Schering-Plough Reports Potent Antiviral Activity With Narlaprevir (SCH 900518), an Investigational, Once-Daily Protease Inhibitor for Hepatitis C

Interim results of Phase IIa NEXT-I study presented at American Association for the Study of Liver Diseases (AASLD) Annual Meeting

BOSTON, Nov. 2 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE: SGP) today reported that interim results from an ongoing Phase IIa study of narlaprevir (SCH 900518), its investigational, once-daily protease inhibitor, demonstrated potent antiviral activity in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1. In the lead-in arms of the study, in which patients received a 4-week lead-in of PEGINTRON(R) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) followed by the addition of narlaprevir, 85-87 percent of patients achieved rapid virologic response (RVR), compared to 58-75 percent of patients in the no lead-in narlaprevir arms and no patients in the PEGINTRON and REBETOL control arm. RVR, defined in this study as undetectable virus (HCV RNA) at week 4 of narlaprevir treatment, is recognized as an important predictor for achieving sustained virologic response. These interim results from the NEXT-1 study were reported in an oral presentation at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting in Boston, Oct. 30-Nov. 3.[1]

"These interim results, while preliminary, are very encouraging, and showed that narlaprevir has potent antiviral activity in hepatitis C," said John Vierling, M.D., professor of medicine and surgery, chief of hepatology, Baylor College of Medicine, Houston, and the lead investigator of the study. "In this study, once-daily narlaprevir greatly improved viral clearance at week 4 of treatment in genotype 1 hepatitis C infection compared to the control group. We look forward to further results from this ongoing study."

Importantly, patients in the lead-in narlaprevir arms also achieved improved rates of early virologic response (EVR), defined as undetectable virus at week 12 of treatment, with 85-87 percent of patients having undetectable virus at week 12 of narlaprevir treatment compared to 17 percent of patients at week 12 in the control arm.

Narlaprevir is a next-generation oral HCV protease inhibitor that achieves once-daily dosing through the use of low-dose ritonavir as a metabolic inhibitor. The NEXT-1 study evaluates 12 weeks of narlaprevir 200 mg or 400 mg once-daily or 100 mg twice daily with low-dose ritonavir (100 mg) in combination with PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (600-1400 mg daily), followed by PEGINTRON and REBETOL alone for an additional 12 or 36 weeks (24 or 48 weeks total). The study includes two treatment arms in which patients receive a 4-week lead-in of PEGINTRON and REBETOL prior to receiving narlaprevir 200 mg or 400 mg once-daily in the above regimen. All patients in the narlaprevir arms have completed narlaprevir dosing. The control arm is PEGINTRON and REBETOL alone for 48 weeks.

In this study, the rate of adverse events in the narlaprevir arms was similar to that in the peginterferon and ribavirin control arm, except for an increase in anemia (there were no discontinuations due to anemia) and an increase in low neutrophil counts (with no clinical sequelae). The most frequently seen adverse events up through 12 weeks of treatment were fatigue, nausea, flu-like illness, headache and insomnia. No increase in skin adverse events (rash or pruritus) beyond what was seen in the peginterferon and ribavirin control was observed.

For more information about ongoing narlaprevir clinical studies, please visit www.clinicaltrials.gov.

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 re-treatment 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 on PEGINTRON

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 > 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 < 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 six months post-treatment. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for six 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 six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

Incidence of Adverse Events

Most common adverse reactions ( > 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 ( > 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 equal to or less than 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 suicide, homicidal ideation, aggressive behavior sometimes directed towards others, hallucinations, bipolar disorders, mania, encephalopathy (usually elderly treated with higher doses of PEGINTRON), hypotension, tachycardia, retinopathy including macular edema, retinal hemorrhage, cotton wool spots, papilledema, serous retinal detachment, 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, pulmonary hypertension, hepatic failure, increases in serum creatinine in patients with renal insufficiency, acute hypersensitivity (angioedema, bronchoconstriction, anaphylaxis and cutaneous eruptions), hypertriglyceridemia, and peripheral neuropathy.

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.

Please see full prescribing information at http://www.spfiles.com/pipeg-intron.pdf.

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. The company is based in Kenilworth, N.J., and its Web site is www.schering-plough.com.

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 narlaprevir, 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 Part II, Item 1A. "Risk Factors" in the Company's third quarter 2009 10-Q, filed October 29, 2009.

Endnote

[1] Vierling J, Poordad F, Lawitz E, et al. Once-Daily Narlaprevir (SCH 900518) in Combination with Peginterferon alfa-2b/Ribavirin for Treatment-Naive Patients with Genotype-1 Chronic Hepatitis C: Interim Results from the NEXT-1 Study. American Association for the Study of Liver Diseases (AASLD) Annual Meeting; Oct. 30-Nov. 3, Boston, MA, USA; oral presentation, Late-Breaker Abstract No. LB4.

SOURCE Schering-Plough Corporation

Media: Robert Consalvo, +1-908-298-7409 office, +1-908-295-0928 mobile; Investors: Janet Barth, +1-908-298-7436 or Joe Romanelli, +1-908-298-7436, all for Schering-Plough Corporation

Posted: November 2009

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