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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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