Merck reported today that final results from two pivotal Phase III studies of boceprevir, its investigational oral hepatitis C protease inhibitor, demonstrated significantly higher sustained virologic response (SVR) rates in adult patients who previously failed treatment (treatment-failure; HCV RESPOND-2) and in adult patients who were new to treatment (treatment-naïve; HCV SPRINT-2) for chronic hepatitis C virus (HCV) genotype 1 compared to control, the primary objective of the studies. The results for the primary endpoints of these studies, which were first reported in a news release in August 2010, and a broad range of further data analyses from these studies are being presented in oral and poster presentations at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
"The most difficult aspect of managing hepatitis C is that treatment is an extremely long process that is often debilitating for many patients," said Dr. Stephen Shafran, MD, FRCPC, FACP, University of Alberta and an investigator in the SPRINT-2 trial. "These results are extremely exciting because boceprevir substantially increased success rates compared to standard therapy and many of the patients were able to be treated for 28 to 36 weeks."
An estimated 242,500 individuals are infected with HCV in Canada and in 2007, there were nearly 8,000 newly infected individuals. It is the leading cause of liver transplants in Canada.
The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir administered in combination with ribavirin plus peginterferon alfa-2b (Peg/riba) to assess whether the addition of boceprevir could improve SVR rates and potentially shorten overall treatment duration compared to the use of Peg/riba alone for 48 weeks, which is the current standard duration of therapy. 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 with 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 Peg/riba lead-in followed by the addition of boceprevir for 44 weeks.
- Control, in which patients received Peg/riba for 48 weeks.
In both studies, all patients were treated with a 4-week lead-in of peginterferon alfa-2b 1.5 mcg/kg/week and an investigational dose of 600-1,400 mg/day of ribavirin, followed by the addition of boceprevir (800 mg three times a day).
In primary results, addition of boceprevir significantly increased SVR rates compared to control
HCV RESPOND-2, which was conducted at U.S., Canadian and other international sites, included 403 adult patients who had failed prior therapy, including patients who relapsed or were non-responders to prior treatment with peginterferon and ribavirin. HCV SPRINT-2 was conducted in 1,097 treatment-naïve adult patients at U.S., Canadian and other international sites who were enrolled in two separate cohorts, one with 938 non-Black patients and the other with 159 Black patients.
As previously reported, the primary results of these two studies were as follows: In treatment-failure patients in HCV RESPOND-2, boceprevir increased 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 in HCV SPRINT-2, boceprevir increased 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). (All primary endpoints achieved statistical significance of p<0.0001 based on intent-to-treat analyses.)
Researchers present new analyses on boceprevir response-guided therapy
In secondary analyses presented for the first time at AASLD, researchers reported that nearly half of all patients in the boceprevir RGT arms met early response criteria and received a shorter total duration of therapy:
- In the RGT arm of the 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).
- In the RGT arm of the treatment-naïve study, 44 percent of patients (162/368) 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 rates were 97 percent (143/147) in non-Black treatment-naïve patients and 87 percent (13/15) in Black treatment-naïve patients.
For the corresponding patients in the boceprevir 48-week treatment arms of these studies, the SVR rates were 88 percent (74/84) in treatment-failure patients, 96 percent (137/142) in non-Black treatment-naïve patients and 95 percent (18/19) in Black treatment-naïve patients.
Patients in the boceprevir RGT arms of these studies who did not meet the early response criteria and were treated for up to 48 weeks also achieved substantially higher SVR rates compared to control. In these patients, the SVR rates were 40 percent (29/72) in treatment-failure patients, 74 percent (52/70) in non-Black treatment-naïve patients and 58 percent (7/12) in Black treatment-naïve patients.
"One of the hardest parts of treating patients with hepatitis C is seeing how physically and emotionally demanding the process is for them to go through," said Jo-Ann Ford, RN, MSN, Associate Director of Clinical Research, BC Hepatitis Program. "Boceprevir provides options to Health Care Professionals to adapt treatment based on individual patient response, avoiding unnecessary exposure to additional weeks of therapy."
Tolerability profile in treatment-failure patients
The five most common treatment-related adverse events in the HCV RESPOND-2 study reported for the boceprevir RGT arm, boceprevir 48-week treatment arm and control, respectively, were: fatigue (54, 57, and 50 percent), headache (41, 39 and 48 percent), nausea (44, 39 and 38 percent), chills (35, 30 and 30 percent) and influenza-like illness (23, 23 and 25 percent). Anemia was reported in 43, 46 and 20 percent of patients in the study arms, respectively. Serious adverse events were reported in 10, 14 and 5 percent of patients in the study arms, respectively.
Treatment discontinuations due to adverse events over the total course of all treatment were 8 percent and 12 percent for the boceprevir RGT and 48-week treatment arms, respectively, compared to 3 percent for control. Treatment discontinuations due to anemia were 0 percent and 3 percent for the boceprevir arms, 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 in the boceprevir RGT and 48-week treatment arms, 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 the boceprevir RGT arm, boceprevir 48-week treatment arm and control, respectively, were: fatigue (52, 57 and 59 percent), headache (45, 43 and 42 percent), nausea (46, 42 and 40 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.
Treatment discontinuations due to adverse events over the total course of all treatment were 12 percent and 16 percent for the boceprevir RGT and 48-week treatment arms, respectively, compared to 16 percent for control. Treatment discontinuations due to anemia were 2 percent for each of the boceprevir treatment arms 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 boceprevir treatment arms 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 arm 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 unnecessary treatment.
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