Healthcare Industry News:  pegylated interferon 

Biopharmaceuticals

 News Release - May 23, 2006

Schering-Plough Initiates PEG-INTRON 'PROTECT' Study in Liver Transplant Patients with Recurrent Hepatitis C

KENILWORTH, N.J., May 23 (HSMN NewsFeed) -- Schering-Plough today announced the initiation of a large multicenter clinical trial in the United States to evaluate the safety and efficacy of PEG-INTRONŽ (peginterferon alfa-2b) and REBETOLŽ (ribavirin, USP) combination therapy in liver transplant recipients with recurrent hepatitis C virus (HCV) infection. Known as the PROTECT study, the trial is targeted to enroll 125 HCV patients at approximately 28 liver transplant centers nationwide.

Hepatitis C is currently the leading indication for liver transplantation in the United States,(1) and more than 17,000 Americans are awaiting liver transplants for all diagnoses.(2) Long-term mortality rates are higher in liver transplant recipients with HCV compared to those without HCV,(3,4) and the majority of patients who receive liver transplants for hepatitis C disease will be reinfected after transplant, most likely from virus sanctuaries in the body.(5,6) Without treatment, these patients will not eradicate their virus and are prone to faster progression of their hepatitis C disease.

To date, only a few small studies have been conducted in this patient population using pegylated interferon and ribavirin, the current standard of care in treating HCV, and results of these small studies have varied widely. (7-9) It is unclear what virologic response rates can be expected in the post-liver transplant setting.

"A large multicenter study in liver transplant recipients with recurrent HCV is needed to better understand how to maximize treatment outcomes for these patients," said Fred Gordon, M.D., Division of Gastroenterology and Hepatology, Lahey Clinic, Burlington, Mass., and lead investigator for the PROTECT study. "Given the potential for diminished long-term survival and the shortage of available resources for liver transplant patients with HCV recurrence, viral eradication is an important goal of treatment and would benefit both patients and society."

Study Design

PROTECT is single-arm, multicenter, open-label Phase IV study evaluating the efficacy and safety of PEG-INTRON (1.5 mcg/kg once weekly) and REBETOL (400-1,200 mg daily) in patients after orthotopic liver transplantation with chronic hepatitis C recurrence. All patients will be enrolled within the first 12 months of this 72-week study, and will be treated with up to 48 weeks of PEG-INTRON and REBETOL therapy.

Sustained virologic response (SVR),(10) the standard measure of successful response to HCV therapy, will be determined at 24 weeks following treatment. Written informed consent will be obtained and all other regulatory requirements adhered to for all patients participating in the study.

"The PROTECT study continues Schering-Plough's research strategy to conduct and support clinical studies with PEG-INTRON therapy to explore new approaches to treatment, particularly for hepatitis patients with difficult-to-treat forms of the disease," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "These research efforts underscore our long-term commitment to this therapeutic area and the hepatitis community."

About PEG-INTRON

PEG-INTRON is approved in the United States as monotherapy and for use in combination therapy with REBETOL for the treatment of chronic hepatitis C in previously untreated patients with compensated liver disease who are at least 18 years of age. The recommended dose in the United States for combination therapy is PEG-INTRON 1.5 mcg/kg once weekly plus REBETOL 800 mg daily for up to 48 weeks.

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 INTRONŽ 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.

Schering-Plough is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs.

Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its more than 32,000 people around the world. The company is based in Kenilworth, N.J., and its Web site is http://www.schering-plough.com.

SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking statements" within the meaning of the Securities Litigation Reform Act of 1995, including statements relating to PEG-INTRON and REBETOL and the company's strategy. 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 Item 1A. Risk Factors in the Company's 2005 10-K.

References

1. U.S. Centers for Disease Control and Prevention; http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm

2. U.S. Organ Procurement and Transplantation Network (OPTN) data as of May 2006; www.OPTN.org

3. Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after liver transplantation. Gastroenterol 2002;122(4):889-96.

4. Mazzaferro V., Regalia E., Pulvirenti A., et al. Prophylaxis against HCV recurrence after liver transplantation; effect of interferon and ribavirin combination. Transpl Proc. 1997; 29:519-521.

5. Wright TL, Donegan E, Hsu HH, et al. Recurrent and acquired hepatitis C viral infection in liver transplant recipients. Gastroenterol 1992;103(1):317-322.

6. Gane EJ, Portmann BC, Naoumov NV, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Eng J Med 1996;334:815-20.

7. Ghalib R, Levine C, McClelland T et al. Factors Predictive of 24 Week Viral Response to PEG IFN alfa-2b plus Ribavirin in Subjects with Recurrent Hepatitis C after Liver Transplantation. Abstract. AASLD Boston, 2004

8. Rodriguez-Luna H, Khatib A, Sharma A, et al. Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha 2b and ribavirin: an open-label series. Transplantation 2004 Jan 27;77(2):190-4.

9. Gordon FD, Morin D, Davis C, et al. High sustained virologic response (SVR) in HCV treatment with Peginterferon-alpha 2B (PEG) and Ribavirin (RBV) after Liver Transplantation (LT). AM J Transpl 2005; 5 (Suppl 11): 181.

10. Sustained Virologic Response (SVR) is defined as undetectable virus (HCV RNA) 24 weeks after the end of treatment.


Source: Schering-Plough

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