New Data Analyses with VICTRELIS (boceprevir), Merck's Investigational Medicine, Examined Possible Predictors of Sustained Virologic Response
Four-Week Lead-In Response and IL28B Status Helped Define Likelihood of Achieving SVR With VICTRELIS Added to Standard Therapy for Chronic Hepatitis C Genotype 1
BERLIN, March 31, 2011 - 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)1 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 today 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 today's 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.
PEGINTRON is indicated for use in combination with ribavirin for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease.
The following points should be considered when initiating therapy with PEGINTRON in combination with ribavirin: (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 ribavirin is preferred over PEGINTRON monotherapy unless there are contraindications to, or significant intolerance of, ribavirin. Combination therapy provides substantially better response rates than monotherapy.
Selected Safety Information on PEGINTRON
WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS
Alpha interferons, including PEGINTRON, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping PEGINTRON therapy.
Use with Ribavirin: Ribavirin may cause birth defects and death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.
PEGINTRON is contraindicated in patients with known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis to interferon alpha or any other component of the product, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic CHC patients before or during treatment. PEGINTRON/ribavirin combination therapy is additionally contraindicated in women who are pregnant or may become pregnant, men whose female partners are pregnant, patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia), and patients with creatinine clearance less than 50 mL per min.
Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for six months after completion of therapy. If this drug is used during pregnancy, or if a patient becomes pregnant, the patient should be apprised of the potential hazard to a fetus. A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment, and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.
Patients with the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy:
· Hemolytic anemia with ribavirin
· Neuropsychiatric events
· History of significant or unstable cardiac disease
· Hypothyroidism, hyperthyroidism, hyperglycemia, diabetes mellitus that cannot be effectively treated by medication
· New or worsening ophthalmologic disorders
· Ischemic and hemorrhagic cerebrovascular events
· Severe decreases in neutrophil or platelet counts
· History of autoimmune disorders
· Pancreatitis and ulcerative or hemorrhagic/ischemic colitis and pancreatitis
· Pulmonary infiltrates or pulmonary function impairment
· Child-Pugh score greater than 6 (Class B and C)
· Increased creatinine levels in patients with renal insufficiency
· Serious, acute hypersensitivity reactions and cutaneous eruptions
· Dental/periodontal disorders reported with combination therapy
· Hypertriglyceridemia may result in pancreatitis (e.g., triglycerides greater than 1000 mg/dL)
· Weight loss and growth inhibition reported with combination therapy in pediatric patients.
Life-threatening or fatal neuropsychiatric events, including suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior, sometimes directed towards others, have occurred in patients with and without a previous psychiatric disorder during PEGINTRON treatment and follow-up.
Serious adverse reactions have occurred in approximately 12 percent of subjects in clinical trials. The most common serious events occurring in subjects treated with PEGINTRON and ribavirin were depression and suicidal ideation, each occurring at a frequency of less than 1 percent. The most common fatal events occurring in subjects treated with PEGINTRON and ribavirin were cardiac arrest, suicidal ideation, and suicide attempt, all occurring in less than 1 percent of subjects.
The incidence of serious adverse reactions was comparable between PEGINTRON monotherapy (about 12 percent) and PEGINTRON/ribavirin combination therapy weight-based (12 percent) or flat-dose (17 percent). In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some patients experienced ongoing or new serious adverse reactions during the 6-month follow-up period. In a study with PEGINTRON/ribavirin (weight-based) combination therapy in adult patients, anemia with weight-based dosing occurred at an increased rate (29 percent vs. 19 percent); however, the majority of these cases were mild and responded to dose reductions. The incidence of serious adverse reactions reported for the weight-based ribavirin group was 12 percent. There were 31 deaths in clinical trials which occurred during treatment or during follow-up. Of the deaths, 19 were patients on either PEGINTRON or PEGINTRON/ribavirin combination therapy and three occurred during the follow-up period but had been on PEGINTRON/ribavirin combination therapy.
Additional serious adverse reactions seen in clinical trials at a frequency of equal to or less than 1 percent included psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis, urticaria, injection site necrosis, vasculitis, and phototoxicity.
Greater than 96 percent of all subjects in clinical trials experienced one or more adverse events. Most common adverse reactions (greater than 40 percent) in adult patients receiving either PEGINTRON or PEGINTRON/ribavirin are injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability.
The adverse reaction profile was similar between weight-based and flat-dose PEGINTRON/ribavirin therapies. Weight-based PEGINTRON/ribavirin dosing resulted in increased rates of anemia. Most common adverse reactions with PEGINTRON/ribavirin (weight-based) therapy were psychiatric, which occurred among 68-69 percent of patients and included depression, irritability, and insomnia, each reported by approximately 30-40 percent of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2 percent of all patients during treatment or during follow-up after treatment cessation. Other common reactions included injection site reactions, fatigue/ asthenia, headache, rigors, fever, nausea, myalgia, anxiety/emotional lability/irritability. The severity of some of these systemic symptoms tends to decrease as treatment continues.
Subjects receiving PEGINTRON/ribavirin as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to previous treatment-naïve patients receiving this regimen.
In general, the adverse reaction profile in the pediatric population was similar to that observed in adults. Most common adverse reactions (greater than 25 percent) in pediatric patients receiving PEGINTRON/ribavirin are pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, abdominal pain, and vomiting.
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VICTRELIS is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.
PEGINTRON® is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.
Please see attached Prescribing Information, Medication Guide, and Instructions for Use including Boxed Warning for PEGINTRON. The Prescribing Information, Medication Guide, and Instructions for Use are also available at http://www.spfiles.com/pipeg-intron.pdf,
1 SVR, the protocol specified primary efficacy endpoint of the studies, 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. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment was utilized.