TREATMENT-NAIVE patients
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Final Results Of Boceprevir Phase II HCV SPRINT-1 Study Showed Significantly
Higher SVR Rates Compared To Standard Of Care
Article Date: 24 Apr 2009 - 4:00 PDT

Schering-Plough Corporation (NYSE: SGP) reported that final results of the
HCV SPRINT-1 study showed boceprevir, its investigational oral hepatitis C
protease inhibitor, in combination with peginterferon alfa-2b and ribavirin,
significantly increased sustained virologic response (SVR)(1) rates with 28
and 48 weeks of therapy compared to current standard of care, peginterferon
and ribavirin for 48 weeks (control group). The results from this Phase II
study in 595 treatment-naive patients with chronic hepatitis C virus (HCV)
genotype 1 were presented at the 44th European Association for the Study of
the Liver (EASL) 2009 Annual Meeting.(2) Genotype 1 is the most common and
hardest to treat form of hepatitis C.

In Part I of the study, a 48-week boceprevir regimen achieved a 75 percent
SVR rate (n=77/103) in patients who received 4 weeks of PEGINTRON(TM)
(peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) (P/R) followed by
the addition of boceprevir (800 mg TID) for 44 weeks (boceprevir P/R lead-in
regimen). This represents a near doubling of the 38 percent SVR rate
(n=39/104) for patients in the control group (p<0.0001). In a 28-week
boceprevir P/R lead-in regimen 56 percent of patients (n=58/103) achieved
SVR (p=0.005).(3)

Importantly, the likelihood (predictability) of attaining SVR was greater
for patients who received the boceprevir P/R lead-in regimens compared to
the no lead-in arms. Of patients in the boceprevir P/R lead-in arms who
achieved a rapid virologic response (RVR), 94 percent in the 48-week regimen
and 82 percent in the 28-week regimen achieved SVR. RVR is defined as
undetectable virus (HCV RNA) in plasma at 4 weeks after the addition of
boceprevir. In the lead-in arms, 64 percent of patients achieved RVR. Fewer
patients in the lead-in arms discontinued treatment due to viral
breakthrough.

"These results are very exciting and provide important insights to help
further define response guided therapy using a P/R lead-in boceprevir
regimen with peginterferon and ribavirin backbone treatment," 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. "Building on these
results, the boceprevir Phase III clinical program individualizes treatment
based on response, utilizing RVR criteria at week 4 of boceprevir treatment
to determine overall duration of therapy. Based on the RVR rate seen in this
Phase II study, we are hopeful that the majority of patients can be treated
with 28 weeks of therapy."

Part II of the HCV SPRINT-1 study explored a low-dose ribavirin strategy in
which boceprevir was given in combination with PEGINTRON and low-dose
REBETOL for 48 weeks. SVR for the low-dose REBETOL arm was 36 percent
(n=21/59) compared to 50 percent for a 48-week control arm with PEGINTRON
and standard-dose REBETOL plus boceprevir (n=8/16). In contrast to the
results seen in Part I, the low-dose REBETOL regimen was associated with
increased viral breakthrough during treatment, higher relapse rates after
the end of treatment and lower SVR, strongly indicating that standard-dose
ribavirin is required to optimize response.

Another key finding of the HCV SPRINT-1 study is that treatment-emergent
anemia appeared to be associated with higher SVR, with anemic patients
(hemoglobin decreasing to less than 10 g/dL) having higher SVR rates than
those without anemia (hemoglobin did not decrease to less than 10 g/dL).
Anemia is a known adverse event with combination therapy for hepatitis C and
this association with higher SVR has been seen in other clinical studies
with peginterferon and ribavirin, including the IDEAL study.(4) Boceprevir
is associated with about a 1 g/dL incremental decrease in hemoglobin. In the
HCV SPRINT-1 study, anemia occurred in approximately half of the patients in
the boceprevir arms and over a third of patients in the control arm.
Erythropoietin (EPO) supplementation was allowed in the study at the
discretion of the investigator and was used by 26 percent of patients in the
control arm and 39-51 percent of patients in the boceprevir arms with
standard-dose REBETOL.

Safety data from the study showed that the most common adverse events
reported in the boceprevir arms were fatigue, anemia, nausea and headache.
The incidence of skin adverse events (rash or pruritus) observed in the
boceprevir arms was similar to that seen in the PEGINTRON and REBETOL
control arm.

Treatment discontinuations due to adverse events in Part I of the study were
between 9 and 19 percent for patients in the boceprevir arms, compared to 8
percent for the control arm. Treatment discontinuations for boceprevir
patients due to viral breakthrough were fewer in the 28- and 48-week lead-in
arms (4 and 5 percent, respectively) compared to the no lead-in arms (7 and
12 percent, respectively).

SCH 900518 (Next-Generation HCV Protease Inhibitor) Data at EASL

Researchers at EASL also presented early phase clinical data for SCH 900518,
Schering-Plough's investigational next-generation HCV protease inhibitor.(5)
This proof-of-concept study explored the safety and antiviral activity of
two different dosing regimens for SCH 900518 administered as monotherapy and
in combination therapy with PEGINTRON with or without ritonavir in
treatment-naive and treatment-experienced patients with HCV genotype 1. In
this study, low doses of ritonavir were used for metabolic inhibition to
enhance the levels of SCH 900518 within the body and reduce the frequency of
SCH 900518 dosing (BID vs. TID).

In the study, SCH 900518 administered as monotherapy exhibited potent
antiviral activity, achieving 4.0-4.5 log10 decreases in viral load (HCV
RNA) from baseline at day 8. SCH 900518 was well tolerated, with no drug
related serious adverse events. Pharmacokinetic and pharmacodynamic modeling
from this study was used to design the ongoing Phase IIa dose-finding study
of SCH 900518 with ritonavir in combination with PEGINTRON and REBETOL. This
study, known as NEXT-1, explores SCH 900518 in 200 mg, 400 mg or 600 mg once
daily (QD) doses with low-dose ritonavir (100 mg) in combination with
PEGINTRON and REBETOL (with and without a 4-week P/R lead-in period) in
treatment-naive patients with HCV genotype 1.

About the HCV SPRINT-1 Study

In this Phase II 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, in Part II of the study,
boceprevir in combination with PEGINTRON and low-dose REBETOL (400-1000 mg
daily based on patient weight) for 48 weeks. In Part I of the study, the
boceprevir regimens were 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). In Part II of the study, boceprevir
in combination with PEGINTRON and low-dose REBETOL for 48 weeks was compared
to a contemporaneous control of PEGINTRON, full-dose REBETOL and boceprevir
for 48 weeks. The primary endpoint of the study was SVR after 24 weeks of
follow up. In the study, the 28-week and 48-week boceprevir no lead-in arms
had SVR rates of 54 percent (n=58/107) and 67 percent (n=69/103),
respectively.

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 represented 16 percent of
the patients enrolled and 7 percent of the patients in the study were
cirrhotic.

Rationale for Lead-In Regimen

The use of the P/R lead-in prior to the addition of boceprevir was shown in
the HCV SPRINT-1 study to reduce the incidence of viral breakthrough
regardless of treatment duration. The rationale for the lead-in treatment
regimen is based on the fact that both PEGINTRON and REBETOL reach
steady-state concentrations by week 4, therefore patients have the protease
inhibitor added at a time when the backbone drug levels have been optimized
and viral load (HCV RNA) has been reduced. 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 agent,
potentially reducing the likelihood for the development of resistance.

About Ongoing Boceprevir Phase III Registration Studies

Patient enrollment has been completed in two ongoing randomized,
double-blind, placebo-controlled registration studies evaluating boceprevir
in combination with PEGINTRON and REBETOL compared to standard of care with
PEGINTRON and REBETOL alone. More than 1,500 patients were enrolled in these
studies at U.S. and international sites.

The HCV SPRINT-2 study evaluates the efficacy of 28- and 48-week lead-in
regimens of boceprevir (800 mg TID) in combination with PEGINTRON (1.5
mcg/kg/week) and REBETOL (600-1400 mg/day) compared to a control of
PEGINTRON and REBETOL alone for 48 weeks in treatment-naive adult patients
with chronic HCV genotype 1. The study enrolled a total of 1,099 patients,
including 158 African-American/Black patients.

The HCV RESPOND-2 study evaluates 36- and 48-week lead-in regimens of
boceprevir in combination with PEGINTRON and REBETOL at the same doses as
described above compared to a control of PEGINTRON and REBETOL alone for 48
weeks in adult patients with chronic HCV genotype 1 who failed prior
treatment (relapsers and nonresponders) with peginterferon and ribavirin
combination therapy. The study enrolled a total of 404 patients.

In both registration studies, RVR criteria at 4 weeks of boceprevir
treatment (treatment week 8) is used to determine which boceprevir patients
can stop all treatment at 28 weeks (HCV SPRINT-2) or 36 weeks (HCV
RESPOND-2).

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

PEGINTRON is indicated for use in combination with REBETOL (ribavirin) for
the treatment of chronic hepatitis C in patients 3 years of age and older
with compensated liver disease.

The following points should be considered when initiating therapy with
PEGINTRON in combination with REBETOL: (1) These indications are based on
achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and
maintaining a Sustained Virologic Response (SVR) 24 weeks after the last
dose. (2) Patients with the following characteristics are less likely to
benefit from retreatment after failing a course of therapy: previous
nonresponse, previous pegylated interferon treatment, significant bridging
fibrosis or cirrhosis, and genotype 1 infection. (3) No safety and efficacy
data are available for treatment of longer than one year.

PEGINTRON is also indicated for use alone for the treatment of chronic
hepatitis C in patients with compensated liver disease previously untreated
with interferon alpha and who are at least 18 years of age.

The following points should be considered when initiating therapy with
PEGINTRON alone: Combination therapy with REBETOL is preferred over
PEGINTRON monotherapy unless there are contraindications to, or significant
intolerance of, REBETOL. Combination therapy provides substantially better
response rates than monotherapy.

Important Safety Information Regarding U.S. Labeling for PEGINTRON and
REBETOL

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

Alpha interferons, including PEGINTRON, 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 therapy.

Use with Ribavirin: Ribavirin may cause birth defects and 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 known hypersensitivity
reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis,
Stevens Johnson syndrome and toxic epidermal necrolysis to interferon alpha
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. PEGINTRON/REBETOL
combination therapy is additionally contraindicated in women who are
pregnant or may become pregnant (see Boxed Warning and Pregnancy section),
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 per min.

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. If this drug is used during pregnancy or if a patient becomes
pregnant, the patient should be apprised of the potential hazard to a fetus.
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

Most common adverse reactions (more than 40%) in adult patients receiving
either PEGINTRON or PEGINTRON/REBETOL are injection site
inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea,
myalgia, and anxiety/emotional lability/irritability. Most common adverse
reactions (more than 25%) in pediatric patients receiving PEGINTRON/REBETOL
are pyrexia, headache, neutropenia, fatigue, anorexia, injection site
erythema and vomiting.

In a study with PEGINTRON/REBETOL (weight-based) combination therapy in
adult patients, anemia with weight-based dosing was 29%; however, the
majority of these cases were mild and responded to dose reductions. The
incidence of serious adverse reactions reported for the weight-based REBETOL
group was 12%. In many but not all cases, adverse reactions resolved after
dose reduction or discontinuation of therapy. Some patients experienced
ongoing or new serious adverse reactions during the 6-month follow-up
period. Discontinuations for adverse events were 15% and were related to
known interferon effects of psychiatric, systemic (e.g., fatigue, headache),
or gastrointestinal adverse reactions. Dose modifications due to adverse
reactions occurred in 29% of patients.

Most common adverse reactions with PEGINTRON/REBETOL (weight-based)
combination therapy were psychiatric which occurred among 68-69% of
patients. These psychiatric adverse reactions included most commonly
depression, irritability, and insomnia, each reported by approximately
30-40% of subjects in all treatment groups. Suicidal behavior (ideation,
attempts and suicides) occurred in 2% of all patients during treatment or
during follow-up after treatment cessation. PEGINTRON induced fatigue or
headache in approximately two-thirds of patients, with fever or rigors in
approximately half of the patients. The severity of some of these systemic
symptoms (e.g., fever and headache) tends to decrease as treatment
continues. There was a 23-24% incidence overall for injection site reactions
or inflammation.

Individual serious adverse reactions occurred at a frequency less than or
equal to 1% and included suicide attempt, suicidal ideation, severe
depression; psychosis, aggressive reaction, relapse of drug
addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy,
myocardial infarction, angina, pericardial effusion, retinal ischemia,
retinal artery or vein thrombosis, blindness, decreased visual acuity, optic
neuritis, transient ischemic attack, supraventricular arrhythmias, loss of
consciousness; neutropenia, infection (sepsis, pneumonia, abscess,
cellulitis); emphysema, bronchiolitis obliterans, pleural effusion,
gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and
hypothyroidism, autoimmune thrombocytopenia with or without purpura,
rheumatoid arthritis, interstitial nephritis, lupus-like syndrome,
sarcoidosis, aggravated psoriasis, urticaria, injection site necrosis,
vasculitis and phototoxicity.

Additional serious adverse events included hallucinations. bipolar disorder,
mania, encephalopathy (usually elderly treated with higher doses of
PEGINTRON), hypotension, tachycardia, retinopathy including macular edema,
retinal hemorrhage, cotton wool spots, papilledema, ischemic and hemorrhagic
cerebrovascular events, bone marrow toxicity (cytopenia and very rarely
aplastic anemia), thyroiditis, dental and periodontal disorders,
hemorrhagic/ischemic colitis, dyspnea, pulmonary infiltrates, pneumonia,
interstitial pneumonitis, hepatic failure, increases in serum creatinine in
patients with renal insufficiency, acute hypersensitivity (angioedema,
bronchoconstriction, anaphylaxis and cutaneous eruptions) and
hypertriglyceridemia.

During the course of therapy lasting up to 48 weeks in patients ages 3
through 17 years receiving PEGINTRON/REBETOL combination therapy, weight
loss and growth inhibition were common.

Patients receiving PEGINTRON and REBETOL as retreatment after failing a
previous interferon combination regimen reported adverse reactions similar
to those previously associated with this regimen during clinical trials of
treatment-naive patients.

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, animal health and consumer health care 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.

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 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 uncertainties in the
regulatory process, 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 Item
1A "Risk Factors" in Schering-Plough's 2008 10-K, filed Feb. 27, 2009.

References

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. Kwo P, Lawitz E, McCone J, et al. HCV SPRINT-1 Final Results: SVR 24 from
a Phase 2 study of Boceprevir Plus PegIntron (Peginterferon
alfa-2b)/Ribavirin in Treatment-Naive Subjects with Genotype 1 Chronic
Hepatitis C. 44th European Association for the Study of the Liver (EASL)
2009 Annual Meeting; April 22-26, Copenhagen, Denmark; oral presentation,
Abstract No. 4.

3. Intention-To-Treat (ITT) analysis - includes any patient who has taken at
least one dose of any study drug.

4. Sulkowski M, Shiffman M, Afdhal N, et al. Hemoglobin decline is
associated with SVR among HCV genotype 1 infected persons treated with
peginterferon (PEG)/ribavirin (RBV): Analysis from the IDEAL Study. 44th
European Association for the Study of the Liver (EASL) 2009 Annual Meeting;
April 22-26, Copenhagen, Denmark; oral presentation, Abstract No. 126.

5. Reesink HW, Bergmann JF, de Bruijne J, et al. Safety and Antiviral
Activity of SCH 900518 Administered as Monotherapy and in Combination with
Peginterferon Alfa-2b to Naive and Treatment-Experienced HCV Infected
Patients. 44th European Association for the Study of the Liver (EASL) 2009
Annual Meeting; April 22-26, Copenhagen, Denmark; oral presentation,
Abstract No. 86.

Source: Schering-Plough Corporation