Monday October 30, 1:08 pm Eastern Time
Press Release
SOURCE: Schering-Plough Corporation
Schering-Plough Reports Phase III
PEG-INTRON(TM) Plus REBETOL(R) Results
at American Association For The Study of Liver
Diseases Meeting
54% Sustained Response Overall Achieved in Patients With Chronic Hepatitis C;
61% Sustained Response Achieved With Optimized Weight-Based Dosing
Studies With Rebetron(TM) Combination Therapy Also Reported
DALLAS, Oct. 30 /PRNewswire/ -- Schering-Plough Corporation (NYSE: SGP - news) today reported that results of a
pivotal Phase III clinical study, presented for the first time here at the Presidential Plenary Session of the 51st Annual
Meeting of the American Association for the Study of Liver Diseases (AASLD), showed that combination therapy
with once-weekly PEG-INTRON(TM) (peginterferon alfa-2b) Injection plus daily REBETOL® (Ribavirin, USP)
Capsules achieved a 54% rate of sustained virologic response overall in previously untreated adult patients with
chronic hepatitis C. Sustained virologic response across hepatitis C virus genotypes ranged from 42% to 82% in
patients receiving PEG-INTRON plus REBETOL combination therapy. When analyzed on an optimized
dose/body-weight basis (>10.6 mg/kg of REBETOL daily), sustained virologic response was 61% for all genotypes,
48% for genotype 1 and 88% for genotypes 2 and 3. Sustained virologic response (SVR) is defined as sustained loss
of detectable (1) hepatitis C virus (HCV-RNA).
``These results are especially encouraging given the increasing interest among physicians in tailoring treatment
doses to an individual patient's needs,'' said Michael P. Manns, M.D., professor and chairman, department of
gastroenterology and hepatology, Hannover Medical School, Hannover, Germany. ``We have learned from this
study and previous studies with alpha interferon that, in addition to genotype, body weight is an important factor in
determining optimal clinical outcome. These results demonstrate that the dosing flexibility provided by PEG-INTRON
plus REBETOL has the potential to take combination therapy to the next level of hepatitis C treatment,'' Manns said.
Results of the PEG-INTRON plus REBETOL study represent the largest and most complete clinical data reported to
date involving peginterferon and ribavirin combination therapy. In all, PEG-INTRON was the subject of seven
presentations by study investigators at AASLD.
PEG-INTRON Plus REBETOL Combination Therapy
In an AASLD Presidential Plenary Session, study investigators presented results of a pivotal Phase III clinical study
designed to establish the activity and tolerance of two dosing regimens of PEG-INTRON plus REBETOL compared
to REBETRON(TM) Combination Therapy containing REBETOL (Ribavirin, USP) Capsules and INTRON® A
(Interferon alfa-2b, recombinant) Injection, the current standard of care, in previously untreated chronic hepatitis C
patients. A total of 1,530 patients from 62 sites worldwide (33 U.S., 5 Canada, 22 Europe, 2 other) were randomized to
three treatment arms:
(A) PEG-INTRON Injection 1.5 mcg/kg once weekly (QW) plus REBETOL Capsules
800 mg/daily for 48 weeks (PEG 1.5/R);
(B) PEG-INTRON 1.5 mcg/kg QW plus REBETOL 1000-1200 mg/daily for four
weeks followed by PEG-INTRON 0.5 mcg/kg QW plus REBETOL
1000-1200 mg/daily for 44 weeks (Peg 0.5/R); or
(C) INTRON A Injection 3 MIU/three times weekly plus REBETOL Capsules
1000-1200 mg/daily for 48 weeks (REBETRON).
The demographic/disease characteristics of patients in this study were similar to those in previous Schering-Plough
hepatitis C registration studies: 66% male; mean age 44 years; mean body weight 83 kg, pretreatment HCV-RNA (NGI
LLQ 100 copies/ml) >2 million copies 68%; and HCV genotype 1 (68%), genotypes 2 and 3 (29%), other genotypes
(3%) (InnoLipa, Innogenetics).
Patients in the PEG 1.5/R arm achieved significantly higher SVR (54%) overall compared to patients in the
REBETRON arm (47%), while patients in the PEG 0.5/R arm achieved numerically similar SVR (47%) to those receiving
REBETRON. When analyzed on a dose/body-weight basis (>10.6 mg/kg of REBETOL daily), SVR was 61% overall
for patients in the PEG 1.5/R arm, compared to 48% for patients in the PEG 0.5/R arm and 47% for patients in the
REBETRON arm.
Consistent with previous studies, the rates of sustained virologic response in this study were greatly influenced by
genotype, with patients in the PEG 1.5/R arm with genotype 1, the predominant genotype worldwide and the most
difficult to treat, achieving 42% SVR compared to 34% and 33% for patients in the PEG 0.5/R arm and REBETRON
arm, respectively. When analyzed on a dose/body-weight basis (>10.6 mg/kg of REBETOL daily), patients in the PEG
1.5/R arm with genotype 1 achieved 48% SVR compared to 34% for patients in both the PEG 0.5/R arm and the
REBETRON arm. Patients with genotypes 2 and 3 in these treatment arms achieved 88%, 80% and 80% SVR,
respectively.
The safety profile of both doses of PEG-INTRON plus REBETOL was similar to that for REBETRON, with no new
types of adverse events observed. Discontinuation of therapy for adverse events was similar in all three treatment
groups: PEG 1.5/R (14%), PEG 0.5/R (13%), REBETRON (13%), as was dose modifications, 42%, 36%, and 34%,
respectively.
PEG-INTRON PLUS REBETOL PIVOTAL PHASE III STUDY
(Sustained Virologic Response)
RESULTS: (A) PEG 1.5/R (B) PEG 0.5/R (C) REBETRON A vs. C
SVR 54% 47% 47% p=0.01
(overall)
SVR 42% 34% 33% p=0.02
Genotype 1
SVR 82% 80% 79%
Genotypes 2&3
Optimized Weight-Based Dosing
(>10.6 mg/kg/daily REBETOL*)
SVR 61% 48% 47%
(overall)
SVR 48% 34% 34%
Genotype 1
SVR 88% 80% 80%
Genotypes 2&3
* 10.6 mg/kg/daily REBETOL = REBETOL 800 mg/daily for patient
weighing 75kg.
PEG-INTRON
Additional PEG-INTRON presentations at AASLD included a study showing that treatment with PEG-INTRON
resulted in higher rates of sustained virologic response in Black and Hispanic patients compared to standard alpha
interferon therapy. Another study with PEG-INTRON showed that sustained virologic response is associated with
marked improvement in hepatic inflammation and fibrosis, and also showed that patients who do not achieve a
sustained response, i.e. those who relapse following treatment or who are nonresponders, also show improvement in
hepatic fibrosis. Study investigators suggested that further evaluation is warranted to determine whether some
patients may benefit from maintenance therapy with PEG-INTRON.
A study presented by John B. Wong, M.D., Tufts University, New England Medical Center, Boston, Mass.,
estimated the cost-effectiveness of PEG-INTRON plus REBETOL for a range of possible trial outcomes as compared
to REBETRON Combination Therapy or no antiviral therapy. In his study, Wong concluded that if trial results
suggest that PEG-INTRON plus REBETOL increases the relative rate of sustained virologic response, then 48 weeks
of combination therapy with PEG-INTRON plus REBETOL should provide good value for its clinical benefit.
REBETRON Combination Therapy
Also presented at AASLD were results of several studies involving REBETRON Combination Therapy containing
REBETOL (Ribavirin, USP) Capsules and INTRON A (Interferon alfa-2b, recombinant) Injection, the current standard
of care in the treatment of chronic hepatitis C. In all, REBETRON was the subject of 92 study abstracts, INTRON A
was the subject of 14 study abstracts and REBETOL was the subject of 50 study abstracts.
``Schering-Plough's commitment to developing improved treatments for hepatitis C is evidenced by the large number
of studies with PEG-INTRON, REBETRON, INTRON A and REBETOL as well as new research leads reported at this
year's meeting,'' said Robert J. Spiegel, M.D., senior vice president of medical affairs and chief medical officer,
Schering-Plough Research Institute.
In an AASLD Presidential Plenary session, study investigators presented results of a randomized controlled trial
designed to assess the safety and efficacy of 48 weeks of REBETRON Combination Therapy compared to no
antiviral therapy in liver transplant patients with hepatitis C reinfection. Intent-to-treat analysis for loss of
detectable* HCV-RNA showed that patients receiving REBETRON therapy had undetectable HCV-RNA at week 24
(29%), at end of treatment (25%) and at the end of the 24-week follow-up period (21%), compared to no patient in the
control group achieving loss of detectable HCV-RNA at any point in the study (p=0.026 at week 48; p=0.019 at end
of follow up).
In a presentation of a study evaluating the effect of dose reduction on sustained virologic response in patients with
chronic hepatitis C, investigators analyzed results from two pivotal Phase III clinical studies with REBETRON
Combination Therapy and concluded that patients who can be maintained on greater than 80% of their REBETRON
regimen for the proposed duration of therapy may have an enhanced rate of sustained response. Investigators
suggested that every effort should be made to continue the maximum tolerated doses of therapy for the duration of
treatment. Toward this goal, Schering-Plough makes available free to all patients on REBETRON Combination
Therapy its Be In Charge(TM) therapy-compliance and patient-counseling program.
Other presentations involving REBETRON Combination Therapy included several studies evaluating different
dosing regimens, including induction dosing, and the use of the combination therapy in specific patient populations,
including patients with decompensated cirrhosis, patients with inherited coagulation disorders, African American
and Hispanic patients, pediatric patients, and patients who relapsed or were nonresponders following prior
treatment.
Schering-Plough markets REBETRON Combination Therapy in the United States for the treatment of chronic
hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have
relapsed following alpha interferon therapy. The company markets REBETOL Capsules in certain international
markets, including the European Union (EU), for use in combination with interferon alfa-2b injection (INTRON A) for
the treatment of both relapsed and previously untreated hepatitis C patients.
Warnings and Contraindications
Anemia associated with the use of REBETOL in combination with interferon alfa-2b (REBETRON Combination
Therapy) may exacerbate symptoms of coronary disease or deteriorate cardiac function. 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.
The most common adverse experiences associated with REBETRON Combination Therapy are ``flu-like'' symptoms,
such as headache, fatigue, myalgia and fever, which appear to decrease in severity as treatment continues. Severe
psychiatric adverse events, including depression, psychoses, aggressive behavior, hallucinations, violent behavior
(suicidal ideation, suicidal attempts, suicides), and rare instances of homicidal ideation have occurred during
combination REBETOL/INTRON A therapy, both in patients with and without a previous psychiatric disorder.
Combination REBETOL/INTRON A 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. Combination REBETOL/INTRON
A 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 (two reliable forms)
during treatment and during the 6-month post-treatment follow-up period. Significant teratogenic and/or embriocidal
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.
REBETOL is an oral formulation of ribavirin, a synthetic nucleoside analog with broad-spectrum antiviral activity.
Schering-Plough has exclusive rights to market oral ribavirin for hepatitis C in all major world markets through a
licensing agreement with ICN Pharmaceuticals, Inc. (NYSE: ICN - news) of Costa Mesa, Calif.
INTRON A is a recombinant version of naturally occurring alpha interferon, which has been shown to exert both
antiviral and immunomodulatory effects. Schering-Plough markets INTRON A, the world's largest-selling alpha
interferon, for 16 major antiviral and anticancer indications worldwide.
PEG-INTRON is a longer-acting form of INTRON A that uses proprietary PEG technology developed by Enzon, Inc.
(Nasdaq: ENZN - news) of Piscataway, N.J. PEG-INTRON, interferon alfa-2b linked to a 12,000 dalton polyethylene
glycol (PEG) molecule, is designed to provide a once-weekly product optimizing the balance between antiviral
activity and elimination half-life. Schering-Plough holds an exclusive worldwide license to PEG-INTRON.
In the European Union, PEGINTRON(TM)(peginterferon alfa-2b) was approved on May 25, 2000, as once-weekly
monotherapy for the treatment of adult patients with chronic hepatitis C, resulting in one Marketing Authorization
with unified labeling that is valid in all 15 EU-Member States. PEGINTRON, the first and only pegylated interferon
approved for marketing in the world, has been launched in seven countries: Austria, Finland, France, Germany,
Portugal, Sweden and the United Kingdom. In the United States, Schering-Plough on Dec. 23, 1999, submitted a
Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) seeking marketing approval
for PEG-INTRON for the treatment of chronic hepatitis C. The BLA is currently under FDA review.
Some 4 million Americans are infected with the hepatitis C virus, according to the Centers for Disease Control and
Prevention (CDC). As many as 5 million Europeans (1 percent to 2 percent of the general population) are chronically
infected with the hepatitis C virus, according to a study conducted by the World Health Organization (WHO).
Chronic hepatitis C is the leading cause of chronic liver disease and the most common reason for liver transplant,
according to WHO.
Schering-Plough Research Institute is the pharmaceutical research and development arm of Schering-Plough
Corporation of Kenilworth, N.J., a research-based company engaged in the discovery, development, manufacturing
and marketing of pharmaceutical products worldwide.
(1) Defined as HCV-RNA below limit of detection using a
research-based RT-PCR assay.
SOURCE: Schering-Plough Corporation |
