Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced interim results from a Phase II, multi-center, randomized, dose-ranging study (n=332) assessing the safety and antiviral activity of MK-5172, an investigational, once-daily, oral NS3/4A protease inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in combination therapy in treatment-naïve patients. These data will be presented this week at the American Association for the Study of Liver Diseases Annual Meeting (AASLD).
The primary efficacy endpoint of the study was to evaluate the complete early viral response (cEVR) of four regimens of MK-5172 in combination with peginterferon alfa-2b and ribavirin (PR) compared to the control arm in which patients received a 4-week lead-in of PR followed by the addition of VICTRELIS® (boceprevir) 200 mg Capsules. cEVR was assessed by the proportion of patients who achieved undetectable virus (HCV RNA) at treatment week (TW) 12 in the investigational arms and at TW 16 in the control arm. The MK-5172 regimens had rates of cEVR ranging from 82.8 to 93 percent, versus the control of 74.2 percent.
In the initial cohort, termed the "Vanguard Cohort," (n=136), 96 percent of patients (25/26) who received a regimen containing 100 mg QD of MK-5172 with PR achieved sustained virologic response (SVR) 12, defined as having undetectable virus (HCV RNA) 12 weeks after treatment ended, compared to 54 percent of patients (13/24) in the control arm.
“We are excited by these interim results evaluating MK-5172 in combination therapy,” said Eliav Barr, M.D., vice president, Infectious Diseases, Project Leadership and Management, Merck Research Laboratories. “Our commitment to chronic hepatitis C remains steadfast. We look forward to continuing our studies of MK-5172, including in interferon-free regimens."
Currently planned studies evaluating interferon-free regimens with MK-5172 will be dosed at 100 mg QD.
Other data to be presented on MK-5172 at AASLD include results from a preclinical study evaluating the antiviral activities of MK-5172 in combination with MK-8742, an oral HCV NS5A inhibitor in Phase I development.
Indications and Usage for VICTRELIS (boceprevir)
VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (PR), in adult patients (18 years 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 HCV infection:
- VICTRELIS must not be used as monotherapy and should only be used in combination with PR.
- 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 PR has not been studied in patients documented to be historical null responders [less than a 2 log10 HCV-RNA decline by treatment week (TW) 12] during prior therapy with PR. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log10 HCV-RNA decline in viral load at TW 4 with PR alone are predicted to have a null response (less than a 2 log10 viral load decline by TW 12) to PR therapy.
- Poorly interferon responsive patients who were treated with VICTRELIS in combination with PR have a lower likelihood of achieving a sustained virologic response (SVR), and higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to PR.
About the Study
This Phase II, multi-center, double-blind, randomized, active-controlled, dose ranging, response-guided therapy (RGT) study is designed to examine the safety and antiviral activity of MK-5172 administered with peginterferon alfa-2b (1.5 µg/kg/week) and an investigational, weight-based dose of ribavirin (600-1,400 mg/day) (PR) in non-cirrhotic, treatment-naïve, adult patients with chronic HCV genotype 1 infection. In the study, 332 patients were enrolled in two cohorts: the Vanguard Cohort of 136 patients, followed by a Second Cohort of 196 patients. In both cohorts, patients were randomized to one of four MK-5172 treatment arms (100 mg QD, 200 mg QD, 400 mg QD, 800 mg QD). All patients received MK-5172 in combination with PR for 12 weeks followed by PR for 12 or 36 weeks, depending on treatment response at TW 4. If the patient's virus (HCV RNA) was target not detected (TND; <10 IU/mL) at TW 4, then the patient was able to stop all therapy at TW 24. If the patient's virus was target detected unquantifiable (TD(u); <25 IU/mL) or target detected quantifiable (TD(q)) at TW 4, then the patient stopped all therapy at TW 48. In the control arm, patients received a 4-week lead-in of PR followed by the addition of VICTRELIS (boceprevir) administered per the U.S. Prescribing Information.
After the primary TW 12 analysis of the MK-5172 arms in the Vanguard cohort, patients receiving the 400 mg and 800 mg doses in the Second Cohort were down-dosed due to elevated liver transaminases and began to receive 100 mg in an open-label fashion between weeks 3 and 12 of MK-5172 therapy.
Current Status of Study
All patients in both cohorts of the study (termed the Combined Cohort when analyzed together) have reached the primary endpoint of the study, cEVR, or have discontinued early. cEVR values reflect both those patients with both undetectable (TND) and detectable unquantifiable (TD(u)) HCV RNA. In the Second Cohort, 134 of 156 patients randomized into the MK-5172 arms are receiving PR (n=17) or are in the follow-up phase (n=117) of the study. All patients in the Vanguard Cohort who received MK-5172 are in the follow-up phase of the study or have discontinued early.
Of the patients randomized to the MK-5172 arms, 2.3 percent (6/266) met the protocol-defined criteria for virologic failure: one (1) patient was re-infected with genotype 3 infection; and four patients had no detectable (n=3) or low (n=1) levels of MK-5172 at time of failure and for a period of time prior. The primary efficacy analysis included the full analysis set (FAS) of all randomized patients who received at least one dose of study treatment.
SVR12 Results in the Vanguard Cohort
In the Vanguard Cohort, higher SVR12 rates were achieved across all MK-5172 arms compared to control (FAS) – 96.2 percent (25/26) in the MK-5172 100 mg arm; 86.7 percent (26/30) in the MK-5172 200 mg arm; 87.0 percent (20/23) in the MK-5172 400 mg arm; and 81.5 percent (22/27) in the MK-5172 800 mg arm; versus 54.2 percent (13/24) in the control arm. In these results, all patients had undetectable (TND) HCV RNA.
In the MK-5172 arms of the study, there were two transient liver abnormalities observed – early elevations in total bilirubin before TW 4, associated with normalization of alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels, and late elevations in liver transaminases (ALT/AST) occurring after TW 4.
Patients with Early Total Bilirubin Elevations
|Arm 1||Arm 2||Arm 3 (N=67)||Arm 4 (N=65)||Arm 5|
800 mg tid
|1 (1.5%)||8 (11.8%)||2 (8.3%)||4 (9.3%)||2 (6.9%)||7 (19.2%)||2 (3.0%)|
PR, peginterferon alfa-2b + ribavirin; ULN, upper limit of normal.
BOC, boceprevir; PR, peginterferon alfa-2b + ribavirin; SC, second cohort; VC, vanguard cohort.
*Patients receiving the 400 mg and 800 mg doses in the SC were down-dosed to receive 100 mg in an open-label fashion. Down dosing occurred in the SC at various time points while on MK-5172. No patients were dosed down in the VC.
Of those patients with bilirubin elevation, 92 percent (22/24) occurred within the first seven to 23 days of therapy, and their bilirubin levels decreased from peak levels despite continued dosing.
Patients With Late ALT/AST Elevations
|Arm 1||Arm 2||Arm 3 (N=67)||Arm 4 (N=65)||Arm 5|
|1 (2%)||6 (9%)||5 (21%)||8 (19%)||7 (24%)||8 (22%)||1 (2%)|
ALT, alanine aminotransferase; AST, aspartate aminotransferase; PR, peginterferon alfa-2b + ribavirin; ULN, upper limit of normal.
*Patients receiving the 400 mg and 800 mg doses in the SC were down-dosed to receive 100 mg in an open-label fashion. Down dosing occurred in SC at various time points while on MK-5172. No patients were down-dosed in the VC.
The frequency and severity of ALT/AST elevations after TW 4 were dose dependent. The frequencies of ALT/AST elevations in the MK-5172 100 mg arm and the control arm after TW 4 were comparable at 2 percent each, (1/66) and (1/66), respectively. The frequency of ALT/AST elevations observed in the MK-5172 200 mg, MK-5172 400 mg and MK-5172 800 mg arms after TW 4 were higher.
One patient in the MK-5172 800 mg arm experienced a serious adverse event due to elevated ALT and total bilirubin levels, which returned to normal after discontinuation of all therapy.
Important Safety Information about VICTRELIS (boceprevir)
All contraindications to PR also apply since VICTRELIS must be administered with PR. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with PR 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 (boceprevir). 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 VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS (boceprevir) 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 orally administered midazolam.
Anemia and/or Neutropenia -- The addition of VICTRELIS (boceprevir) to PR is associated with an additional decrease in hemoglobin concentrations compared to PR alone and/or may result in worsening of neutropenia associated with PR therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of PR.
Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at TW 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.
The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with PR 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 PR alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and 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 (boceprevir), extensive research efforts are underway to develop additional oral therapies for viral hepatitis treatment.
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Please see Prescribing Information for VICTRELIS (boceprevir) 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.
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