SAN FRANCISCO, Nov. 12 /PRNewswire-FirstCall/ -- Patients with chronic hepatitis C treated with PEG-INTRON(R) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) combination therapy achieved consistently high sustained virological response (SVR)(1) rates across all weight groups, with an overall SVR rate of 66 percent, according to preliminary results on 952 patients from a large observational study involving more than 2,000 previously untreated patients at 160 clinics across Canada. Body weight has been shown in previous studies to affect SVR. In this study, patients were treated, followed and managed per standard of care in a “real-life” treatment setting with no study- related intervention beyond collection of data. PEG-INTRON and REBETOL combination therapy is marketed in Canada as PEGETRON(R).
These results were reported for the first time at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
In the study, PEG-INTRON (1.5 mcg/kg weekly) and REBETOL (800 - 1200 mg daily) combination therapy achieved SVR rates of greater than 62 percent in all weight groups (ranging from 62.9 percent to 68.9 percent), with no significant differences in SVR between the different weight groups, in 952 patients for whom SVR results have been collected to date. As expected, a higher percentage of patients with genotypes 2 or 3 achieved an SVR (85 percent and 78 percent, respectively) than patients with genotype 1 (52 percent). Genotype 1 is the most common form of the virus and is considered the most difficult to treat successfully.
“These findings are particularly encouraging given that this is a ‘real- life’ community study with similar patient distribution by genotype within each weight group,” said Paul Marotta, M.D., lead investigator, London (Ontario) Health Sciences Centre. “These results are consistent with the Canadian registration data for PEG-INTRON and REBETOL and underscore for patients the value of seeking treatment for hepatitis C, because the virus can be eradicated in a significant percentage of patients.”
In the United States, PEG-INTRON (1.5 mcg/kg weekly) is approved in combination with REBETOL (800 mg daily) for a duration of treatment of 48 weeks. In the U.S. label, the SVR rate for this regimen is 52 percent. Weight- based dosing of REBETOL is currently under investigation in U.S. studies.
Canadian Observational Study and Results
In the study, known as the PEGETRON Prospective Optimal Weight-Based Dosing Response program (POWeR)(2), 2,194 treatment-naive patients with chronic hepatitis C virus (HCV) infection were prospectively enrolled between December 2002 and December 2004 in an open label trial conducted at 160 academic and community clinics across Canada. Patients were grouped by weight into one of five categories: less than 50 kg, 50 kg to less than 64 kg, 64 kg to less than 75 kg, 75 kg to less than 85 kg, and 85 kg or more, with the highest percentage of patients (33.8 percent) weighing 85 kg or more.
All patients were eligible for treatment with PEG-INTRON and REBETOL combination therapy according to criteria listed in the Canadian Product Monograph. Patients received treatment for 24 weeks (non-genotype 1) or 48 weeks (genotype 1).
SVR results have been collected on 952 patients to date. SVR by body weight did not differ significantly across weight groups: less than 50 kg (67 percent); 50 kg to less than 64 kg (67 percent); 64 kg to less than 75 kg (63 percent); 75 kg to less than 85 kg (65 percent); and 85 kg or more (69 percent). Patient distribution by genotype within each weight group was similar, ranging from 48 percent to 52 percent of patients having genotype 1 and 46 percent to 52 percent having genotype 2 or 3.
Of the patients in the study for whom baseline fibrosis data has been reported, more than one-third (37 percent) had severe or cirrhotic fibrosis (Metavir score F3 or F4) and 63 percent had mild to moderate (F0-F2) levels of fibrosis. Importantly, as weight increased, an increasing number of patients had severe or cirrhotic fibrosis (64 kg to less than 75 kg: F3/F4 = 33 percent; 75 kg or more: F3/F4 = 38 percent). More patients with a baseline fibrosis level of F0, F1 or F2 achieved an SVR (76 percent or 68 percent, respectively) than patients with a severe fibrosis level of F3 or F4 (42 percent or 41 percent, respectively).
PEG-INTRON and REBETOL Combination Therapy
PEG-INTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy dosed according to patient body weight that is designed to achieve an effective balance between antiviral activity and elimination half-life. REBETOL is an oral formulation of ribavirin, a synthetic nucleoside analog with broad-spectrum antiviral activity.
Chronic hepatitis C is estimated to affect more than 10 million people in major world markets, including in Canada, Europe and the United States. It is a leading cause of chronic liver disease and one of the most common reasons for liver transplant.
Important Information Regarding U.S. Labeling for PEG-INTRON and REBETOL
WARNING
Alpha interferons, including PEG-INTRON, 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 PEG-INTRON therapy.
Ribavirin causes hemolytic anemia. Anemia associated with REBETOL therapy may exacerbate cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL. It is advised that complete blood counts (CBC) be obtained at baseline and at weeks 2 and 4 of therapy or more frequently if clinically indicated.
REBETOL and combination REBETOL/PEG-INTRON therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and during the 6 months after stopping therapy. REBETOL and combination REBETOL/PEG-INTRON therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (at least two reliable forms) during treatment and during the 6- month post-treatment follow-up period. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of REBETOL. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling (800) 727-7064.
PEG-INTRON
There are no new adverse events specific to PEG-INTRON as compared to INTRON(R) A (interferon alfa-2b, recombinant) for Injection, however, the incidence of some (e.g., injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEG-INTRON were “flu- like” symptoms, occurring in approximately 50% of patients, which may decrease in severity as treatment continues. Application site disorders were common (47%), but all were mild (44%) or moderate (4%) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation). Injection site pain was reported in 2% of patients receiving PEG-INTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEG-INTRON.
Psychiatric adverse events, which include insomnia, were common (57%) with PEG-INTRON, but similar to INTRON A (58%). Depression was most common at 29%. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1% of patients during or shortly after completing treatment with PEG-INTRON.
PEG-INTRON/REBETOL is contraindicated in patients with autoimmune hepatitis, decompensated liver disease, and in patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia).
The following serious or clinically significant adverse events have been reported at a frequency less than 1% with PEG-INTRON or interferon alpha: severe decreases in neutrophil or platelet counts, hypothyroidism, hyperglycemia, hypotension, arrhythmia, ulcerative and hemorrhagic colitis, development or exacerbation of autoimmune disorders including thyroiditis, RA, systemic lupus erythematosus, psoriasis, pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, some resulting in patient deaths), urticaria, angioedema, bronchoconstriction, anaphylaxis, retinal hemorrhages, and cotton wool spots.
In the PEG-INTRON/REBETOL combination trial the incidence of serious adverse events was 17% in the PEG-INTRON/REBETOL groups compared to 14% in the INTRON A/REBETOL group. The incidence of severe adverse events in the PEG- INTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEG-INTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-INTRON (1.5 mcg/kg)/ REBETOL and in 34% of those receiving INTRON A/REBETOL.
REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.
Schering-Plough Corporation is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough’s vision is to earn the trust of the physicians, patients and customers served by its more than 30,000 people around the world. The company’s Web site is http://www.schering-plough.com.
SCHERING-PLOUGH DISCLOSURE NOTICE: This press release contains certain “forward-looking statements” within the meaning of the Securities Litigation Reform Act of 1995, including statements related to the market for PEG-INTRON and REBETOL combination therapy. 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 market forces, economic factors, product availability, current and future branded, generic or over-the-counter competition and 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 the company’s third quarter 2005 10-Q.
References 1. Sustained virological response (SVR) is defined as undetectable virus (HCV-RNA) levels in the blood at 6 months after the end of therapy. 2. Abadir, N., P. Marotta, S.V. Feinman, L. Scully, M. Varenbut, J. Daiter, J. Farley, Pegetron Prospective Optimal Weight-Based Dosing Response Program (POWeR): Preliminary Results, Poster 1256, American Association for the Study of Liver Diseases (AASLD) 2005.
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