dialing (877) 381-5782 or (706) 758-9927. Journalists are invited to listen in on the call by dialing (800) 399-7917 or (706) 758-9928. A replay of the webcast will be available starting at 11 a.m. EDT today through 5 p.m. EDT on Aug. 11. To listen to the replay, dial (800) 642-1687 or (706) 645-9291. The conference ID No. is 92380347.
About PEGINTRON
PEGINTRON is indicated for use in combination with REBETOL (ribavirin) for the treatment of chronic hepatitis C in patients three years of age and older with compensated liver disease.
The following points should be considered when initiating therapy with PEGINTRON in combination with REBETOL: (1) These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose. (2) Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. (3) No safety and efficacy data are available for treatment of longer than one year.
PEGINTRON is also indicated for use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha and who are at least 18 years of age.
The following points should be considered when initiating therapy with PEGINTRON alone: Combination therapy with REBETOL is preferred over PEGINTRON monotherapy unless there are contraindications to, or significant intolerance of, REBETOL. Combination therapy provides substantially better response rates than monotherapy.
Selected Safety Information on PEGINTRON......Continue Reading
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