First Large Study Comparing Leading Hepatitis C Therapies Provides
Important Insights to Help Guide Clinical Practice MILAN, Italy,
April 26 /PRNewswire-FirstCall/ -- Final results of the IDEAL
study, the first large, randomized, clinical study comparing the
leading therapies for chronic hepatitis C, were presented today at
the 43rd Annual Meeting of the European Association for the Study
of the Liver (EASL), providing important insights that may help
guide clinical practice for physicians worldwide treating this
serious and potentially life-threatening disease. The IDEAL study
compared combination therapy with PEGINTRON(TM) (peginterferon
alfa-2b) and REBETOL(R) (ribavirin, USP) vs. Pegasys (peginterferon
alfa-2a) and Copegus (ribavirin, USP),(1) as well as a lower dose
of PEGINTRON in an investigational combination with REBETOL. The
results showed that sustained virologic response (SVR),(2) the
primary endpoint of the study, was similar for all three treatment
regimens. The study also showed in secondary analyses that
PEGINTRON combination therapy provided greater predictability of
response at important treatment milestones and significantly lower
relapse rates after the end of treatment than Pegasys and Copegus
combination therapy, despite patients in the Pegasys arm overall
receiving a significantly higher median ribavirin dose over the
duration of the study. Safety and tolerability were similar among
the treatment arms. "IDEAL provides important insights about the
similarities and differences of the two leading combination
therapies for hepatitis C, and how physicians can use these
findings to help manage their patients," said Robert J. Spiegel,
M.D., chief medical officer and senior vice president,
Schering-Plough Research Institute. In IDEAL (Individualized Dosing
Efficacy vs. flat dosing to assess optimaL pegylated interferon
therapy), 3,070 previously untreated U.S. patients with HCV
genotype 1, the most common form of the virus worldwide and most
difficult to treat, were randomized and treated with one of three
treatment regimens: (1) PEGINTRON 1.5 mcg/kg/week and REBETOL
800-1,400 mg/day; (2) PEGINTRON 1.0 mcg/kg/week and REBETOL
800-1,400 mg/day; and (3) Pegasys 180 mcg/week and Copegus
1,000-1,200 mg/day Patients received up to 48 weeks of combination
therapy with 24 weeks of follow-up. In IDEAL, the combination
regimen of Pegasys and Copegus used the recommended doses in
accordance with their approved U.S. labeling, which includes a flat
dose of Pegasys (180 mcg/week) for all patients regardless of body
weight, and 1,000 or 1,200 mg/day of Copegus, adjusted for two
weight categories. PEGINTRON was dosed either at 1.5 mcg/kg/week or
an investigational combination dose of 1.0 mcg/kg/week with REBETOL
at a dose of 800-1,400 mg/day, adjusted by four weight categories.
As a result, 51 percent of patients in the study were assigned the
same dose of ribavirin (either REBETOL or Copegus) based on their
weight groups, 39 percent of patients in the Pegasys arm were
assigned a higher dose of ribavirin and 10 percent of patients in
the PEGINTRON arms were assigned a higher dose of ribavirin. Key
Findings from IDEAL (For the PEGINTRON 1.5 mcg, PEGINTRON 1.0 mcg,
and Pegasys combination arms, respectively.) -- SVR, the primary
endpoint of the study, was similar for the three treatment regimens
(40 vs. 38 vs. 41 percent, respectively) overall, and among those
patients who were assigned equivalent doses of ribavirin based on
their weight group (40 vs. 38 vs. 38 percent, respectively)
(ITT).(3,4) -- Predictability of response at early treatment
milestones was confirmed in a secondary analysis as an important
assessment tool for physicians. More patients in the PEGINTRON
combination arms who had undetectable virus (HCV-RNA) in plasma at
treatment week 4 or treatment week 12 went on to achieve SVR
(positive predictive value, PPV) than patients in the Pegasys
combination arm (92 vs. 87 vs. 80 percent, and 81 vs. 83 vs. 74
percent, respectively).(5) -- Relapse after the end of treatment
was lower for patients in the PEGINTRON combination therapy arms
compared to patients receiving Pegasys and Copegus (24 vs. 20 vs.
32 percent, respectively). In a multivariate logistic regression
analysis, among the factors significantly affecting relapse were:
baseline viral load greater than 600,000 IU/mL vs. less than or
equal to 600,000 IU/mL (p-value less than 0.001); age greater than
40 vs. less than or equal to 40 (p-value less than 0.001); fibrosis
F3/4 vs. F0/1/2 (p-value equal to 0.001); Pegasys regimen vs.
PEGINTRON 1.0 mcg regimen (p-value less than 0.001); glucose
fasting greater than or equal to 5.6 vs. less than 5.6 (p-value
equal to 0.002); steatosis 0 percent vs. greater than 0 percent
(p-value equal to 0.002); ALT normal vs. elevated (p-value equal to
0.008); and Pegasys regimen vs. PEGINTRON 1.5 mcg regimen (p-value
equal to 0.012). -- End of treatment response was higher in the
Pegasys combination arm (53 vs. 49 vs. 64 percent, respectively).
-- Ribavirin dose: One of the key questions of the study has been
whether the protocol-assigned ribavirin dose regimen or the
protocol-specified dose reduction schedule disadvantaged patients
in any of the treatment arms, particularly in the Pegasys
combination arm. However, the final results of IDEAL showed that
the majority of patients in the Pegasys therapy arm received a
higher ribavirin dose over the duration of the study, including
patients with ribavirin dose reductions or discontinuations, based
on the actual median ribavirin dose received (mg/kg/day),
regardless of treatment outcome (SVR, relapsers and nonresponders)
[p-value less than 0.001 for ribavirin dose received in the
PEGINTRON 1.5 mcg arm vs. Pegasys arm and p-value less than or
equal to 0.001 for ribavirin dose received in the PEGINTRON 1.0 arm
vs. Pegasys arm]. -- Safety and tolerability were similar among the
three treatment groups, with no new peginterferon or ribavirin
related adverse events identified in this large study. Overall
adverse events reported for the three treatment regimens were
similar. As seen in other studies with these treatments, a range of
"flu-like symptoms" were the most commonly reported adverse events
for all three treatment regimens. Overall, the proportion of
patients reporting serious adverse events was similar (9 vs. 9 vs.
12 percent, respectively). Discontinuation rates due to adverse
events were similar across the three treatment arms (13 vs. 10 vs.
13 percent, respectively) as were discontinuations due to
psychiatric adverse events (3 vs. 2 vs. 2 percent, respectively).
The complete results of the IDEAL study will be submitted for
peer-reviewed publication, as well as to health authorities
worldwide. About IDEAL The IDEAL study was undertaken by
Schering-Plough as an important step in meeting the needs of the
hepatitis C medical and patient communities to identify improved
treatment strategies to optimize outcomes for patients. IDEAL, a
Phase IIIb, randomized, parallel-group study, was conducted at 118
academic and community centers across the United States. The study
treated 3,070 adult patients with chronic HCV genotype 1. Of these,
82 percent of patients had high viral load (greater than 600,000
IU/mL),(3) 11 percent had grade F3/4 fibrosis/cirrhosis, and 19
percent were African Americans. There were no significant
differences in patient demographics or disease characteristics
across the three treatment arms. The comparison of the two
PEGINTRON combination therapy doses (1.5 vs. 1.0 mcg/kg/week) was
conducted as a post-approval commitment to the U.S. Food and Drug
Administration (FDA). The comparison of the PEGINTRON and Pegasys
combination therapy regimens was added to the study because no
randomized, controlled head-to-head study of the two available
peginterferon regimens had been conducted to date. Cross-study
comparisons and retrospective analyses of previous data are
difficult to interpret because of differences in study designs,
patient populations and assay limits. Mark Sulkowski, M.D., and
John McHutchison, M.D., are the co-principal investigators of the
IDEAL study. They also are co-chairmen of the IDEAL Publication
Committee, which also includes three independent expert members not
associated with the study to provide an unbiased evaluation of the
data. The Publication Committee was responsible for the preparation
of the prespecified data analysis plan for the statistical analysis
conducted for the primary publication of the study results. About
PEGINTRON In the United States, PEGINTRON is indicated for use
alone or with ribavirin for the treatment of chronic hepatitis C in
patients with compensated liver disease who have not been
previously treated with interferon alpha and who are at least 18
years of age. Important Safety Information Regarding U.S. Labeling
for PEGINTRON and REBETOL Alpha interferons, including PEGINTRON
and INTRON(R) A, 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 and/or INTRON A therapy. Use with
Ribavirin: Ribavirin may cause birth defects and/or 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. Contraindications PEGINTRON is contraindicated in
patients with hypersensitivity to PEGINTRON 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. INTRON A (Interferon alfa-2b,
recombinant) for Injection is contraindicated in patients with
hypersensitivity to INTRON A or any component of the product,
autoimmune hepatitis, and decompensated liver disease. PEGINTRON or
INTRON A in combination with REBETOL therapy is additionally
contraindicated in patients with hypersensitivity to ribavirin or
any other component of the product, women who are 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/min. Avoid
Pregnancy 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. 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 There
are no new adverse events specific to PEGINTRON as compared to
INTRON A; however, the incidence of some (e.g., injection site
reactions, fever, rigors, nausea) were higher. The most common
adverse events associated with PEGINTRON 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 PEGINTRON. Alopecia
(thinning of the hair) is also often associated with alpha
interferons including PEGINTRON. Psychiatric adverse events, which
include insomnia, were common (57%) with PEGINTRON 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 PEGINTRON. The following serious or
clinically significant adverse events have been reported at a
frequency less than 1% with PEGINTRON 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 PEGINTRON/REBETOL combination trial,
the incidence of serious adverse events was 17% in the
PEGINTRON/REBETOL groups compared to 14% in the INTRON A/ REBETOL
group. The incidence of severe adverse events in the
PEGINTRON/REBETOL combination therapy trial was 23% in the INTRON
A/REBETOL group and 31-34% in the PEGINTRON/REBETOL groups. Dose
reductions due to adverse reactions occurred in 42% of patients
receiving PEGINTRON (1.5 mcg/kg)/REBETOL and in 34% of those
receiving INTRON A/REBETOL. In a study with weight-based ribavirin,
there was a higher rate of anemia among patients in the
weight-based dosing group (29%) compared to the flat-dosing group
(19%). The majority of these cases were mild and responded to dose
reductions. Serious adverse events were similar between the two
groups (12%), and discontinuations for adverse events (15% in
weight-based dosing and 14% in flat dosing) were also similar. Dose
modifications due to adverse events occurred more frequently in the
weight-based dosing group (29%) compared to the flat-dosing (23%)
group. Additional Safety Information Relapse of drug
addiction/overdose has occurred in patients on PEGINTRON therapy.
Aggressive behavior sometimes directed towards others has occurred
in patients with and without a previous psychiatric disorder during
PEGINTRON and/or INTRON A treatment and follow-up. If patients
develop psychiatric problems, including clinical depression, it is
recommended that patients be carefully monitored during treatment
and in the 6-month follow-up period. If psychiatric symptoms
persist or worsen, or suicidal ideation or aggressive behavior
towards others is identified, it is recommended that treatment with
PEGINTRON and/or INTRON A be discontinued, and the patient be
carefully followed with psychiatric intervention, as appropriate.
Cases of encephalopathy have been observed in some patients,
usually elderly, treated with higher doses of PEGINTRON and/or
INTRON A. Ischemic and hemorrhagic cerebrovascular events have been
observed in patients treated with interferon alpha therapies,
including PEGINTRON and INTRON A. Dental and periodontal disorders
have been reported in patients receiving PEGINTRON or INTRON A in
combination with REBETOL therapy. Please see important full U.S.
prescribing information and the Medication Guide for PEGINTRON at
http://www.schering-plough.com/. About Schering-Plough
Schering-Plough is an innovation-driven, science-centered global
health care company. Through its own biopharmaceutical research and
collaborations with partners, Schering-Plough creates therapies
that help save and improve lives around the world. The company
applies its research-and-development platform to human prescription
and consumer products as well as to animal health 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 http://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 IDEAL study and 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 market
forces, economic factors, product availability, patent and other
intellectual property protection, current and future branded,
generic or over-the-counter competition, the regulatory process,
and any developments following regulatory approval, 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 Part I, Item 1A. "Risk Factors" in Schering-Plough's 2007
10-K/A. Endnotes: 1 Pegasys and Copegus are registered trademarks
of Hoffmann-La Roche Inc. Please see the Pegasys and Copegus
product inserts for information on these products. 2 SVR, the
protocol specified primary efficacy endpoint, is defined as
achievement of undetectable HCV-RNA in plasma at 24 weeks after the
end of treatment. Per protocol, if a patient did not have a 24-week
post- treatment assessment, the patient's 12-week post-treatment
assessment was utilized. 3 Roche Cobas Taqman 1.0 assay; lower
limit of quantitation (LLQ) is 27 IU/mL. 4 Intention-To-Treat (ITT)
analysis includes any patient who has taken at least one dose of
any study drug. 5 Sensitivity Analysis: Patients with missing data
at follow-up week 24 are included in the analysis if treatment week
4 and treatment week 24 undetectable (HCV-RNA): PPVs at treatment
week 4 were 94 vs. 91 vs. 89 percent for the PEGINTRON 1.5 mcg arm,
PEGINTRON 1.0 mcg arm and Pegasys arm, respectively. DATASOURCE:
Schering-Plough Corporation CONTACT: Robert J. Consalvo,
+1-908-298-7409, or Investors, Alex Kelly, +1-908-298-7436, or
Joseph Romanelli, +1-908-298-7904, all for Schering-Plough
Corporation Web site: http://www.schering-plough.com/ Company News
On-Call: http://www.prnewswire.com/comp/777050.html
Copyright
