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Top-Line Results of Boceprevir Phase II Study Showed High Rate of Sustained Response (SVR) in Genotype 1 Treatment-Naive Hepatitis C Patients
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74 percent of patients achieved SVR 12 with 48-week boceprevir-based combination therapy
High SVR 24 rate also reported for 28-week boceprevir arm
KENILWORTH, N.J., Aug. 4 /PRNewswire-FirstCall/ -- Schering-Plough
Corporation (NYSE: SGP) today reported top-line results from a planned
interim analysis of a Phase II study of boceprevir, its investigational
oral hepatitis C protease inhibitor. The analysis showed a high rate of
sustained virologic response (SVR) in patients receiving boceprevir-based
combination therapy in this study of 595 treatment-naive patients with
chronic hepatitis C virus (HCV) genotype 1.
In a 48-week treatment regimen, the SVR rate at 12 weeks after the end
of treatment (SVR 12) was 74 percent (ITT) in patients who received 4 weeks
of PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP)
prior to the addition of boceprevir (800 mg TID) (P/R lead-in), compared to
38 percent for patients in the control group receiving 48-weeks of
PEGINTRON and REBETOL alone.(1-3)
Patients in the study who received 48-weeks of boceprevir in
combination with PEGINTRON and REBETOL from the beginning of treatment (no
P/R lead-in) achieved 66 percent SVR 12.
In the two 28-week boceprevir arms of the study, SVR at 24 weeks after
the end of treatment (SVR 24) was 56 percent and 55 percent for patients in
the lead-in and no lead-in arms, respectively.
Importantly, for patients who received the PEGINTRON and REBETOL lead
in and had rapid virologic response (RVR), defined as undetectable virus
(HCV-RNA) in plasma after 4 weeks of boceprevir treatment, SVR (ITT) was 82
percent in the 28-week regimen and 92 percent in the 48 week regimen.
"These top-line results with boceprevir are very exciting, especially
given that genotype 1 is the most common and hardest to treat form of
hepatitis C," said Paul Kwo, M.D., associate professor of medicine and
medical director, liver transplantation, Department of Medicine, Division
of Gastroenterology/Hepatology, Indiana University School of Medicine,
Indianapolis, and lead investigator of the study. "Boceprevir was well
tolerated by patients in this study, including those who received 48 weeks
of boceprevir in the longer duration treatment arms."
Safety data from the study showed that the most common adverse events
reported in the boceprevir arms were fatigue, anemia, nausea and headache.
No increase in skin adverse events (rash or pruritus) beyond what was seen
in the PEGINTRON and REBETOL control arm was observed. Treatment
discontinuations due to adverse events were between 9 and 19 percent for
patients in the boceprevir arms, compared to 8 percent for the control arm.
In the study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor
Therapy-1), boceprevir (800 mg TID) was evaluated in three treatment
regimens: 4 weeks of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL
(800-1400 mg daily based on patient weight) therapy followed by the
addition of boceprevir to the combination for 24 or 44 weeks (totaling 28
or 48 weeks of treatment); boceprevir in combination with PEGINTRON and
REBETOL at the doses described above for 28 or 48 weeks; and boceprevir in
combination with PEGINTRON and low-dose REBETOL (400-1000 mg daily) for 48
weeks, compared to a control of PEGINTRON (1.5 mcg/kg once weekly) and
REBETOL (800-1400 mg daily based on patient weight) alone for 48 weeks (an
approved treatment regimen). The primary endpoint of the study is SVR after
24 weeks of follow up (SVR 24). This is an ongoing study and SVR 24 rates
are not yet available for patients in the 48-week boceprevir arms or the
48-week control arm of the study.
P/R Control equals PEGINTRON and REBETOL alone for 48 weeks
* SVR 12 for 48 week arms; SVR 24 for 28 week arms(1-3)
"These top-line results further validate this novel treatment paradigm
and the design of our pivotal Phase III studies of boceprevir, one in
treatment-naive patients and one in patients who had failed prior
treatment, in which all patients will receive 4 weeks of PEGINTRON and
REBETOL prior to the addition of boceprevir," said Thomas P. Koestler,
Ph.D., executive vice president and president of Schering-Plough Research
Institute. "Additionally, this strategy has the potential to reduce the
likelihood of the development of resistance by identifying patients who are
responders to interferon and ribavirin prior to their receiving a protease
inhibitor."
The rationale for this novel treatment regimen is based on the fact
that both PEGINTRON and REBETOL reach steady-state concentrations by week
4, so patients have the protease inhibitor added at a time when the
backbone drug levels have been optimized. In addition, the patient's immune
system will have been activated and primed by PEGINTRON at the time that
boceprevir is added to the regimen. This approach may minimize the period
of time when there is a "functional monotherapy" with a direct antiviral,
potentially reducing the likelihood for the development of resistance.
The HCV SPRINT-1 study was conducted at sites across the United States,
Canada and Europe. Overall, 77 percent of the 595 patients in the study
were enrolled in the United States. African-Americans represent 16 percent
of the patients enrolled and 7 percent of patients in the study are
cirrhotic.
Results from the HCV SPRINT-1 study will be submitted for presentation
at a major medical conference later this year.
About Boceprevir Phase III Studies
The boceprevir Phase III studies are expected to begin enrolling
patients this summer. For more information about the Phase III study of
boceprevir in treatment-naive patients, known as HCV SPRINT-2, and the
Phase III study in patients who failed prior treatment, known as HCV
RESPOND-2, please visit http://www.clinicaltrials.gov, search term boceprevir.
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.
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 company's clinical development plans and the potential for
boceprevir. 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 II, Item 1A, "Risk Factors" in company's
second quarter 2008 10-Q.
Endnotes:
(1) SVR, the protocol specified primary efficacy endpoint, is defined
as achievement of undetectable HCV-RNA at 24 weeks after the end of
treatment. Per protocol, if a patient does not have a 24-week
post-treatment assessment, the patient's 12-week post-treatment assessment
will be utilized.
(2) SVR 12 is defined as undetectable HCV-RNA in plasma at 12 weeks
after the end of treatment. The protocol specified primary efficacy
endpoint of the HCV SPRINT-1 study is SVR as defined above.
(3) Intention-To-Treat (ITT) analysis includes any patient who has
taken at least one dose of any study drug.
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