Merck & Co., Inc. : Merck Reports Phase III Study Results Evaluating Anemia Management Strategies Used With VICTRELIS® (boceprevir) Combination Therapy

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced final results from a Phase III, open-label study designed to compare the impact of two anemia management strategies on sustained virologic response (SVR)¹ in patients with chronic hepatitis C virus (HCV) genotype 1 infection treated with VICTRELIS^® (boceprevir) in combination with PEGINTRON^® (peginterferon alfa-2b) and ribavirin (P/R). The rates of SVR were 71 percent for both groups: those patients whose anemia was managed by ribavirin dose reduction (178/249) and those patients whose anemia was managed by the addition of erythropoietin (EPO) (178/251). The rates of relapse were identical at 10 percent in both groups. These results were presented today for the first time as part of a late breaker poster session [poster #1419] at The International Liver Congress™ / 47th European Association for the Study of the Liver (EASL) annual meeting.

"Chronic hepatitis C treatment regimens with peginterferon alfa and ribavirin are commonly associated with the development of anemia, and this effect is further increased with the addition of VICTRELIS," said Fred Poordad, M.D., chief of hepatology and liver transplantation, Cedars-Sinai Medical Center, Los Angeles. "The results of this study show there was no difference in SVR rates among these anemia management strategies and that ribavirin dose reduction should be the primary strategy for managing anemia in patients taking VICTRELIS combination therapy."

Indications and usage for VICTRELIS

VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (P/R), 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 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 viral load 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.

About the Study

In this study, 687 treatment-naïve adult patients with chronic HCV genotype 1 who had baseline hemoglobin levels of less than or equal to 15 g/dL were enrolled in a multinational, open-label trial and monitored for the development of anemia. Patients were treated with a 4-week lead-in of peginterferon alfa-2b (1.5 mcg/kg/week) and an investigational dose of ribavirin (600-1,400 mg/day), followed by the addition of VICTRELIS (800 mg three times a day) after week 4 for 24 or 44 weeks based on HCV-RNA levels at treatment week 8. Sixteen (16) percent (111/687) of patients were enrolled in Cohort 1 and assigned a fixed-dose regimen that included the 4-week lead-in of P/R followed by the addition of VICTRELIS for 44 weeks. A protocol amendment was then added to allow the use of the response-guided therapy (RGT) paradigm, consistent with findings in the pivotal clinical studies for VICTRELIS, and the rest of the patients were enrolled in Cohort 2. The results for patients receiving the fixed-dose regimen (Cohort 1) versus the RGT paradigm (Cohort 2) did not differ and have been combined in the presentation of these data. Patients with a less than 2-log₁₀ decline in HCV-RNA at week 12, or a greater than or equal to lower limit of quantification of HCV-RNA at week 24 were considered treatment failures and were discontinued from the studies.

A total of 500 patients developed anemia, defined by having hemoglobin of less than or equal to 10 g/dL (or less than 11 g/dL and were expected to reach less than or equal to 10 g/dL before the next visit). These patients were randomized to receive either ribavirin dose reduction (by 200 to 400 mg/d) or the addition of EPO (40,000 IU/week). A secondary method of anemia management, such as the addition of EPO, ribavirin dose reduction or transfusion, was later permitted if a patient's hemoglobin reached less than or equal to 8.5 g/dL. Treatment was discontinued if hemoglobin levels reached less than or equal to 7.5 g/dL. If the initial hemoglobin measurement qualifying a patient as anemic was less than or equal to 8.5 g/dL, that patient was not randomized to one of the anemia management strategies.

The primary endpoint of the study was the comparison of SVR in patients who were randomized to receive ribavirin dose reduction or the addition of EPO.

Safety Findings

The safety profiles were similar regardless of anemia management strategy. The most common adverse events (occurring in 30 percent or more of patients in either group) were anemia, neutropenia, diarrhea, dysgeusia, nausea, chills, fatigue, headache, insomnia and alopecia. There was no difference in the incidence of adverse events between the ribavirin dose reduction and EPO treatment arms, including influenza-like symptoms (27 percent each), fatigue (70 percent vs. 71 percent), depression (20 percent vs. 21 percent), anxiety (12 percent each), shortness of breath (19 percent vs. 21 percent) and cardiovascular events (14 percent vs. 13 percent), respectively.

Serious adverse events occurred in 16 percent of patients in the ribavirin dose reduction arm and 13 percent of patients in the EPO arm. The discontinuation rates were 11 and 13 percent, due to any adverse event, and 2.0 and 2.4 percent due to anemia, respectively. There was one death in the ribavirin dose reduction arm that occurred three weeks following the end of treatment, with cause of death reported as "sudden cardiac death".

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 and concomitant ribavirin.

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 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 to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared to peginterferon alfa and ribavirin alone and/or may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. If hemoglobin is less than 10 g/dL, a decrease in dosage or interruption of ribavirin is recommended. If hemoglobin is less than 8.5 g/dL, discontinuation of ribavirin is recommended. Decreases in neutrophil counts also may require dose reduction or discontinuation of PR. 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 peginterferon alfa and ribavirin.

In the pivotal clinical trials, the proportion of patients who experienced hemoglobin values less than 10 g/dL and less than 8.5 g/dL was higher in subjects treated with the combination of VICTRELIS plus P/R than in those treated with P/R alone, respectively.

-- Treatment-naïve patients experienced hemoglobin levels less than 10 g/dL and less than 8.5 g/dL in 49 percent and six percent of patients treated with VICTRELIS plus P/R, compared to 29 percent and three percent of patients treated with P/R alone, respectively.

-- Patients who previously failed P/R therapy experienced levels less than 10 g/dL and less than 8.5 d/L in 49 percent and 10 percent of patients treated with VICTRELIS plus P/R, compared to 25 percent and 1 percent of patients treated with P/R alone, respectively.

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 treatment weeks 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 peginterferon alfa 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 were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin 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, extensive research efforts are underway to develop additional innovative 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 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.

¹ SVR, the protocol specified primary efficacy endpoint of the study, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment was utilized.

VICTRELIS^® and PEGINTRON^® are trademarks of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Revatio^® and Adcirca^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

INFC-1029581-0004

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