FDA Grants Priority Review for Schering-Plough's Peginterferon Alfa-2b for the Adjuvant Treatment of Patients With Stage III Melanoma.

Schering-Plough Corporation (Kenilworth, NJ) announced that the United States Food and Drug Administration (FDA) has accepted the Peg-IFN (peginterferon alfa-2b) supplemental Biologics License Application (sBLA) for review and has granted Priority Review status for the adjuvant treatment of patients with Stage III melanoma. Schering-Plough submitted its application to the agency in the fall of 2007.

The Priority Review designation is intended to expedite the review process for therapies that provide a significant improvement in the treatment of serious or life-threatening diseases. Based on this Priority Review status, the FDA reviews the application with the goal of taking action within six months of the sponsor's submission of the sBLA. The application will be discussed by the FDA Oncology Drugs Advisory Committee on March 12, 2008.

Approximately 60,000 people worldwide die each year from skin cancer caused in particular by excessive sun exposure according to the World Health Organization (WHO). According to the American Cancer Society, there will be almost 108,000 new cases of melanoma in the United States in 2007, and approximately 8,000 people will die from this disease.

Melanoma is the deadliest form of skin cancer and the primary cause of ultraviolet (UV) radiation related disease in the Americas, Europe, Australia, and New Zealand. However, when detected in its earliest stages, melanoma is highly curable.

Interferon is a protein produced naturally by white blood cells to help the immune system fight viral infections and certain cancer growths. Interferon alfa-2b has similar actions to natural interferon. Pegylated interferon alfa-2b is a longer-acting form of interferon made by attaching an inert molecule called polyethylene glycol, or PEG, to the alpha interferon molecule. This modification increases the size of the interferon molecule and results in slower elimination from the body, allowing for less frequent dosing than required for standard interferon.

Peginterferon alfa-2b is not approved for treatment of melanoma. In the United States, peginterferon alfa-2b, marketed as 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.

In the EU, peginterferon alfa-2b and ribavirin combination therapy is approved for the treatment of chronic hepatitis C who have elevated transaminases without liver decompensation and who are positive for serum HCV-RNA or anti-HCV, including naive patients with clinically stable HIV co-infection and in patients who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy. Peginterferon alfa-2b had

previously received centralized marketing authorization and is marketed as a monotherapy in cases of intolerance or contraindication to ribavirin for the treatment of adult patients with chronic hepatitis C.

In the malignant melanoma trial and other clinical studies, patients receiving peginterferon alfa-2b experienced mild-to-moderate or severe/life-threatening side effects. The most common side effects of peginterferon alfa-2b are: flu-like symptoms, including headache, fatigue, aches and pains, fevers and chills; depression, nausea, loss of appetite and diarrhea; insomnia; alopecia (hair loss); a reaction at the site of injection; changes in blood liver function tests and in blood cell counts, including leukopenia (low white blood cell count), thrombocytopenia (low platelet count) and neutropenia (low neutrophil count); thyroiditis (inflammation of the thyroid gland); and autoimmunity (production of antibodies against the body's own tissues.)

Depression and suicidal behavior, including suicidal ideation, suicidal attempts and completed suicides, have been reported in association with treatment with alfa interferons.

Important Safety Information Regarding United States Labeling for PEGINTRON Alpha interferons, including PEGINTRON and INTRON 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.

PEGINTRON is contraindicated in patients with hypersensitivity to PEGINTRON or any other component of the product, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score >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.

There are no new adverse events specific to PEGINTRON as compared to INTRON A; however, the incidence of some (eg, 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 (ie, 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 or equal to 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.

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.

Schering-Plough applies its research-and-development platform to human prescription and consumer products as well as to animal health products. In November 2007, Schering-Plough acquired Organon BioSciences, with its Organon human health and Intervet animal health businesses, marking a pivotal step in the company's ongoing transformation.

Schering-Plough Corporation

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