Merck Announces Pivotal Phase III Data for Boceprevir will be Presented at the American Association for the Study of Liver Diseases 2010 Annual Meeting
WHITEHOUSE STATION, N.J., Oct. 1, 2010 - Merck today announced that final results from two pivotal Phase III studies of boceprevir, its investigational oral hepatitis C protease inhibitor, will be presented in oral plenary sessions at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), which is taking place from Oct. 29 through Nov. 2 in Boston. Results for boceprevir in response-guided therapy strategies, which evaluated treatment durations shorter than current standard therapy, will be presented during the meeting. In total, more than 20 oral and poster presentations of clinical studies highlighting Merck medicines and investigational therapies for chronic hepatitis C virus (HCV) infection will be presented.
Boceprevir, in combination with PEGINTRON® (peginterferon alfa-2b) and REBETOL® (ribavirin, USP) (Peg/riba), is being studied for the treatment of patients with HCV genotype 1 infection who were previously treated (treatment-failure; HCV RESPOND-2) and in patients who are new to treatment (treatment-na´ve; HCV SPRINT-2).
As previously reported, Merck plans to submit a New Drug Application (NDA) for boceprevir to the U.S. Food and Drug Administration (FDA) on a rolling basis, and expects to complete regulatory submissions in the U.S. and E.U. in 2010.
The AASLD presentations of the boceprevir Phase III data will include sustained virologic response (SVR)╣ rates by patient sub-groups, including treatment-na´ve patients (African-American/Black and non-African-American/Black), patients who experienced prior relapse, prior non-responders, and patients with a poor response to interferon, defined as having achieved less than a 1 log decrease in viral load (HCV-RNA) after a 4-week Peg/riba lead-in period.
The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir to assess the ability to improve SVR and potentially shorten overall treatment duration compared to Peg/riba alone:
* Response-guided therapy, in which treatment-failure patients with undetectable virus at week 8 were able to stop all treatment at 36 weeks, and in which treatment-na´ve patients with undetectable virus during weeks 8 through 24 were able to stop all treatment at 28 weeks; and
* 48 weeks of treatment (4-week Peg/riba lead-in followed by the addition of boceprevir for 44 weeks).
In both studies, all patients were treated with a 4-week lead-in of PEGINTRON
(1.5 mcg/kg/week) and an investigational dose of REBETOL (600-1,400 mg/day), followed by the addition of boceprevir (800 mg three times a day).
The abstracts were published today and can be accessed on the AASLD website. For program information, please visit www.aasld.org.
Boceprevir Oral Presentations
HCV SPRINT-2 Final Results (Late-Breaking Oral Session)
Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Na´ve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results; F. Poordad
et al. Abstract LB-4. Monday, Nov. 1, 5:30 - 5:45 PM, Location: Hynes Auditorium
HCV RESPOND-2 Final Results (Viral Hepatitis Plenary Session)
HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/Ribavirin; B. R. Bacon et al.
Abstract 216. Tuesday, Nov. 2, 9:15 - 9:30 AM, Location: Hynes Auditorium
Boceprevir Poster Presentations
HCV SPRINT-2 (Late-Breaking Poster Session)
Response-Guided Therapy (RGT) with Boceprevir (BOC) + Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Na´ve Patients with Hepatitis C Virus (HCV) Genotype (G) 1 Was Similar to a
48-Wk Fixed-Duration Regimen with BOC + P/R in SPRINT-2; J. Bronowicki et al. Abstract
LB-15. Monday, Nov. 1, 8:00 AM - 5:00 PM, Location: Hynes Exhibit Hall C
HCV SPRINT-1 Phase II Data
Hemoglobin Decline During Lead-In Phase as an Early Predictor of Anemia After the Addition of Boceprevir: A Retrospective Analysis of HCV SPRINT-1; F. Poordad et al. Abstract 933. Sunday, Oct. 31, 8:00 AM - 5:30 PM, Location: Hynes Exhibit Hall C
Frequencies of Resistance-Associated Amino Acid Variants Following Combination Treatment with Boceprevir Plus PEGINTRON (PegInterferon Alfa-2b)/Ribavirin in Patients With Chronic Hepatitis C (CHC), Genotype 1 (G1); J. M. Vierling et al. Abstract 801. Sunday, Oct. 31,
8:00 AM - 5:30 PM, Location: Hynes Exhibit Hall C
Other Key Merck Data
High Correlation Between Week 4 and Week 12 as the Definition for Null Response to Peginterferon alfa (PEG) plus Ribavirin (R) Therapy: Results from the IDEAL Trial; F. Poordad et al. Abstract 797. Sunday, Oct. 31, 8:00 AM - 5:30 PM, Location: Hynes Exhibit Hall C
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. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to viral hepatitis care.
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
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 REBETOL 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/REBETOL 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.
REBETOL 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 REBETOL 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 REBETOL 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/REBETOL 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/REBETOL (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 REBETOL 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/REBETOL combination therapy and three occurred during the follow-up period but had been on PEGINTRON/REBETOL 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/REBETOL 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/REBETOL therapies. Weight-based PEGINTRON/REBETOL dosing resulted in increased rates of anemia. Most common adverse reactions with PEGINTRON/REBETOL (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/REBETOL as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to previous treatment-na´ve 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/REBETOL are pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, abdominal pain, and vomiting.
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Please see attached Prescribing Information and Medication Guide including Boxed Warning for PEGINTRON and REBETOL. The full Prescribing Information and Medication Guide is also available at http://www.spfiles.com/pipeg-intron.pdf.
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. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment was utilized.