Interim results of HCV SPRINT-1 study presented at AASLD annual meeting
Pivotal Phase III studies ongoing in treatment naive patients and those who failed prior treatment
SAN FRANCISCO, Nov. 1 /PRNewswire-FirstCall/ -- Schering-Plough Corporation today reported that a planned interim analysis of a Phase II study showed that boceprevir, its investigational oral hepatitis C protease inhibitor, in combination with peginterferon and ribavirin markedly increased sustained virologic response (SVR) rates with 28 weeks of therapy and nearly doubled SVR with 48 weeks of therapy compared to current standard of care, peginterferon and ribavirin (control group) for 48 weeks. These results from the HCV SPRINT-1 study in 595 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 were presented at the 59th American Association for the Study of Liver Diseases (AASLD) Annual Meeting.(1)
In a 48-week boceprevir regimen, the SVR rate was 74 percent at 12 weeks after the end of treatment (SVR 12) in patients who received 4 weeks of PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) prior to the addition of boceprevir (800 mg TID) (P/R lead-in). In a 28-week boceprevir regimen, the SVR rate was 56 percent at 24 weeks after the end of treatment (SVR 24) in patients who received the P/R lead-in. These results compared to a 38 percent SVR rate (SVR 12) for patients in the control group receiving 48-weeks of PEGINTRON and REBETOL alone (ITT).(2-4)
Importantly, predictability of attaining SVR 12 or 24 based on rapid virologic response (RVR) was greater for boceprevir patients in the lead-in arms compared to the no lead-in arms. In addition, fewer patients in the lead-in arms discontinued treatment due to viral breakthrough. RVR is defined as undetectable virus (HCV-RNA) in plasma on or before week 4 of boceprevir treatment.
“The high response rates seen with boceprevir in this study are very exciting, especially given that genotype 1 is the most common and hardest to treat form of hepatitis C,” 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. “Boceprevir was well tolerated by patients in this study, and the use of the 4-week lead-in prior to the addition of boceprevir appears to reduce the incidence of viral breakthrough regardless of treatment duration and may improve SVR over a 48-week treatment period.”
The rationale for this novel lead-in treatment regimen is based on the fact that both PEGINTRON and REBETOL reach steady-state concentrations by week 4, so patients have the protease inhibitor added at a time when the backbone drug levels have been optimized. 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, potentially reducing the likelihood for the development of resistance.
Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. No increase in skin adverse events (rash or pruritus) was observed in the boceprevir arms beyond what was seen in the PEGINTRON and REBETOL control arm.
Treatment discontinuations due to adverse events 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 11 percent, respectively).
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, 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). The primary endpoint of the study is SVR after 24 weeks of follow up (SVR 24). This is an ongoing study and SVR 24 rates are not yet available for patients in the 48-week boceprevir arms or the 48-week control arm of the study. In addition, SVR rates are not yet available and consequently results are not being reported for the boceprevir arm with low-dose REBETOL (n=59) compared to contemporaneous control (n=16) as described above.
In the study, predictability of attaining SVR (12 or 24) based on rapid virologic response (RVR) following 28 or 48 weeks of the boceprevir regimen was greater for patients in the lead-in arms (82 and 92 percent respectively) compared to the no lead-in arms (74 and 82 percent, 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 represent 16 percent of the patients enrolled and 7 percent of patients in the study are cirrhotic.
Update on Boceprevir Phase III Studies
Schering-Plough is conducting two large ongoing pivotal Phase III studies of boceprevir in patients chronically infected with HCV genotype 1. One study is in treatment-naive patients and the other in patients who failed prior treatment (relapsers and nonresponders). The two randomized, double-blind, placebo-controlled studies evaluate the efficacy of boceprevir in combination with PEGINTRON and REBETOL compared to standard of care with PEGINTRON and REBETOL alone.
The study in treatment-naive patients is known as HCV SPRINT-2 and the study in patients who failed prior treatment is known as HCV RESPOND-2. The two studies are expected to enroll a total of more than 1,400 patients at U.S. and international sites.
For more information about these ongoing Phase III studies, please visit www.clinicaltrials.gov, search term boceprevir.
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
In the United States, 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.
Important Safety Information Regarding U.S. Labeling for PEGINTRON and REBETOL
Alpha interferons, including PEGINTRON and INTRON(R) 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.
Use with Ribavirin: Ribavirin may cause birth defects and/or 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 hypersensitivity to PEGINTRON 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. 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. PEGINTRON or INTRON A in combination with REBETOL therapy is additionally contraindicated in patients with hypersensitivity to ribavirin or any other component of the product, women who are pregnant, 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/min.
Avoid 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. 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
There are no new adverse events specific to PEGINTRON as compared to INTRON A; however, the incidence of some (e.g., 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 (i.e., 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 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.
In the PEGINTRON/REBETOL combination trial, the incidence of serious adverse events was 17% in the PEGINTRON/REBETOL groups compared to 14% in the INTRON A/ REBETOL group. The incidence of severe adverse events in the PEGINTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEGINTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEGINTRON (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL.
In a study with weight-based ribavirin, there was a higher rate of anemia among patients in the weight-based dosing group (29%) compared to the flat-dosing group (19%). The majority of these cases were mild and responded to dose reductions. Serious adverse events were similar between the two groups (12%), and discontinuations for adverse events (15% in weight-based dosing and 14% in flat dosing) were also similar. Dose modifications due to adverse events occurred more frequently in the weight-based dosing group (29%) compared to the flat-dosing (23%) group.
Additional Safety Information
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. Dental and periodontal disorders have been reported in patients receiving PEGINTRON or INTRON A in combination with REBETOL therapy.
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 and consumer products as well as to animal health 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 company’s clinical development plans and the potential for boceprevir. 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 Part II, Item 1A, “Risk Factors” in the company’s third quarter 2008 10-Q.
Endnotes
1. Kwo P, Lawitz E, McCone J, et al. Boceprevir Plus Peginterferon alfa-2b/Ribavirin for Treatment of Genotype 1 Chronic Hepatitis C in Previously Untreated Patients: Interim Results from the HCV SPRINT-1 Study. 59th American Association for the Study of Liver Diseases (AASLD) Annual Meeting; Oct. 31-Nov. 2, 2008, San Francisco, CA, USA; Poster No. LB16.
2. 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.
3. SVR 12 is defined as undetectable HCV-RNA in plasma at 12 weeks after the end of treatment. The protocol specified primary efficacy endpoint of the HCV SPRINT-1 study is SVR as defined above.
4. Intention-To-Treat (ITT) analysis includes any patient who has taken at least one dose of any study drug.
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