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Schering-Plough Reports FDA Grants Fast Track Designation to Oral HCV Protease
Inhibitor SCH 503034
KENILWORTH, NJ -- January 31, 2006 -- Schering-Plough yesterday reported that
the U.S. Food and Drug Administration (FDA) has granted Fast Track designation
to its investigational oral hepatitis C protease inhibitor (SCH 503034),
currently in phase 2 clinical development for the treatment of chronic hepatitis
C virus (HCV) infection.
The FDA granted Fast Track designation for the following reasons:
The proposed first indication for SCH 503034 is for treatment of HCV in patients
with HCV genotype 1 virus who have not responded to combination therapy with
pegylated interferon and ribavirin, the current standard of care, thus
representing an unmet medical need.
SCH 503034 is an orally active inhibitor of the hepatitis C virus serine
protease that inhibits HCV replication. This mechanism is distinct from those of
current therapies, thus SCH 503034 represents a novel class of HCV inhibitor.
Fast Track designation allows FDA to expedite review of drugs and biologics for
serious or life-threatening conditions and which demonstrate the potential to
address unmet medical needs. An important feature of Fast Track designation is
that it emphasizes the critical nature of close, early communication between the
FDA and the sponsor company to improve the efficiency of product development.
Status of SCH 503034 Clinical Development
SCH 503034 has demonstrated potent antiviral activity and was well- tolerated,
both as monotherapy(1) and in combination with PEG-Intron(R) (peginterferon
alfa-2b),(2) in Phase I clinical studies in patients chronically infected with
HCV genotype 1 who were nonresponders to previous therapy, including
peginterferon and ribavirin combination therapy. Results of Phase I clinical
studies with SCH 503034, including in healthy subjects,(3) were presented at the
56th Annual Meeting of the American Association for the Study of Liver Diseases
(AASLD) in November 2005. HCV genotype 1 is the most common form of the virus
worldwide and is considered the most difficult to treat successfully.
Phase 2 Study Ongoing
Based on the results of the Phase I clinical program and extensive preclinical
safety and pharmacology studies, Schering-Plough is conducting a large,
randomized Phase II dose-finding study involving 300 patients worldwide.
This study evaluates the safety and efficacy of SCH 503034 in combination with
PEG-Intron, with and without added ribavirin, for 24 or 48 weeks in patients
with chronic HCV genotype 1 who were nonresponders to previous peginterferon and
ribavirin combination therapy.
The primary objective of this study is to determine the safe and effective dose
range of SCH 503034 in combination with PEG-Intron in this patient population. A
secondary objective is to explore whether or not ribavirin provides an
additional benefit when combined with SCH 503034 plus PEG-Intron.
Additionally, an extensive preclinical and Phase I clinical development program
is ongoing to support the potential broad utility of SCH 503034 in treating
chronic hepatitis C.
About PEG-Intron
PEG-Intron is approved in the United States as monotherapy and for use in
combination therapy with Rebetol(R) (ribavirin, USP) for the treatment of
chronic hepatitis C in patients with compensated liver disease who are at least
18 years of age, and is not approved for treatment of patients who are
nonresponders to previous therapy.
Important Safety Information Regarding U.S. Labeling for PEG-Intron and Rebetol
Warning
Alpha interferons, including PEG-Intron, 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 PEG-Intron therapy.
Ribavirin causes hemolytic anemia. Anemia associated with Rebetol therapy may
exacerbate cardiac disease that has led to fatal and nonfatal myocardial
infarctions. Patients with a history of significant or unstable cardiac disease
should not be treated with Rebetol. It is advised that complete blood counts
(CBC) be obtained at baseline and at weeks 2 and 4 of therapy or more frequently
if clinically indicated.
Rebetol and combination Rebetol/PEG-Intron therapy must not be used by women, or
male partners of women, who are or may become pregnant during therapy and during
the 6 months after stopping therapy. Rebetol and combination Rebetol/PEG-Intron
therapy should not be initiated until a report of a negative pregnancy test has
been obtained immediately prior to initiation of therapy. Women of childbearing
potential and men must use effective contraception (at least two reliable forms)
during treatment and during the 6- month post-treatment follow-up period.
Significant teratogenic and/or embryocidal effects have been demonstrated for
ribavirin in all animal species in which adequate studies have been conducted.
These effects occurred at doses as low as one twentieth of the recommended human
dose of Rebetol. If pregnancy occurs in a patient or partner of a patient during
treatment or during the 6 months after treatment stops, physicians are
encouraged to report such cases by calling (800) 727-7064.
PEG-Intron
There are no new adverse events specific to PEG-Intron as compared to INTRON(R)
A (interferon alfa-2b, recombinant) for Injection, however, the incidence of
some (e.g., injection site reactions, fever, rigors, nausea) were higher. The
most common adverse events associated with PEG-Intron 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 PEG-Intron. Alopecia
(thinning of the hair) is also often associated with alpha interferons including
PEG-Intron.
Psychiatric adverse events, which include insomnia, were common (57%) with
PEG-Intron, 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
PEG-Intron.
PEG-Intron/Rebetol is contraindicated in patients with autoimmune hepatitis,
decompensated liver disease, and in patients with hemoglobinopathies (e.g.,
thalassemia major, sickle-cell anemia).
The following serious or clinically significant adverse events have been
reported at a frequency less than or equal to 1% with PEG-Intron 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 PEG-Intron/Rebetol combination trial the incidence of serious adverse
events was 17% in the PEG-Intron/Rebetol groups compared to 14% in the INTRON
A/Rebetol group. The incidence of severe adverse events in the PEG-
INTRON/Rebetol combination therapy trial was 23% in the INTRON A/Rebetol group
and 31-34% in the PEG-Intron/Rebetol groups. Dose reductions due to adverse
reactions occurred in 42% of patients receiving PEG-Intron (1.5 mcg/kg)/ Rebetol
and in 34% of those receiving INTRON A/Rebetol.
Rebetol should not be used in patients with creatinine clearance less than 50
mL/min.
REFERENCES:
1. Zeuzem S et al. Antiviral Activity of SCH 503034, a HCV Protease Inhibitor,
Administered as Monotherapy in Hepatitis C Genotype-1 (HCV-1) Patients
Refractory to Pegylated Interferon (Peg-IFN-a), Abstract 67484, AASLD 2005.
2. Zeuzem S et al. Combination therapy with the HCV Protease Inhibitor, SCH
503034, Plus PEG-Intron in Hepatitis C Genotype-1 PEG-Intron Nonresponders:
Phase Ib Results, Abstract 67627, AASLD 2005.
3. Zhang J et al. Single Dose Pharmacokinetics of a Novel Hepatitis C Protease
Inhibitor, SCH 503034, in an Oral Capsule Formulation, Abstract 66787, AASLD
2005.
SOURCE: Schering-Plough
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