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The Merck Manuals
Oncology Information Center
BOSTON--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from a 24-week interim analysis of an ongoing 48-week Phase IIb clinical study evaluating the investigational use of VICTRELIS™ (boceprevir), the company’s first-in-class, oral hepatitis C virus (HCV) NS3/4A protease inhibitor, in combination with peginterferon alfa and ribavirin for the treatment of chronic HCV genotype 1 infection in adult patients coinfected with HIV-1. All patients in the study were new to treatment for chronic HCV, on an optimized antiretroviral regimen and had stable HIV-1 disease. The interim analysis showed that at week 24 of treatment, 70.5 percent (n=43/61) of patients receiving VICTRELIS in combination with peginterferon alfa-2b and ribavirin had undetectable hepatitis C virus (HCV-RNA) compared to 34.4 percent (n=11/32) of patients receiving peginterferon alfa-2b and ribavirin alone, a treatment difference of 36.1 percent. These interim results are being presented for the first time in a late-breaker oral presentation at the Infectious Diseases Society of America (IDSA) 2011 annual meeting in Boston. Final results from the study are expected in 2012.
"We are encouraged by these interim results with VICTRELIS in combination therapy in this difficult-to-treat patient population,” said Roger J. Pomerantz, M.D., F.A.C.P., senior vice president, Infectious Diseases, Merck Research Laboratories. "Helping patients who are dealing with both chronic hepatitis C and HIV-1 is a critical issue in infectious diseases today, and Merck is committed to evaluating VICTRELIS in these patients. In addition to this ongoing Phase IIb study in patients new to HCV treatment, we are collaborating with the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) on an ongoing Phase II study in patients who failed previous HCV treatment. We also plan to begin a Phase III coinfection study for VICTRELIS in combination therapy later this year in collaboration with the AIDS Clinical Trials Group (ACTG), which is funded by the U.S. National Institute of Allergy and Infectious Diseases."
Indications and usage for VICTRELIS
VICTRELIS was approved by the U.S. Food and Drug Administration (FDA) on May 13 for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients (18 years of age and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
The following points should be considered when initiating VICTRELIS for treatment of chronic hepatitis C infection:
-- VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.
-- VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors. VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than a 2 log HCV-RNA decline by treatment week 12) to peginterferon alfa and ribavirin therapy.
-- Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin.
Key interim results
One hundred (100) adult patients with previously untreated HCV genotype 1 infection and stable HIV-1 disease (HIV-RNA less than 50 copies/mL; CD4 cell counts equal to or greater than 200 cells/mm3) were randomized into the study. Two patients randomized to the treatment arm receiving VICTRELIS in combination with peginterferon alfa-2b (P) and ribavirin (R) did not receive VICTRELIS. Thus, the interim analysis was based on 98 patients who received at least one dose of study drug: 64 patients in the arm receiving VICTRELIS plus P/R, and 34 patients in the control arm receiving P/R alone. All patients treated in the study received a 4-week lead-in with P/R alone followed by VICTRELIS plus P/R or placebo plus P/R for 44 weeks, for a total treatment duration of 48 weeks.
Virologic response (proportion HCV-RNA undetectable) over time
|VICTRELIS vs. Control|
|n/N (%)||95% CI||n/N (%)||95% CI||Difference (%)||95% CI|
|(0.0, 9.9)||-4.1||(-15.0, 6.7)|
|(25.6, 49.4)||22.8||(6.0, 39.6)|
|(44.1, 68.8)||31.5||(12.0, 50.9)|
|(59.0, 81.9)||36.1||(16.1, 56.2)|
* Analyses exclude patients still on treatment who had not yet received 12 or 24 weeks of treatment
(Roche Taqman v. 2.0, LOD = 9.3 IU/mL; LLQ = 25 IU/mL)
Preliminary safety data for VICTRELIS in combination therapy in HCV/HIV coinfected patients demonstrated a profile similar to that previously observed in patients with HCV mono-infection. There were no unexpected trends in HIV-RNA levels or CD4 cell counts.
The most common clinical adverse events with a difference of equal to or greater than 10 percent for the treatment arm receiving VICTRELIS plus P/R compared to the P/R control arm, respectively, were: neutropenia (13 vs. 3 percent), dysgeusia (bad taste) (25 vs. 15 percent), vomiting (25 vs. 15 percent), pyrexia (34 vs. 21 percent), headache (28 vs. 12 percent) and decreased appetite (30 vs. 18 percent) [median days on study, 211 vs. 166, respectively]. Serious clinical adverse events occurred in 8 percent and 21 percent of patients in the two treatment arms, respectively. Dose modification for any study drug due to a clinical adverse event occurred in 19 percent and 21 percent of patients, respectively, and study discontinuation due to a clinical adverse event occurred in 14 percent and 9 percent of patients, respectively.
About the Phase IIb coinfection study
The primary objective of this ongoing randomized, multicenter, double-blinded for VICTRELIS, Phase IIb study is to compare the efficacy of VICTRELIS 800 mg three times daily in combination with peginterferon alfa-2b (P) 1.5 mcg/kg weekly plus ribavirin (R) 600 to 1,400 mg daily to therapy with P/R alone in adult patients coinfected with chronic HCV genotype 1 and HIV-1. Patients were randomized in a 2:1 ratio to the treatment arm with VICTRELIS plus P/R or the P/R control arm, respectively. Patients were stratified by cirrhosis (yes/no) and baseline HCV-RNA (less than 800,000 IU/mL vs. equal to or greater than 800,000 IU/mL). The majority of patients were non-cirrhotic (95 percent), white (82 percent) and male (69 percent), with a median age of about 43 years. Most patients had high HCV-RNA (88 percent) at baseline and HCV genotype 1a infection (65 percent).
Antiretroviral regimens for HIV-1 that included non-nucleoside reverse transcriptase inhibitors (NNRTIs), zidovudine, stavudine or didanosine were not permitted. Patients with detectable HCV-RNA and less than a 2 log HCV-RNA decline at treatment week 12 or detectable HCV-RNA at treatment week 24 were considered treatment failures and discontinued all treatment.
Important safety information about VICTRELIS
All contraindications to peginterferon alfa and ribavirin also apply since VICTRELIS must be administered with peginterferon alfa and ribavirin. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS.
VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and midazolam (orally administered).
Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. The addition of VICTRELIS may result in a worsening of neutropenia associated with peginterferon alfa and ribavirin alone. Complete blood count (with white blood cell differential counts) must be conducted in all patients prior to initiating VICTRELIS combination therapy. Complete blood counts should be obtained pretreatment, and at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate. If a patient has a serious adverse reaction potentially related to peginterferon alfa and ribavirin therapy, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin. Dose reduction of VICTRELIS is not recommended.
The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with peginterferon alfa-2b and ribavirin were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for peginterferon alfa and ribavirin alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who received VICTRELIS combination therapy compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent), dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previously treated patients who received VICTRELIS combination therapy compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent), dysgeusia (44 vs. 11 percent), respectively.
VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.
Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.
Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.
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Please see Prescribing Information for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and Medication Guide for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.
Pamela Eisele, 908-423-5042
Robert Consalvo, 908-423-6595
Carol Ferguson, 908-423-4465