Merck's VICTRELIS phase III study results against HCV presented at EASL annual meeting

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced results from several new data analyses from the pivotal Phase III studies evaluating the addition of its investigational oral protease inhibitor VICTRELIS™ (boceprevir) to peginterferon alfa-2b and ribavirin (PR) in adult patients with chronic hepatitis C virus (HCV) genotype 1 infection. The new data analyses identified potential predictors for the likelihood of achieving sustained virologic response (SVR) based on a patient's response during a four-week lead-in period with PR alone prior to the addition of VICTRELIS, as well as the genetic marker IL28B. The results were presented at The International Liver Congress™ / 46th European Association for the Study of the Liver (EASL) annual meeting.

"In the pivotal studies using a four-week lead-in strategy, the addition of VICTRELIS to current standard therapy achieved higher SVR rates compared to standard therapy alone in patients with chronic hepatitis C genotype 1," 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. "Based on new analyses of these studies, identification of a patient's IL28B status prior to treatment, used in conjunction with a patient's response after the four-week lead-in period, provided information on the likelihood of achieving SVR when VICTRELIS was added to standard therapy."

The presentation of these new analyses coincide with the publication of the primary data from the pivotal Phase III studies of VICTRELIS in the April 2011 edition of The New England Journal of Medicine. These results showed that the addition of VICTRELIS significantly improved SVR in adult patients who failed previous treatment (HCV-RESPOND-2 study) or who were new to treatment (HCV-SPRINT-2 study) for chronic HCV genotype 1 compared to PR alone, the primary endpoint of the studies.

In these studies, all patients receiving VICTRELIS were treated with a 4-week lead-in of PEGINTRON^® (peginterferon alfa-2b) (1.5 mcg/kg/week) and an investigational dose of ribavirin (600-1,400 mg/day) prior to the addition of VICTRELIS (800 mg three times daily).

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 VICTRELIS 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 VICTRELIS 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).

HCV-RNA decline after 4-week PR lead-in period helped predict likelihood of SVR

In pre-specified analyses [Poster #481], researchers evaluated the relationship between decline in levels of virus (HCV-RNA) after the 4-week PR lead-in period to overall SVR.

In the HCV SPRINT-2 treatment-naïve study, patients receiving VICTRELIS who had good response after the 4-week lead-in period, defined by a greater than or equal to 1.0-log₁₀ decline in HCV-RNA , achieved SVR rates of 81 percent (203/252) in the RGT arm and 79 percent (200/254) in the 48-week treatment arm compared to 51 percent (133/260) in the PR control arm. Patients with poor response after the 4-week lead-in, defined by a less than 1.0-log₁₀ decline in HCV-RNA, achieved SVR rates of 28 percent (27/97) in the RGT arm and 38 percent (36/95) in the 48-week treatment arm compared to 4 percent (3/83) in the PR control arm.

Similarly, in the HCV RESPOND-2 treatment-failure study, patients receiving VICTRELIS who had good response after the lead-in achieved SVR rates of 73 percent (80/110) in the RGT arm and 79 percent (90/114) in the 48-week treatment arm compared to 25 percent (17/67) in the PR control arm. Patients with poor response after the 4-week lead-in achieved SVR rates of 33 percent (15/46) in the RGT arm and 34 percent (15/44) in the 48-week treatment arm compared to 0 percent (0/12) in the PR control arm.

These analyses showed that 4-week lead-in response helped predict SVR in all three treatment groups, and the addition of VICTRELIS to the treatment regimen improved SVR rates regardless of whether patients had good or poor response during the lead-in period.

IL28B genotype helped predict likelihood of treatment response

In pre-specified analyses of the pivotal Phase III studies [Oral presentation Parallel Session: HCV Therapy], researchers found that IL28B status (CC, CT or TT) was a strong baseline predictor of viral response at treatment week 4, week 8 and SVR among patients receiving VICTRELIS. Among those carrying the CC gene allele, 89 percent of treatment-naïve patients and 82 percent of treatment-failure patients had an early response, defined by undetectable virus (HCV-RNA) at treatment week 8, and were eligible for a shorter duration of therapy. Among those with the less favorable gene allele (CT or TT), 52 percent of treatment-naïve patients and 48 percent of treatment-failure patients had an early response and were eligible for a shorter duration of therapy. The analyses also showed that response after the 4-week lead-in was a stronger predictor of SVR than any single baseline variable, including IL28B status.

The analyses included data from 63 percent of patients (912/1442) in the pivotal Phase III studies who received at least one dose of VICTRELIS or standard therapy and consented to genomic analysis to test for IL28B polymorphisms. In total, 28 percent of tested patients carried the CC allele, while 54 percent carried the CT allele and 18 percent carried TT.

Data on resistance-associated variants also presented

To better understand resistance-associated variants when VICTRELIS was added to standard therapy, researchers analyzed blood samples from 343 patients who did not achieve SVR in the HCV SPRINT-2 and HCV RESPOND-2 studies. Samples were obtained at various time points of virologic failure (breakthrough, incomplete virologic response, relapse and nonresponse), and resistance-associated variants were detected by population sequencing.

Results of this analysis [Oral presentation Parallel Session: HCV Therapy] showed that resistance-associated variants were highly associated with those patients not achieving SVR, and that the majority of patients with virologic breakthrough or incomplete virologic response had viruses with detectable resistance-associated variants.

When analyzed as a function of poor response after the 4-week lead-in (less than 1-log₁₀ viral load decrease) versus good response (greater than or equal to 1-log₁₀ viral load decrease), resistance-associated variants were more frequent in patients with a poor lead-in response (68 percent) compared with patients with a good lead-in response (31 percent). Additional analyses are ongoing, with a 3.5-year long-term follow-up study underway to evaluate the persistence of resistance-associated variants over time.

Tolerability profile in the pivotal studies of VICTRELIS

In the HCV SPRINT-2 study in treatment-naïve patients, the five most common treatment-related adverse events reported for patients receiving VICTRELIS in RGT, VICTRELIS in 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 VICTRELIS groups. Two suicides (one patient in the control group and one patient receiving VICTRELIS in RGT) were judged to have possibly been related to peginterferon. No other deaths were considered to be drug-related.

In HCV SPRINT-2, treatment discontinuations due to adverse events over the total course of all treatment were 12 percent and 16 percent for patients receiving VICTRELIS in RGT and VICTRELIS in 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 VICTRELIS 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 VICTRELIS compared to 24 percent for control.

In the HCV RESPOND-2 study in treatment-failure patients, the five most common treatment-related adverse events reported for patients receiving VICTRELIS in RGT, VICTRELIS 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 VICTRELIS in RGT, which occurred 18 weeks after the end of the study treatment and was considered to be unrelated to the study treatment.

In HCV RESPOND-2, treatment discontinuations due to adverse events over the total course of all treatment were 8 percent and 12 percent for patients receiving VICTRELIS in RGT and VICTRELIS in 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 receiving VICTRELIS, 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 VICTRELIS in RGT and VICTRELIS in a 48-week treatment regimen, respectively, compared to 21 percent for control.

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.