Final results from three large PEGINTRON(TM) clinical studies address key questions in the treatment of hepatitis C
COPENHAGEN, Denmark, April 27 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE: SGP) today reported that final results of three large PEGINTRON(TM) (peginterferon alfa-2b) clinical studies address longstanding questions in the hepatitis C research community and provide important insights. The results of the studies, involving a total of more than 2,700 patients, were presented at the 44th European Association for the Study of the Liver (EASL) 2009 Annual Meeting.
"Physicians are constantly looking for ways to improve hepatitis C treatment outcomes by increasing response rates or reducing side effects and making treatment more tolerable for their patients," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "We undertook these large PEGINTRON studies to help investigators address these important clinical issues. Conducting these studies demonstrates Schering-Plough's longstanding commitment to investigating potential new treatment strategies for patients with hepatitis C."
Combination therapy with peginterferon and ribavirin is a recognized standard of care worldwide for treating chronic hepatitis C virus (HCV) infection. Patients with HCV genotype 1, the most common and hardest to treat form of hepatitis C, are typically treated for 48 weeks, while patients with HCV genotypes 2 or 3 are treated for 24 weeks.
The aim of the three PEGINTRON studies was to evaluate investigational regimens in these patient populations compared to current standard practice.
PEGINTRON Maintenance Therapy in Cirrhotic (Metavir F4) HCV Patients Who Failed to Respond to Interferonimal health and consumer health care products. Schering-Plough's vision is to "Earn Trust, Every Day" with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is www.schering-plough.com.
SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the potential market for PEGINTRON and REBETOL. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including uncertainties in the regulatory process, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Item 1A "Risk Factors" in Schering-Plough's 2008 10-K, filed Feb. 27, 2009.
1. Bruix J, Poynard T, et al. PEGINTRON Maintenance Therapy in Cirrhotic (Metavir F4) HCV Patients Who Failed to Respond to Interferon/Ribavirin (IR) Therapy: Final Results of the EPIC3 Cirrhosis Maintenance Trial. Oral presentation at: 44th European Association for the Study of the Liver (EASL); April 22-26, Copenhagen, Denmark.
2. Buti M, Esteban R, et al. Extended Treatment Duration in Chronic Hepatitis C Genotype 1-Infected Slow-Responders: Final Results of the SUCCESS Study. Oral presentation at: 44th annual meeting of the European Association for the Study of the Liver (EASL); April 22-26, Copenhagen, Denmark.
3. SVR is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment.
4. Manns M, Zeuzem S, et al. Reduced Dose and Duration of Peginterferon Alfa-2b + Weight-Based Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial). Oral presentation at: 44th European Association for the Study of the Liver (EASL); April 22-26, Copenhagen, Denmark./Ribavirin (IR) Therapy: Final Results of the EPIC3 Cirrhosis Maintenance Trial(1)
The large EPIC3 clinical study program includes a prospective trial designed to assess the efficacy and tolerability of long-term, low-dose maintenance therapy with PEGINTRON 0.5 mcg/kg/week in patients who previously failed treatment with any alfa-interferon plus ribavirin combination therapy. A total of 631 patients were randomized to PEGINTRON or observational control. Of these, 454 patients were from the retreatment study portion of the EPIC3 program and 172 were direct enrollers into the maintenance study. The primary efficacy measure for the study was time to development of first clinical event, defined as liver decompensation (variceal bleeding, Child-Pugh class C, grade 2 or higher hepatic encephalopathy, ascites requiring therapeutic paracentesis and/or additional therapy), development of hepatocellular carcinoma (HCC), liver transplantation or death. All events other than transplantation and death were adjudicated by an independent committee of experts blinded to the study arm. The secondary efficacy analyses included time to disease progression, including additional events of Child-Pugh class B, emergence of varices and enlargement of pre-existing varices requiring additional therapy.
In the primary efficacy analysis, 36 patients in the control arm and 27 in the treatment arm had clinical events (P=0.14), a non-statistically significant difference. However, in the secondary efficacy analysis there were 87 clinical events in the control arm and 63 in the treatment arm (P=0.01), a statistically significant difference. The main events causing the difference on secondary analysis were emergence or enlargement of varices (43 control vs. 16 treatment). In patients with pre-existing esophageal varices (n=82) there were significantly more events (n=14) in the observation arm compared to the treatment arm (n=4) (P=0.01). Overall the safety profile for PEGINTRON was similar to that in previous studies; however, there were more serious infections in the treatment group (25 vs. 3), although these were not linked to neutropenia. None were unexpected events, nor was there a pattern to them.
In the primary analysis, PEGINTRON maintenance therapy was not superior to observational control in preventing the occurrence of clinical events. However, there was a statistically significant reduction in clinical events of hepatic decompensation on protocol-defined secondary analysis as well as in subjects with pre-existing esophageal varices.
Extended Treatment Duration in Chronic Hepatitis C Genotype 1-Infected Slow Responders: Final Results of the SUCCESS Study(2)
The primary objective of the SUCCESS study was to evaluate the effect of extending treatment duration to 72 weeks with PEGINTRON and REBETOL(R) (ribavirin, USP) combination therapy in genotype 1-infected patients who have slow response to therapy, defined as having detectable virus (HCV RNA) with at least a 2 log10 reduction in viral load at treatment week 12 and undetectable virus at treatment week 24. In this large, prospective, randomized, multinational clinical trial, slow responders were randomized at treatment week 36 to receive PEGINTRON combination therapy for a total of 48 weeks (n=86) (standard approved duration) or 72 weeks (n=73). Patients with undetectable virus at week 12 (complete early virologic response), received treatment for 48 weeks (n=816), whereas patients who did not respond to treatment (less than a 2 log10 reduction in viral load at week 12) were discontinued from the study. In total, 1,419 patients were treated.
In this study, sustained virologic response (SVR)(3) with 72-week treatment was not statistically superior to the 48-week treatment in slow responders (47.9 percent (35/73) vs. 43.0 percent (37/86), respectively), the primary endpoint of the study. Relapse rates between these two arms also were not significantly different (32.7 percent (16/49) vs. 47.1 percent (32/68), respectively) and adverse events were similar among treatment groups (secondary endpoints). Early discontinuation rates were higher in the 72-week arm compared to the 48-week arm (23.3 percent (17/73) vs. 9.3 percent (8/86), respectively).
Reduced Dose and Duration of Peginterferon Alfa-2b + Weight-Based Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial)(4)
Shorter duration treatment of patients chronically infected with HCV genotype 2 or 3 (G2/3) with peginterferon and ribavirin has been largely unsuccessful compared with standard-duration treatment (24 weeks). The implications of a reduced peginterferon dose in G2/3 patients were unknown. The primary objective of the REDD 2/3 study was to evaluate the effect of reduced treatment duration or a reduced PEGINTRON dose on SVR and relapse rates among treatment-naive G2/3 patients in an international, multicenter, non-inferiority study. The study began as a real-world, investigator-initiated study conducted in Germany and then the patient population was expanded to include centers in Europe and Asia-Pacific. In total, 682 patients were treated. Of these, 80.2 percent were G3 and 53.1 percent had high baseline viral load (greater than or equal to 600,000 IU/mL), both negative factors for achieving SVR.
Eligible patients were randomized to one of three arms: (A) PEGINTRON (1.5 mcg/kg/wk) for 24 weeks (approved dose), (B) PEGINTRON (1.0 mcg/kg/wk) for 24 weeks (low dose) or (C) PEGINTRON (1.5 mcg/kg/wk) for 16 weeks (short duration), each in combination with weight-based REBETOL (800-1200 mg/day). Co-primary end points were non-inferiority between arms A and B and A and C. SVR rates overall were (A) 66.5 percent (153/230), (B) 64.3 percent (144/224) and (C) 56.6 percent (129/228). Neither co-primary endpoint was met. Relapse rates were lower with 24 weeks compared to 16 weeks of therapy (17.8 percent (29/163) and 16.3 percent (27/166) vs. 29.3 percent (49/167), respectively). Adverse events were similar, regardless of treatment duration or PEGINTRON dose.
About Hepatitis C
Hepatitis C is a serious and potentially life-threatening disease. It is the most common blood-borne infection in America and Europe, and the most common form of liver disease, affecting nearly 5 million people in the United States, 5 million in Europe and some 200 million people worldwide. It is the leading cause of cirrhosis and liver cancer, and the number one reason for liver transplants in the United States and Europe.
PEGINTRON is indicated for use in combination with REBETOL (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 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 retreatment 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.
Important Safety Information Regarding U.S. Labeling for PEGINTRON and REBETOL
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 (see Boxed Warning and Pregnancy section), 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. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients during therapy and 6 months post-treatment. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for 6 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 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.
Incidence of Adverse Events
Most common adverse reactions (more than 40%) 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. Most common adverse reactions (more than 25%) in pediatric patients receiving PEGINTRON/REBETOL are pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema and vomiting.
In a study with PEGINTRON/REBETOL (weight-based) combination therapy in adult patients, anemia with weight-based dosing was 29%; 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%. 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. Discontinuations for adverse events were 15% and were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. Dose modifications due to adverse reactions occurred in 29% of patients.
Most common adverse reactions with PEGINTRON/REBETOL (weight-based) combination therapy were psychiatric which occurred among 68-69% of patients. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30-40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts and suicides) occurred in 2% of all patients during treatment or during follow-up after treatment cessation. PEGINTRON induced fatigue or headache in approximately two-thirds of patients, with fever or rigors in approximately half of the patients. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues. There was a 23-24% incidence overall for injection site reactions or inflammation.
Individual serious adverse reactions occurred at a frequency less than or equal to 1% and included suicide attempt, suicidal ideation, severe depression; psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, myocardial infarction, 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.
Additional serious adverse events included hallucinations. bipolar disorder, mania, encephalopathy (usually elderly treated with higher doses of PEGINTRON), hypotension, tachycardia, retinopathy including macular edema, retinal hemorrhage, cotton wool spots, papilledema, ischemic and hemorrhagic cerebrovascular events, bone marrow toxicity (cytopenia and very rarely aplastic anemia), thyroiditis, dental and periodontal disorders, hemorrhagic/ischemic colitis, dyspnea, pulmonary infiltrates, pneumonia, interstitial pneumonitis, hepatic failure, increases in serum creatinine in patients with renal insufficiency, acute hypersensitivity (angioedema, bronchoconstriction, anaphylaxis and cutaneous eruptions) and hypertriglyceridemia.
During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years receiving PEGINTRON/REBETOL combination therapy, weight loss and growth inhibition were common.
Patients receiving PEGINTRON and REBETOL as retreatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naive patients.
Please see important full U.S. prescribing information and the Medication Guide for PEGINTRON at www.schering-plough.com.
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