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 log 10 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 log 10 HCV-RNA decline in viral load at TW 4 with PR alone are predicted to have a null response (less than a 2 log 10 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.
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.
Safety FindingsIn 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|
|100 mg+ PR||200 mg+ PR||MK-5172||MK-5172||MK-5172||MK-5172||800 mg tid+ PR|
|400 mg+ PR||400 mg+ PR||800 mg+ PR||800 mg+ PR|
|TotalBilirubin >2 x ULN||1 (1.5%)||8 (11.8%)||2 (8.3%)||4 (9.3%)||2 (6.9%)||7 (19.2%)||2 (3.0%)|
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|
|100 mg+ PR||200 mg+ PR||MK-5172||MK-5172||MK-5172||MK-5172|
|400 mg+ PR||400 mg+ PR||800 mg+ PR||800 mg+ PR||100 mg+ PR|
|Patientswith LateALT/AST> 2x ULN||1 (2%)||6 (9%)||5 (21%)||8 (19%)||7 (24%)||8 (22%)||1 (2%)|
*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. About Merck Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube. Forward-Looking Statement This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.
The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation and/or regulatory actions.Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov). 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 . VICTRELIS ® is a trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. INFC-1056915-0000 Revatio ® and Adcirca ® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.