Final Results of Boceprevir Phase II HCV SPRINT-1 Study

Final Results of Boceprevir Phase II HCV SPRINT-1 Study Showed Significantly Higher SVR Rates Compared to Standard of Care in Treatment-Naive Genotype 1 Hepatitis C Patients

48-week investigational regimen yielded nearly double SVR rate compared to standard of care

Update on next-generation HCV protease inhibitor SCH 900518 presented at EASL annual meeting

COPENHAGEN, Denmark, April 23 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE: SGP) today reported that final results of the HCV SPRINT-1 study showed boceprevir, its investigational oral hepatitis C protease inhibitor, in combination with peginterferon alfa-2b and ribavirin, significantly increased sustained virologic response (SVR)(1) rates with 28 and 48 weeks of therapy compared to current standard of care, peginterferon and ribavirin for 48 weeks (control group). The results from this Phase II study in 595 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 were presented at the 44th European Association for the Study of the Liver (EASL) 2009 Annual Meeting.(2) Genotype 1 is the most common and hardest to treat form of hepatitis C.

In Part I of the study, a 48-week boceprevir regimen achieved a 75 percent SVR rate (n=77/103) in patients who received 4 weeks of PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) (P/R) followed by the addition of boceprevir (800 mg TID) for 44 weeks (boceprevir P/R lead-in regimen). This represents a near doubling of the 38 percent SVR rate (n=39/104) for patients in the control group (p<0.0001). In a 28-week boceprevir P/R lead-in regimen 56 percent of patients (n=58/103) achieved SVR (p=0.005).(3)

Importantly, the likelihood (predictability) of attaining SVR was greater for patients who received the boceprevir P/R lead-in regimens compared to the no lead-in arms. Of patients in the boceprevir P/R lead-in arms who achieved a rapid virologic response (RVR), 94 percent in the 48-week regimen and 82 percent in the 28-week regimen achieved SVR. RVR is defined as undetectable virus (HCV RNA) in plasma at 4 weeks after the addition of boceprevir. In the lead-in arms, 64 percent of patients achieved RVR. Fewer patients in the lead-in arms discontinued treatment due to viral breakthrough.

"These results are very exciting and provide important insights to help further define response guided therapy using a P/R lead-in boceprevir regimen with peginterferon and ribavirin backbone treatment," said Paul Kwo, M.D., associate professor of medicine and medical director, liver transplantation, Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, and lead investigator of the study. "Building on these results, the boceprevir Phase III clinical program individualizes treatment based on response, utilizing RVR criteria at week 4 of boceprevir treatment to determine overall duration of therapy. Based on the RVR rate seen in this Phase II study, we are hopeful that the majority of patients can be treated with 28 weeks of therapy."

Part II of the HCV SPRINT-1 study explored a low-dose ribavirin strategy in which boceprevir was given in combination with PEGINTRON and low-dose REBETOL for 48 weeks. SVR for the low-dose REBETOL arm was 36 percent (n=21/59) compared to 50 percent for a 48-week control arm with PEGINTRON and standard-dose REBETOL plus boceprevir (n=8/16). In contrast to the results seen in Part I, the low-dose REBETOL regimen was associated with increased viral breakthrough during treatment, higher relapse rates after the end of treatment and lower SVR, strongly indicating that standard-dose ribavirin is required to optimize response.

Another key finding of the HCV SPRINT-1 study is that treatment-emergent anemia appeared to be associated with higher SVR, with anemic patients (hemoglobin decreasing to less than 10 g/dL) having higher SVR rates than those without anemia (hemoglobin did not decrease to less than 10 g/dL). Anemia is a known adverse event with combination therapy for hepatitis C and this association with higher SVR has been seen in other clinical studies with peginterferon and ribavirin, including the IDEAL study.(4) Boceprevir is associated with about a 1 g/dL incremental decrease in hemoglobin. In the HCV SPRINT-1 study, anemia occurred in approximately half of the patients in the boceprevir arms and over a third of patients in the control arm. Erythropoietin (EPO) supplementation was allowed in the study at the discretion of the investigator and was used by 26 percent of patients in the control arm and 39-51 percent of patients in the boceprevir arms with standard-dose REBETOL.

Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. The incidence of skin adverse events (rash or pruritus) observed in the boceprevir arms was similar to that seen in the PEGINTRON and REBETOL control arm.

Treatment discontinuations due to adverse events in Part I of the study were between 9 and 19 percent for patients in the boceprevir arms, compared to 8 percent for the control arm. Treatment discontinuations for boceprevir patients due to viral breakthrough were fewer in the 28- and 48-week lead-in arms (4 and 5 percent, respectively) compared to the no lead-in arms (7 and 12 percent, respectively).

SCH 900518 (Next-Generation HCV Protease Inhibitor) Data at EASL

Researchers at EASL also presented early phase clinical data for SCH 900518, Schering-Plough's investigational next-generation HCV protease inhibitor.(5) This proof-of-concept study explored the safety and antiviral activity of two different dosing regimens for SCH 900518 administered as monotherapy and in combination therapy with PEGINTRON with or without ritonavir in treatment-naive and treatment-experienced patients with HCV genotype 1. In this study, low doses of ritonavir were used for metabolic inhibition to enhance the levels of SCH 900518 within the body and reduce the frequency of SCH 900518 dosing (BID vs. TID).

In the study, SCH 900518 administered as monotherapy exhibited potent antiviral activity, achieving 4.0-4.5 log10 decreases in viral load (HCV RNA) from baseline at day 8. SCH 900518 was well tolerated, with no drug related serious adverse events. Pharmacokinetic and pharmacodynamic modeling from this study was used to design the ongoing Phase IIa dose-finding study of SCH 900518 with ritonavir in combination with PEGINTRON and REBETOL. This study, known as NEXT-1, explores SCH 900518 in 200 mg, 400 mg or 600 mg once daily (QD) doses with low-dose ritonavir (100 mg) in combination with PEGINTRON and REBETOL (with and without a 4-week P/R lead-in period) in treatment-naive patients with HCV genotype 1.

About the HCV SPRINT-1 Study

In this Phase II study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir (800 mg TID) was evaluated in three treatment regimens: 4 weeks of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) therapy followed by the addition of boceprevir to the combination for 24 or 44 weeks (totaling 28 or 48 weeks of treatment), boceprevir in combination with PEGINTRON and REBETOL at the doses described above for 28 or 48 weeks, and, in Part II of the study, boceprevir in combination with PEGINTRON and low-dose REBETOL (400-1000 mg daily based on patient weight) for 48 weeks. In Part I of the study, the boceprevir regimens were compared to a control of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) alone for 48 weeks (an approved treatment regimen). In Part II of the study, boceprevir in combination with PEGINTRON and low-dose REBETOL for 48 weeks was compared to a contemporaneous control of PEGINTRON, full-dose REBETOL and boceprevir for 48 weeks. The primary endpoint of the study was SVR after 24 weeks of follow up. In the study, the 28-week and 48-week boceprevir no lead-in arms had SVR rates of 54 percent (n=58/107) and 67 percent (n=69/103), respectively.

The HCV SPRINT-1 study was conducted at sites across the United States, Canada and Europe. Overall, 77 percent of the 595 patients in the study were enrolled in the United States. African-Americans represented 16 percent of the patients enrolled and 7 percent of the patients in the study were cirrhotic.

Rationale for Lead-In Regimen

The use of the P/R lead-in prior to the addition of boceprevir was shown in the HCV SPRINT-1 study to reduce the incidence of viral breakthrough regardless of treatment duration. The rationale for the lead-in treatment regimen is based on the fact that both PEGINTRON and REBETOL reach steady-state concentrations by week 4, therefore patients have the protease inhibitor added at a time when the backbone drug levels have been optimized and viral load (HCV RNA) has been reduced. In addition, the patient's immune system will have been activated and primed by PEGINTRON at the time that boceprevir is added to the regimen. This approach may minimize the period of time when there is a "functional monotherapy" with a direct antiviral agent, potentially reducing the likelihood for the development of resistance.

About Ongoing Boceprevir Phase III Registration Studies

Patient enrollment has been completed in two ongoing randomized, double-blind, placebo-controlled registration studies evaluating boceprevir in combination with PEGINTRON and REBETOL compared to standard of care with PEGINTRON and REBETOL alone. More than 1,500 patients were enrolled in these studies at U.S. and international sites.

The HCV SPRINT-2 study evaluates the efficacy of 28- and 48-week lead-in regimens of boceprevir (800 mg TID) in combination with PEGINTRON (1.5 mcg/kg/week) and REBETOL (600-1400 mg/day) compared to a control of PEGINTRON and REBETOL alone for 48 weeks in treatment-naive adult patients with chronic HCV genotype 1. The study enrolled a total of 1,099 patients, including 158 African-American/Black patients.

The HCV RESPOND-2 study evaluates 36- and 48-week lead-in regimens of boceprevir in combination with PEGINTRON and REBETOL at the same doses as described above compared to a control of PEGINTRON and REBETOL alone for 48 weeks in adult patients with chronic HCV genotype 1 who failed prior treatment (relapsers and nonresponders) with peginterferon and ribavirin combination therapy. The study enrolled a total of 404 patients.

In both registration studies, RVR criteria at 4 weeks of boceprevir treatment (treatment week 8) is used to determine which boceprevir patients can stop all treatment at 28 weeks (HCV SPRINT-2) or 36 weeks (HCV RESPOND-2).

For more information about ongoing studies, please visit www.clinicaltrials.gov, search term boceprevir or SCH 900518.

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 retreatment 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 Regarding U.S. Labeling for PEGINTRON and REBETOL

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 greater than 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 less than 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 6 months post-treatment. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for 6 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 6 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 (more than 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 (more than 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 less than or equal to 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 hallucinations. bipolar disorder, mania, encephalopathy (usually elderly treated with higher doses of PEGINTRON), hypotension, tachycardia, retinopathy including macular edema, retinal hemorrhage, cotton wool spots, papilledema, 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, hepatic failure, increases in serum creatinine in patients with renal insufficiency, acute hypersensitivity (angioedema, bronchoconstriction, anaphylaxis and cutaneous eruptions) and hypertriglyceridemia.

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.

Patients receiving PEGINTRON and REBETOL as retreatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naive patients.

Please see important full U.S. prescribing information and the Medication Guide for PEGINTRON at www.schering-plough.com.

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 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 Item 1A "Risk Factors" in Schering-Plough's 2008 10-K, filed Feb. 27, 2009.

Endnotes

1. SVR, the protocol specified primary efficacy endpoint, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment. Per protocol, if a patient does not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment will be utilized.

2. Kwo P, Lawitz E, McCone J, et al. HCV SPRINT-1 Final Results: SVR 24 from a Phase 2 study of Boceprevir Plus PegIntron (Peginterferon alfa-2b)/Ribavirin in Treatment-Naive Subjects with Genotype 1 Chronic Hepatitis C. 44th European Association for the Study of the Liver (EASL) 2009 Annual Meeting; April 22-26, Copenhagen, Denmark; oral presentation, Abstract No. 4.

3. Intention-To-Treat (ITT) analysis - includes any patient who has taken at least one dose of any study drug.

4. Sulkowski M, Shiffman M, Afdhal N, et al. Hemoglobin decline is associated with SVR among HCV genotype 1 infected persons treated with peginterferon (PEG)/ribavirin (RBV): Analysis from the IDEAL Study. 44th European Association for the Study of the Liver (EASL) 2009 Annual Meeting; April 22-26, Copenhagen, Denmark; oral presentation, Abstract No. 126.

5. Reesink HW, Bergmann JF, de Bruijne J, et al. Safety and Antiviral Activity of SCH 900518 Administered as Monotherapy and in Combination with Peginterferon Alfa-2b to Naive and Treatment-Experienced HCV Infected Patients. 44th European Association for the Study of the Liver (EASL) 2009 Annual Meeting; April 22-26, Copenhagen, Denmark; oral presentation, Abstract No. 86.

Website: http://www.schering-plough.com/