The New England Journal of Medicine (NEJM) Publishes Pivotal Studies Showing Merck's Investigational Medicine VICTRELIS (boceprevir) in Combination Therapy Significantly Increased SVR In Patients with Chronic HCV Genotype 1 Who Failed Previous Treatment or Who Were New to Treatment Compared to Control
Publications in NEJM:
Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection - (03/31/11)
Boceprevir for Untreated Chronic HCV Genotype 1 Infection - (03/31/11)
WHITEHOUSE STATION, N.J., March 30, 2011 - Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that final results from the two pivotal Phase III studies of VICTRELIS (boceprevir), its investigational oral hepatitis C protease inhibitor, will be published in the March 31st edition of The New England Journal of Medicine (NEJM). In the studies, the addition of VICTRELIS to peginterferon alfa-2b and ribavirin (PR) significantly improved sustained virologic response (SVR)1 - the goal of treatment - for adult patients who failed previous treatment (treatment-failure) and those who were new to treatment (treatment-naïve) for chronic hepatitis C virus (HCV) genotype 1, compared to standard therapy (PR) alone. In these studies, nearly half of all patients receiving response-guided therapy with VICTRELIS were eligible for a shorter course of treatment that was 12 to 20 weeks less than the standard 48 weeks of therapy.
These data formed the basis of Merck's New Drug Application (NDA) for VICTRELIS, which has been granted priority review status by the U.S. Food and Drug Administration (FDA). The FDA advisory committee meeting to review the application is scheduled to occur on April 27, 2011. In the European Union, Merck's Marketing Authorization Application for VICTRELIS has been accepted for accelerated assessment.
"We initially presented the results of these two landmark studies for VICTRELIS at The Liver Meeting late last year, and their publication in this prestigious journal further underscores the importance of these data to the medical community," said Bruce Bacon, M.D., professor of internal medicine, Saint Louis University School of Medicine, and lead author for the HCV RESPOND-2 study in patients who failed previous treatment.
"Evaluating response-guided therapy with VICTRELIS was an important component of these pivotal studies. Using this approach enabled many patients in the studies - both those who failed previous treatment and those who were new to treatment - to achieve success with a shorter duration of therapy compared to current therapy," 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. "Using response-guided therapy in these studies provided physicians flexibility in the management of their patients' HCV therapy, which enabled them to adapt treatment duration based on individual patient response."
The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with VICTRELIS added to PEGINTRON (peginterferon alfa-2b) and ribavirin (PR) to assess the ability of VICTRELIS to improve SVR rates and potentially shorten overall treatment duration compared to the use of PR alone for 48 weeks, which is the current standard duration of therapy. In both studies, all patients receiving VICTRELIS were treated with a 4-week lead-in of PEGINTRON (1.5 mcg/kg/week) and an investigational dose of ribavirin (600-1,400 mg/day), followed by the addition of VICTRELIS (800 mg three times a day). 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 who had 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 lead-in with PR followed by the addition of VICTRELIS for 44 weeks.
· Control, in which patients received PR for 48 weeks.
Primary results: Adding VICTRELIS significantly increased SVR compared to control
The HCV RESPOND-2 study was conducted at U.S. and international sites, and included 403 adult patients who had failed prior therapy, including patients who relapsed or were non-responders to prior treatment with peginterferon and ribavirin. The HCV SPRINT-2 study was conducted at U.S. and international sites in 1,097 adult patients who were new to treatment. 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).
VICTRELIS in response-guided therapy: nearly half of all patients were eligible to receive a shorter duration of therapy than current standard treatment duration
Study authors reported that nearly half of all patients receiving VICTRELIS in the response-guided therapy arms of these studies met early response criteria, and received a shorter total duration of therapy. Key secondary analyses for the two studies were reported in NEJM as follows:
· VICTRELIS in RGT:
· 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).
· 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 rate was 96 percent (156/162).
· Corresponding results for patients receiving VICTRELIS who met early response criteria in the 48-week treatment arms:
· Treatment-failure study: the SVR rate was 88 percent (74/84).
· Treatment-naïve study: the SVR rate was 96 percent (155/161).
Tolerability profile in treatment-failure patients
The five most common treatment-related adverse events in the HCV RESPOND-2 study 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.
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.
Tolerability profile in treatment-naïve patients
The five most common treatment-related adverse events in the HCV SPRINT-2 study 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.
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.
The HCV RESPOND-2 and HCV SPRINT-2 studies each employed futility or "stopping" rules, whereby patients in any treatment group 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.
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.
Please see full prescribing information at http://www.spfiles.com/pipeg-intron.pdf.
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Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2010 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).
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.