Schering-Plough Corporation
(NYSE: SGP) reported that results from a planned interim analysis of
an ongoing Phase II study of boceprevir, its investigational oral hepatitis
C protease inhibitor, in 595 treatment-naive patients with chronic
hepatitis C virus (HCV) genotype 1 were presented at the 43rd Annual
Meeting of the European Association for the Study of the Liver (EASL). The
ongoing study evaluates boceprevir in 28-week and 48-week treatment
regimens.
In a 28-week treatment regimen in which patients received 4 weeks of
PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) prior
to the addition of boceprevir (800 mg TID), the rate of sustained
virological response at 12 weeks after the end of treatment (SVR 12) was 57
percent (ITT).(1-3) Importantly, this treatment regimen provided an
indication of early predictability of response, with patients who had
undetectable virus (HCV-RNA) in plasma after 4 weeks of boceprevir
treatment achieving an SVR 12 rate of 86 percent.
"These interim results are very encouraging, especially given the
response seen with a shorter course of therapy in a difficult-to-treat
patient population," said principal investigator 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, who presented the data.
"Boceprevir has been well tolerated by patients in this study, including in
the longer duration treatment arms, and we look forward to further results
from this ongoing study."
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.
In the ongoing study, known as HCV SPRINT-1 (HCV Serine Protease
Inhibitor Therapy-1), boceprevir (800 mg TID) is being 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 (triple
combination); 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 sustained virologic response after 24
weeks of follow up.
During a late-breaker oral presentation at EASL, Dr. Kwo presented
interim results for the two 28-week boceprevir arms of the study. For
patients receiving 4 weeks of PEGINTRON and REBETOL therapy prior to the
addition of boceprevir, SVR 12 was 57 percent (59/103), compared to 55
percent (59/107) for patients in the boceprevir triple combination arm. For
patients in these two boceprevir arms who had undetectable virus (HCV-RNA)
after 4 weeks of boceprevir treatment (RVR), the SVR 12 rates were 86
percent (53/62) and 74 percent (31/42), respectively. SVR 12 rates are not
yet available for patients in the 48-week boceprevir arms or the 48-week
control arm, as treatment of these patients is ongoing.
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 11 and 15 percent for
patients in the boceprevir arms, compared to 8 percent for the control arm.
Early response rates at week 4 (RVR) and week 12 (EVR) of boceprevir
treatment were increased for patients who received 4 weeks of PEGINTRON and
REBETOL therapy prior to the administration of boceprevir (62 and 79
percent, respectively), compared to patients in the triple combination (38
and 69 percent) and control (8 and 34 percent) arms, respectively. In the
28-week boceprevir arms, these patients also had a reduction in viral
breakthrough compared to patients in the triple combination arm (4 vs. 7
percent, respectively).
"The results seen with this novel treatment paradigm will influence the
design of our future clinical studies, as we plan to consider RVR at week 4
of boceprevir treatment as the criterion for determining which patients can
receive a shorter course of boceprevir therapy and which patients should
continue treatment for 48 weeks," said Robert J. Spiegel, M.D., chief
medical officer and senior vice president, 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 is currently ongoing at sites across the United
States, Canada and Europe. Final results from the study are anticipated to
be available in early 2009, and will be submitted for presentation at an
appropriate medical meeting.
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.
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 schering-plough.
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 schering-plough.
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 I, Item 1A. "Risk Factors" in
Schering-Plough's 2007 10-K/A.
References
(1) 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 study is SVR 24, defined as undetectable HCV-RNA in plasma at 24
weeks after the end of treatment.
(2) Intention-To-Treat (ITT) analysis includes any patient who has taken at
least one dose of any study drug.
(3) Roche Cobas Taqman 1.0 assay; lower limit of detect
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