- Schering-Plough Reports Results of PEG-INTRON(TM) Phase III Studies at
European Association for The Study of The Liver (EASL) Meeting
Phase II PEG-INTRON Plus RIBAVIRIN Results Also Reported
ROTTERDAM, Netherlands, May 1 /PRNewswire/ -- Schering-Plough
(NYSE: SGP) today reported that results of a pivotal Phase III clinical
study presented for the first time here at the 35th Annual Meeting of
European Association for the Study of the Liver (EASL) demonstrated that
once weekly administration of PEG-INTRON(TM) (peginterferon alfa-2b)
Injection is twice as active as INTRON(R) A (interferon alfa-2b,
recombinant) Injection administered three times weekly as monotherapy in
achieving sustained loss of detectable(1) hepatitis C virus (HCV) in
patients with chronic hepatitis C.
PEG-INTRON is a longer-acting form of INTRON A that uses proprietary PEG
technology developed by Enzon, Inc. (Nasdaq: ENZN) of Piscataway, N.J.
Schering-Plough holds an exclusive worldwide license to PEG-INTRON.
"PEG-INTRON at all three doses studied showed higher rates of sustained
response than INTRON A and was just as well tolerated," said Christian
Trepo, M.D., Ph.D., director, hepatitis research unit, Hopital Hotel
Service d'Hepatologie, Lyon, France, who presented the data.
with previous studies, the rates of sustained virologic response
in this study were greatly influenced by genotype, and ranged from 11%
patients with genotype 1, the predominant genotype worldwide and the
difficult to treat, to 49% for patients with genotype 2 or 3, compared
6% to 28% for INTRON A," Trepo said.
In this study, patients treated with PEG-INTRON achieved significantly
greater loss of detectable hepatitis C virus during treatment, at the
of treatment and at the end of follow up, compared to patients treated
with INTRON A.
The randomized, controlled Phase III study was designed to establish the
safety and efficacy of PEG-INTRON versus INTRON A monotherapy in adult
patients with previously untreated chronic hepatitis C and compensated
liver disease. A total of 1,219 patients, who were positive for serum
HCV-RNA(2) and who had elevated liver enzymes (serum alanine
aminotransferase), were treated with one of three doses of PEG-INTRON
(0.5, 1.0, 1.5 &g/kg) administered once weekly or INTRON A (3 MIU)
administered three times weekly for 48 weeks. The primary efficacy
endpoint of the study was sustained loss of detectable HCV-RNA at 24
from the end of 48 weeks of treatment.
The demographic/disease characteristics of patients in this study were
similar to those in previous Schering-Plough hepatitis C registration
studies, with a majority of patients having genotype 1, the most
genotype to treat (70% genotype 1), and high viral load (74% HCV-RNA > 2
Adverse events (AEs) for all doses of PEG-INTRON were similar to those
INTRON A. Most AEs were mild to moderate and were manageable with dose
adjustment. Discontinuation of therapy due to AEs was similar for all
treatment groups (6-11%). Dose reductions were similar for INTRON A and
PEG- INTRON 0.5 &g/kg and higher for PEG-INTRON 1.0 and 1.5 &g/kg (6%,
14% and 19%, respectively). The most common side effects occurring with
PEG-INTRON were "flu-like" symptoms, such as headache, fatigue, myalgia
and fever, which appeared to decrease in severity as treatment
PEG-INTRON PLUS REBETOL(R) COMBINATION THERAPY
Results of a Phase II dose-ranging study of PEG-INTRON in combination
REBETOL (Ribavirin, USP) Capsules were presented by Rafael Esteban Mur,
M.D., professor of medicine, Servei de Medicina Interna-Hepatologia,
Hospital Vall d'Hebron, Barcelona, Spain, at a satellite symposium
sponsored by Schering-Plough. "The results of this study indicate that
REBETOL enhances the antiviral activity of PEG-INTRON and that sustained
virologic response with the combination therapy is dose dependent,"
Esteban Mur said. "While preliminary, these results are encouraging."
The combination of PEG-INTRON and REBETOL is currently being studied in
Phase III trials to further define its clinical profile.
A total of 72 patients with chronic hepatitis C and compensated liver
disease were enrolled into the Phase II, open-label, randomized, active
controlled study. Fewer patients in this study than in the PEG-INTRON
Phase III monotherapy study were genotype 1 (44% vs. 70% respectively)
fewer had high viral load (58% vs. 74% HCV-RNA > 2 million copies/ml).
Patients in this study received either PEG-INTRON (0.35, 0.7 or 1.4
once weekly alone or in combination with daily REBETOL (600, 800 or
1,000-1,200 mg) for 24 weeks, with 24 weeks of follow up. Patients
treated with PEG-INTRON 0.35, 0.7 or 1.4 &g/kg in combination with
achieved higher rates of sustained virologic response at 48 weeks
to patients receiving the same doses of PEG-INTRON alone. In this
the tolerance profile of PEG-INTRON/REBETOL was comparable to the known
tolerance profile of INTRON A/REBETOL.
PEG-INTRON FOR HCV
Schering-Plough on Dec. 23, 1999 submitted a Biologics License
(BLA) to the U.S. Food and Drug Administration (FDA) seeking marketing
approval for PEG-INTRON for the treatment of chronic hepatitis C. On
17, 2000, the European Union's (EU) Committee for Proprietary Medicinal
Products (CPMP) of the European Agency for the Evaluation of Medicinal
Products (EMEA) issued a positive opinion recommending approval of
PEG-INTRON for the treatment of hepatitis C. The CPMP opinion serves as
the basis for European Commission approval, which would result in one
single Marketing Authorization with unified labeling that would be valid
in all 15 EU-Member States.
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% to 2% 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
the leading cause of chronic liver disease and the most common reason
liver transplant, according to WHO.
INTRON A is a recombinant version of naturally occurring alpha
which has been shown to exert both antiviral and immunomodulatory
Schering-Plough markets INTRON A, the world's largest-selling alpha
interferon, worldwide for 16 major antiviral and anticancer indications.
REBETOL is an oral formulation of ribavirin, a synthetic nucleoside
with broad-spectrum antiviral activity. Schering-Plough has exclusive
rights to market oral ribavirin for hepatitis C in all major world
through a licensing agreement with ICN Pharmaceuticals, Inc. (NYSE: ICN)
of Costa Mesa, Calif.
Schering-Plough is a research-based company engaged in the discovery,
development, manufacturing and marketing of pharmaceutical products
(1) Detection limit 100 copies/ml (NGI Assay)
(2) HCV-RNA: hepatitis C viral RNA (ribonucleic acid)
SOURCE Schering-Plough Corporation
CO: Schering-Plough Corporation
ST: New Jersey, Netherlands
- Hepatology Focus
Update on Hepatitis C Treatment
Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA
Medicine, Los Angeles, California
Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los
Angeles, California, and
Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai
Associate Professor of Medicine, UCLA School of Medicine, Los Angeles,
[Medscape Gastroenterology 3(1), 2001. © 2001 Medscape, Inc.]
Although screening of blood products and other interventions such as
programs have significantly reduced the incidence of acute hepatitis C
in the United States and
elsewhere, there remains a large reservoir of chronically infected
individuals, many of whom are
unaware of their infection. Current estimates suggest a seroprevalence
of 1.8% among Americans,
most of whom are viremic. The clinical burden of chronic hepatitis C
virus (HCV) infection is
expected to increase over the next 2-3 decades as a large cohort of
patients infected between the
1960s and 1980s, primarily as a result of recreational drug use,
develops progressive liver disease.
Between 8000 and 10,000 deaths each year in the United States are
believed to be caused by
infection with HCV -- which is now the most frequent indication for
Even before identification of HCV, interferon-alfa (IFN-alfa) had been
evaluated as a potential
therapy for what had been called chronic non-A, non-B hepatitis.
Further studies using normalization of serum alanine aminotransferase
(ALT) levels and
improvement in liver histology as endpoints demonstrated the efficacy of
IFN-alfa as therapy for
the causative agent of chronic non-A, non-B hepatitis (HCV).[4,5]
Subsequent advances in
molecular diagnosis have now increasingly allowed establishment of
virologic criteria to evaluate
efficacy of treatment in patients with chronic hepatitis C (see Table).
Definition of Virologic Response in Patients Receiving Therapy for
Chronic Hepatitis C
End-of-treatment response (ETR) refers to absence of viremia (ie, serum
HCV RNA below level
of detection) at completion of therapy. Sustained response (SR)
indicates persistent absence of
serum HCV RNA 6 months or more after cessation of therapy. A study by
coworkers on the long-term clinical outcome in 80 patients with
chronic HCV followed for a
mean of 4 years following therapy highlighted the clinical implications
of a virologic SR. Persistent
absence of HCV RNA from serum was observed in 96% of patients with a
lack of histologic
progression on serial liver biopsy. In addition, ALT levels were
persistently normal in over 90%.
The most recent follow-up biopsy showed normal or near normal histologic
findings in 62% of
these patients. Thus, virologic SR was shown to be associated with both
an absence of detectable
serum HCV RNA and marked histologic improvement.
Relapsers are defined as patients who have undetectable serum HCV RNA at
therapy but who subsequently redevelop viremia. Nonresponders (NRs) are
patients who fail to
clear HCV RNA from serum during therapy.
A recent paper by Everson and associates underscores the importance
of HCV RNA testing in
defining treatment response. In patients with marked fibrosis and
cirrhosis, they found a major
discrepancy between biochemical (ALT) and virologic (HCV RNA) responses
to therapy. Two of
7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with
cirrhosis cleared HCV RNA
without normalizing ALT. In contrast, only 3 patients (10%) without
significant fibrosis had an
HCV RNA response without normalization of ALT. Thus, clinical trials for
chronic HCV are now
typically reported using virologic response rates.
What then are the current goals of antiviral therapy in patients with
chronic hepatitis C? Immediate
goals are eradication of viral replication and improvement in hepatic
inflammation and fibrosis.
Long-term potential goals include prevention of cirrhosis,
hepatocellular carcinoma, and liver
IFN-alfa 2 was the first agent approved for the treatment of chronic
HCV. Since the initial trials
establishing its efficacy, data regarding treatment duration and dose
have evolved. Currently, 2
forms of IFN-alfa that differ by a single amino acid residue are
approved for treatment of chronic
HCV infection: IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey) and
(Hoffmann-La Roche, Basel, Switzerland). The recommended dose is 3
million units 3 times each
week for up to 12 months.
When used alone in monotherapy, the alfa interferons have similar
efficacies, with SRs of only 10%
to 20%, with the modestly higher response rates associated with more
Higher-dose IFN-alfa (ie, > 9 million units per week) results in SRs
between 8% and 20% in
treatment-naive patients. High-dose IFN-alfa has also been studied in
NRs and relapsers, but with
mixed results. With prior NR, SRs achieved with higher doses are only
between 0% and 4%. In
relapsers, SRs range from 20% to 40%. However, side effects are more
troublesome with higher
Because of the low overall response rate to standard IFN-alfa, more
recent studies have focused
on newer regimens, including synthetic IFN (IFN alfacon-1),
"combination" therapy (IFN-alfa 2b
+ ribavirin), and longer-acting IFNs (pegylated IFNs). A number of major
of NR have been identified, notably HCV genotype 1, the presence of
cirrhosis, and higher viral
load. In addition, patient's race appears to affect response to IFN,
with African Americans
having an overall low SR to therapy.
A significant improvement in SR resulted from the addition of ribavirin
to standard IFN-alfa.
Ribavirin, a guanosine analogue, was initially evaluated as monotherapy
for chronic HCV because
of its antiviral activity against other RNA viruses.[11-13] Although as
monotherapy it reduces ALT
levels, it does not appear to have a direct antiviral effect and fails
to lower serum HCV RNA
levels. Moreover, results of most studies with ribavirin have found no
improvement in hepatic
histology, although a longer 2-year treatment regimen was shown to
However, in combination with IFN-alfa 2b, ribavirin leads to a
significant increase in SR in
treatment-naive patients. SRs of 31% with 24 weeks and 38% with 48
weeks of combination
therapy were achieved vs 6% with 24 weeks and 13% with 48 weeks of IFN
relapsers, enhanced SR rates also occur on retreatment using combination
therapy, from 30% to
49%; in prior NRs, SR of 14% has been reported with 6 months of
Histologic improvement was more common among treatment-naive patients
combination therapy. Similar improvement was found in a randomized
controlled trial of
However, the improved SR rates observed with combination therapy are
also associated with
more expense and an increased frequency of adverse effects compared with
monotherapy. Dose-related hemolytic anemia is a particular concern
with ribavirin[11,13] as is
teratogenicity, based on animal studies. The mean drop in hemoglobin
in patients treated with
combination therapy is between 2 and 3 g/dL, although a fall of more
than 4 g/dL has been
observed in about 10% of patients. The anemia may be poorly tolerated in
patients with ischemic
heart disease in particular as treatment is extended to older
patients. Accumulation of ribavirin
metabolites that are not cleared by dialysis occurs in end-stage renal
Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is
engineered compound synthesized by combining the most common amino acid
naturally occurring IFNs.[19,20] CIFN shares 88% homology with IFN-alfa
and 30% with
IFN-beta. Although it has greater cytokine induction, antiviral,
antiproliferative, natural killer cell,
and gene-induction activities than both IFN-alfa 2a and IFN-alfa 2b on
an equal mass basis, initial
studies with the recommended CIFN dose of 9 mcg in IFN-naive patients
with chronic hepatitis C
resulted in viral response rates similar to those achieved with standard
More recently, higher-dosage CIFN regimens of 15 mcg thrice weekly were
reported to result in
virologic SRs of 13% in prior NRs and 58% in relapsers treated for 48
Pharmacokinetic studies have provided a rationale for enhanced IFN
dosing. The initial decline in
serum HCV RNA levels seen after a single dose of IFN therapy is believed
to reflect a direct
antiviral effect, whereas the subsequent and more delayed decline in HCV
RNA levels is due to
destruction of infected hepatocytes. An important limitation of the
antiviral effect of standard
IFN dosing is the rapid decline in circulating drug level with
thrice-weekly administration. The short
half-life of the drug and the rapid production of HCV virions diminish
the efficacy of standard IFN
therapy. In an effort to achieve more stable and efficacious IFN
activity, pegylated formulations
have been developed.
The production of a pegylated IFN involves the addition of a nontoxic
long-acting formulation of
interferon using the drug delivery system of pegylation. Polyethylene
glycol molecules are added to
IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa 2b (PEG-Intron,
Pegylation is already used in the delivery of other drugs. Its
attachment to IFN-alfa permits
In a recent report, Zeuzem and colleagues indicate that at week 72,
the SR was 39% after 48
weeks of therapy at a dose of 180 mcg with pegylated IFN alfa-2a
compared with a 19% SR in
control patients. Drug discontinuation in these treatment-naive patients
and frequency of dose
reduction were similar in the 2 treatment arms. Heathcote and
colleagues have also reported on
the use of pegylated IFN alfa-2a in a controlled trial in cirrhotic
patients. SR was 30% following 48
weeks of therapy with 180 mcg, compared with 8% for patients treated
with standard alfa IFN,
again without a significant increase in side effects with the pegylated
Trepo and colleagues have also reported, in abstract form, initial
studies with pegylated IFN-alfa
2b. Virologic SR for the unmodified IFN-alfa 2b (3 million units, thrice
weekly for 48 weeks) was
12%, whereas the SR for the pegylated IFN-alfa 2b was 18%, 25%, and 23%
with 0.5 mcg/kg,
1.0 mcg/kg, and 1.5 mcg/kg, respectively, administered weekly in
As with standard IFN-alfa monotherapy, ribavirin may augment response
rates when combined
with the pegylated IFNs.[26,27] Recent trials will help evaluate further
the role of ribavirin in
augmenting the efficacy of pegylated IFN (see Figure).
Figure. Initial antiviral therapy against hepatitis C virus.*
* Abbreviations: IFN = interferon; CSN = consensus interferon;
interferon + ribavirin; PEG = pegylated interferon; PEG/RIB =
pegylated interferon +
There has been continued interest in developing non-IFN-based therapies
for HCV despite the
promise of the pegylated IFNs. A recent study examined the role of human
treating prior NRs with chronic HCV. Although, HCV RNA remained
detectable in all patients
at the end of treatment, 5 (23%) of the 22 treated patients had
persistent ALT normalization at
the end of follow-up. Future studies should determine whether combining
interleukin-10 with other
antiviral agents will increase efficacy in this setting. Interleukin-12
has also been evaluated as
monotherapy, again without clear antiviral benefit.
There is also increasing enthusiasm for targeting HCV molecular
products. For example, ribozyme
gene therapy has the potential to accurately degrade HCV RNA. Human
studies are anticipated.
Treatment options for HCV infection continue to expand. Whereas SRs of
10% were achieved
with IFN monotherapy only several years ago, it may soon be possible to
achieve SR rates greater
than 50% with combination pegylated IFN and ribavirin. Molecular-based,
strategies are also likely to become a reality in the future, although
therapy will remain
interferon-based the next several years.
Table. Response (HCV RNA/ALT*) to Antiviral Therapy
Type of Response
6 Months After
* HCV RNA measured by polymerase chain reaction; ALT = alanine
aminotransferase; HCV = hepatitis C virus.
Positive denotes HCV RNA present in the serum by polymerase chain
abnormal alanine aminotransferase values. Negative denotes no serum
HCV RNA by
polymerase chain reaction and normal alanine aminotransferase
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