Merck Reports New Phase III Analyses on Anemia Management Strategies Used With VICTRELIS® (boceprevir) Combination Therapy, Including Cirrhotic Patients

November 10, 2012 9:00 am ET

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced results of retrospective sub-analyses from a Phase III, open-label study designed to compare the impact of two anemia management strategies – ribavirin dose reduction and an investigational use of erythropoietin (EPO) – on sustained virologic response (SVR)¹ in patients with chronic hepatitis C virus (HCV) genotype 1 infection treated with VICTRELIS^® (boceprevir) 200 mg Capsules in combination with peginterferon alfa and ribavirin (PR). These data will be presented this week at The American Association for the Study of Liver Diseases 2012 Annual Meeting (AASLD).

In the sub-analysis evaluating eligible patients who were randomized to receive ribavirin dose reduction for anemia management, SVR rates were generally similar regardless of when patients began ribavirin dose reduction, the number of steps of ribavirin dose reduction, or the lowest ribavirin dose of 400 to 1,000 mg/day received for at least 14 days for anemia management. However, SVR rates were lower in patients who received less than 50 percent of their total assigned dose of ribavirin compared to those who received at least 50 percent of their assigned dose. SVR rates were higher in those patients who had undetectable HCV RNA than those who had detectable HCV RNA at the start of their anemia management intervention, and these respective SVR rates were the same regardless of anemia management strategy.

“These analyses further confirm that ribavirin dose reduction should be the primary strategy for managing anemia in patients taking VICTRELIS combination therapy, including cirrhotic patients,” said Fred Poordad, M.D., chief medical officer, Alamo Medical Research, and professor of medicine at the University of Texas Health Science Center, San Antonio.

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 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 treatment week 4 with PR alone are predicted to have a null response (less than a 2 log₁₀ viral load decline by treatment week 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.

Anemia and/or Neutropenia — The addition of VICTRELIS 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 (boceprevir) is not recommended. VICTRELIS must not be administered in the absence of PR.

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.

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.

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 (boceprevir) 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 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 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

About the Study

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, and those results were presented at the European Association for the Study of the Liver (EASL) 2012 annual meeting. 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 EPO (178/251). The rates of relapse were 10 percent in both groups.

In this study, 687 treatment-naïve adult patients with chronic HCV genotype 1 who had baseline hemoglobin levels at least 12 g/dL for females and at least 13 g/dL for males, but less than or equal to 15 g/dL were enrolled in a randomized, 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 weight-based ribavirin (600-1,400 mg/day), followed by the addition of VICTRELIS (boceprevir) (800 mg three times a day) after week 4 for 24 or 44 weeks based on response-guided therapy. Patients with compensated cirrhosis were allowed (METAVIR fibrosis score of F1-F4) provided they had no other concurrent liver diseases. Patients with HIV or hepatitis B virus were excluded.

A total of 500 patients developed anemia, defined by having hemoglobin of approximately less than or equal to 10 g/dL. Patients with anemia were randomized to receive either ribavirin dose reduction (by 200 mg/d [or 400 mg/d if the initial ribavirin dose was 1,400 mg/d]) or the addition of EPO (starting at 40,000 units/week, but could be modified at the investigator’s discretion to doses of 20,000 – 60,000 units/week). A secondary method of anemia management, such as the addition of EPO or ribavirin dose reduction 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.

Impact of timing and magnitude of ribavirin dose reduction on SVR

In the ribavirin dose reduction arm, SVR rates were generally similar regardless of when patients began ribavirin dose reduction, the number of steps of ribavirin dose reduction, or the lowest ribavirin dose of 400 to 1,000 mg/day received for at least 14 days for anemia management. There were few patients, ranging from 3 to 12 in each subgroup, in the ribavirin dose reduction arm who received the lowest ribavirin doses outside the range of 400 to 1,000 mg/day for at least 14 days.

SVR rates according to the time of the initial ribavirin dose reduction were 70 percent (38/54) at less than or equal to 4 weeks; 64 percent (58/90) from more than 4 to 8 weeks; 79 percent (49/62) from more than 8 to 12 weeks; 82 percent (18/22) from more than 12 to 16 weeks; and 71 percent (15/21) from more than 16 weeks.

SVR rates according to the number of steps of ribavirin dose reduction

Steps

SVR %

(n/N)

67
(47/70)

76
(44/58)

80
(20/25)

64
(9/14)

77
(23/30)

69
(24/35)

83
(10/12)

* One step = decrease of 200 mg ribavirin per day for greater than or equal to 3 days

SVR rates by lowest ribavirin dose received for at least 14 days

Dose (mg/day)

200

400

600

800

1000

1200

1400

SVR %

(n/N)

92 (11/12)

60 (3/5)

70 (28/40)

75 (58/77)

77 (43/56)

67 (30/45)

36 (4/11)

33 (1/3)

*Lowest ribavirin dose (mg/day) received for at least 14 days during the treatment period based on information in patient diaries.

This sub-analysis included small numbers of patients in some subgroups. Patients were not randomized into subgroups so there could be baseline differences that affected the results.

Impact of HCV-RNA levels at start of anemia management intervention on SVR

The SVR rates for patients with undetectable levels of virus (HCV RNA) at the start of the anemia management intervention were the same – 86 percent – among patients who had ribavirin dose reduction (111/129) and patients who received EPO (107/124). Additionally, the SVR rates for patients with detectable levels of HCV RNA at the start of intervention were the same – 56 percent – among patients who had ribavirin dose reduction (67/120) and patients who received EPO (71/127).

Anemia management interventions in cirrhotic patients

In another sub-analysis of the study, nine percent (60/664) of patients with available central pathology biopsy results were cirrhotic (METAVIR fibrosis score of F4). Of these, 80 percent (48/60) met the protocol definition for anemia and were randomized to one of the two anemia management strategies.

Of the patients requiring an anemia management strategy, the rates of SVR in the ribavirin dose reduction arm were 57 percent (13/23) in cirrhotic patients and 73 percent (162/221) in non-cirrhotic patients, while the rates of SVR in the EPO arm were 64 percent (16/25) in cirrhotic patients and 72 percent (157/217) in non-cirrhotic patients.

A higher percentage of cirrhotic patients received secondary interventions for anemia management than non-cirrhotic patients at 44 percent (21/48) and 26 percent (114/438), respectively.

This sub-analysis was limited by a small sample size of patients with cirrhosis, and the study was not stratified by cirrhotic versus non-cirrhotic patients.

Safety findings

In the sub-analysis evaluating anemia management strategies in cirrhotic patients, the most common adverse events occurring in 25 percent or more of either cirrhotic or non-cirrhotic patients were fatigue, anemia, nausea, diarrhea, dysguesia (bad taste), headache, neutropenia, alopecia, chills, dizziness, decreased appetite, insomnia and influenza-like illness.

Cirrhotic patients were more likely to develop lower platelet counts than non-cirrhotic patients.

Serious adverse events occurred in 20 percent of cirrhotic patients and 12 percent of non-cirrhotic patients. The discontinuation rates due to any adverse event were 17 and 16 percent, respectively. One non-cirrhotic patient who had multiple cardiac risk factors died of sudden cardiac arrest 23 days after discontinuing study drugs.

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 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

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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).

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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.

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.

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