FDA Approves Merck's VICTRELIS™ (boceprevir), First-in-Class Oral Hepatitis C Virus (HCV) Protease Inhibitor

Merck (NYSE:MRK) (known as MSD outside the United States and Canada) announced today that the U.S. Food and Drug Administration (FDA) has approved VICTRELIS™ (boceprevir), the company's innovative new medicine for the treatment of chronic hepatitis C (CHC). VICTRELIS is approved for the treatment of CHC 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)¹, 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.

VICTRELIS is the first in a new class of medicines approved to treat chronic hepatitis C

VICTRELIS is the first in a new class of medicines known as hepatitis C virus (HCV) protease inhibitors approved for use in combination with peginterferon alfa and ribavirin, which is the current standard therapy, for the treatment of chronic hepatitis C.

"This is an exciting day for physicians and patients because VICTRELIS is the first major advancement for the treatment of chronic hepatitis C approved in a decade,” said Bruce Bacon, M.D., professor of internal medicine, Saint Louis University School of Medicine, and a clinical investigator for VICTRELIS. "Compared to current standard therapy, VICTRELIS can significantly increase a patient’s chance of achieving undetectable levels of the virus, thereby obtaining an SVR. For many patients, VICTRELIS may allow for a shorter total duration of treatment.”

"Merck is deeply committed to innovation in bringing forward new medicines that significantly address unmet medical needs, and VICTRELIS is a shining example of our commitment being realized," said Kenneth C. Frazier, president and chief executive officer, Merck. "We look forward to building on our legacy in the fight against infectious diseases, and to being a part of this exciting new era in the treatment of chronic hepatitis C."

Merck will begin shipping VICTRELIS to pharmacies within a week so that patients will have access to this new medication as soon as possible. In addition, the company is expanding its support of public awareness and education programs for chronic hepatitis C. Resources include coupons to help eligible patients with their medication cost, reimbursement support to help patients understand their insurance coverage for VICTRELIS, and 24/7 nurse phone support.

Separately, Merck will also add VICTRELIS to its patient assistance program through which eligible patients may be able to receive product free of charge.

Current standard therapy for HCV works to strengthen the body’s natural immune response to the virus, but only about 40 percent of patients with chronic HCV genotype 1 infection are able to achieve SVR. VICTRELIS is a Direct Acting Antiviral (DAA) agent that interferes with the ability of the hepatitis C virus to replicate by inhibiting a key viral enzyme (NS3/4A serine protease).

The FDA approval of VICTRELIS is based on the efficacy and safety results from two large Phase III clinical studies that evaluated approximately 1,500 adult patients with chronic HCV genotype 1 infection. Both studies included two treatment arms with VICTRELIS: a response-guided therapy (RGT) arm, in which patients with undetectable virus (HCV-RNA) at treatment week 8 were eligible for a shorter duration of therapy, as well as a 48-week treatment arm. All patients receiving VICTRELIS in these studies were first treated with peginterferon alfa-2b and ribavirin (P/R) in a 4-week lead-in phase, followed by the addition of VICTRELIS after week 4. The studies also included a control arm in which patients received 48 weeks of treatment with P/R alone. Historical null responders were not enrolled.

Adding VICTRELIS to P/R achieved a significant increase in SVR rates compared to P/R alone

Primary results from the two pivotal studies:

• Treatment-failure patients: the addition of VICTRELIS to P/R resulted in nearly a three-fold increase in SVR rates to 59 percent (96/162) for the RGT arm and 66 percent (106/161) for the 48-week treatment arm, compared to 23 percent (18/80) for control. Relapse rates were 14 percent (16/111) for the RGT arm and 12 percent (14/121) for the 48-week treatment arm, compared to 28 percent (7/25) for control.
• Treatment-naïve patients: the addition of VICTRELIS to P/R resulted in a significant increase (1.7 fold) in SVR rates to 63 percent (232/368) for the RGT arm and 66 percent (242/366) for the 48-week treatment arm, compared to 38 percent (138/363) for control. Relapse rates were 9 percent (24/257) for the RGT arm and 9 percent (24/265) for the 48-week treatment arm, compared to 22 percent (39/176) for control.

In a separate, pre-specified cohort of 159 Black treatment-naïve patients, the addition of VICTRELIS to P/R resulted in a significant increase in SVR to 42 percent (22/52) for the RGT arm and 53 percent (29/55) for the 48-week treatment arm, compared to 23 percent (12/52) for control. Relapse rates were 12 percent (3/25) for the RGT arm and 17 percent (6/35) for the 48-week treatment arm, compared to 14 percent (2/14) for control.

Many patients receiving VICTRELIS in combination therapy were early responders at treatment week 8

Secondary analyses from the two pivotal studies were as follows:

• Treatment-failure patients: 46 percent (74/162) of patients in the RGT arm and 52 percent (84/161) of patients in the 48-week treatment arm receiving VICTRELIS had undetectable virus (HCV-RNA) at treatment week 8 and were considered early responders, compared to 9 percent (7/80) for control. The SVR rate for these early responders was 88 percent (65/74) in the RGT arm and 88 percent (74/84) in the 48-week treatment arm, compared to 100 percent (7/7) for control. Early responders in the RGT arm were eligible to stop all treatment at week 36.
• Treatment-naïve patients: 57 percent (208/368) of patients in the RGT arm and 56 percent (204/366) of patients in the 48-week treatment arm receiving VICTRELIS had undetectable virus (HCV-RNA) at treatment week 8 and were considered early responders, compared to 17 percent (60/363) for control. The SVR rate for these early responders was 88 percent (184/208) in the RGT arm and 90 percent (184/204) in the 48-week treatment arm, compared to 85 percent (51/60) for control. Early responders in the RGT arm were eligible to stop all treatment at week 28.

SVR achieved with VICTRELIS in combination therapy in late responders

• Treatment-failure patients: Patients who had detectable virus (HCV-RNA) at treatment week 8, but undetectable virus (HCV-RNA) at treatment week 12, and completed at least 36 weeks of treatment, were considered late responders. The SVR rate for these late responders was 79 percent (27/34) in the RGT arm and 72 percent (29/40) in the 48-week treatment arm. Late responders in the RGT arm stopped VICTRELIS at week 36 and continued P/R alone for an additional 12 weeks (48 weeks total).
• Treatment-naïve patients: Patients who had detectable virus (HCV-RNA) at treatment week 8, but undetectable virus (HCV-RNA) at treatment week 24, and completed at least 28 weeks of treatment, were considered late responders. The SVR rate for these late responders was 66 percent (45/68) in the RGT arm and 75 percent (55/73) in the 48-week treatment arm. Late responders in the RGT arm stopped VICTRELIS at week 28 and continued P/R alone for an additional 20 weeks (48 weeks total).

VICTRELIS in combination therapy increased SVR rates in specific patient populations

• The addition of VICTRELIS to P/R in treatment-failure patients with less than a 1 log decline in virus (HCV-RNA) during the 4-week lead-in resulted in an increase in SVR rates to 33 percent (15/46) for the RGT arm and 34 percent (15/44) for the 48-week treatment arm, compared to 0 percent (0/12) for control.
• In treatment-failure patients with cirrhosis at baseline, 77 percent (17/22) achieved SVR with the addition of 44 weeks of VICTRELIS to P/R, compared to 35 percent (6/17) for those who received RGT.
• In treatment-naïve patients with cirrhosis at baseline, 42 percent (10/24) achieved SVR with the addition of 44 weeks of VICTRELIS to P/R, compared to 31 percent (5/16) for those who received RGT.

Safety and tolerability profile of VICTRELIS in 2,095 patients in Phase II and III studies

• Serious adverse events were reported in 11 percent of patients receiving VICTRELIS in combination with P/R, compared to 8 percent of patients receiving P/R alone.
• During the entire course of treatment, the proportion of patients who discontinued treatment due to adverse reactions was 13 percent for patients receiving VICTRELIS in combination with P/R, compared to 12 percent for patients receiving P/R alone. Events resulting in discontinuation were similar to those seen in previous studies with P/R alone.
• Adverse reactions that led to dose modifications of any drug (primarily P/R) occurred in 39 percent of patients receiving the combination of VICTRELIS with P/R compared to 24 percent of patients receiving P/R alone.
• The most common reason for dose reduction was anemia, which occurred more frequently in patients receiving the combination of VICTRELIS with P/R than in patients receiving P/R alone.
• The proportion of patients who experienced anemia was higher in patients receiving VICTRELIS in combination with P/R than in those treated with P/R alone. With management of anemia, the average additional decrease of hemoglobin was approximately 1 g/dL. Dose modifications (generally of P/R) due to anemia occurred more often in patients treated with VICTRELIS in combination with P/R (26 percent), compared to those treated with P/R alone (13 percent). Treatment discontinuations due to anemia were similar for patients receiving VICTRELIS in combination with P/R
  (1 percent) compared to those treated with P/R alone (1 percent). Erythropoietin (EPO) with or without ribavirin dose reduction for management of anemia was allowed at the discretion of the investigator per the study protocol.

In pivotal clinical studies, the 4-week lead-in provided important clinical insights

Interferon-responsiveness (equal to or greater than a 1 log decline in virus (HCV-RNA) at treatment week 4) was predictive of SVR. Patients receiving VICTRELIS who demonstrated interferon-responsiveness at treatment week 4 achieved higher SVR rates than those with poor interferon-responsiveness (less than a 1 log decline in virus (HCV-RNA) at treatment week 4). During the four-week lead-in period with P/R in the treatment arms containing VICTRELIS, 2 percent (28/1263) of patients experienced adverse reactions leading to discontinuation of treatment.

Background on the pivotal Phase III studies for VICTRELIS

The HCV RESPOND-2 study (treatment-failure patients) and the HCV SPRINT-2 study (treatment-naïve patients) each evaluated two treatment strategies with VICTRELIS added to P/R to assess the ability of VICTRELIS to improve SVR rates and potentially shorten overall treatment duration, compared to the use of P/R alone for 48 weeks, which is the current standard duration of therapy.

In both studies, all patients receiving VICTRELIS 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.

In each study, patients were randomized to three groups:

• Response-guided therapy (RGT), in which patients with undetectable virus (HCV-RNA) at treatment week 8 were considered early responders and were eligible for a shorter duration of therapy. Treatment-naïve patients with undetectable HCV-RNA during weeks 8 through 24 were eligible to stop all treatment at week 28. Treatment-failure patients with undetectable HCV-RNA at treatment weeks 8 and 12 were eligible to stop all treatment at week 36.
• 48 weeks of treatment, in which patients received a 4-week lead-in with P/R followed by 44 weeks of VICTRELIS in combination with P/R.
• Control, in which patients received P/R for 48 weeks.

In the HCV RESPOND-2 study, all patients with detectable virus (HCV-RNA) at treatment week 12 were discontinued from treatment. In the HCV SPRINT-2 study, all patients with detectable virus (HCV-RNA) at treatment week 24 were discontinued from treatment.

The HCV RESPOND-2 study was conducted at U.S. and international sites, and included 403 adult patients who had failed prior treatment, including patients who relapsed or were partial responders to prior treatment with standard therapy. Historical null responders were not enrolled. Patients were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. partial responders) and by HCV genotype (1a or 1b).

The HCV SPRINT-2 study was conducted at U.S. and international sites in 1,097 adult patients who were new to treatment. Patients were randomized in a 1:1:1 ratio within two separate cohorts (938 non-Black patients and 159 Black patients) and were stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (less than or equal to 400,000 IU/mL vs. greater than 400,000 IU/mL). Black patients with chronic HCV historically have been shown to be harder to treat successfully.

Final results of the HCV RESPOND-2 and HCV SPRINT-2 studies were published in the New England Journal of Medicine on March 31, 2011.

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 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 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.

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 that were treated with 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 untreated patients that were treated with 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 prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.

Dosing and administration

VICTRELIS must be administered in combination with peginterferon alfa and ribavirin. Therapy is initiated with peginterferon alfa and ribavirin for 4 weeks. Beginning in treatment week 5, VICTRELIS is added at a dose of 800 mg (four 200 mg capsules) orally three times daily (every 7-9 hours) with food (a meal or light snack). Based on the patient's virus (HCV-RNA) levels at treatment weeks 8, 12 and 24, dosing is adjusted using the following response-guided therapy guidelines.

• Treatment-naive patients: Patients who are undetectable at treatment weeks 8 and 24 complete all therapy at treatment week 28. Patients who are detectable at treatment week 8, but undetectable at treatment week 24, complete VICTRELIS at treatment week 36 and continue on peginterferon alfa and ribavirin alone until treatment week 48.
• Treatment-failure patients: Patients (previous partial responders or relapsers) who are undetectable at treatment weeks 8 and 24 complete all therapy at treatment week 36. Patients who are detectable at treatment week 8, but undetectable at treatment week 24, complete VICTRELIS at treatment week 36 and continue on peginterferon alfa and ribavirin alone until treatment week 48. Response-guided therapy was not studied in treatment-failure patients who had less than a 2 log decrease in virus (HCV-RNA) at treatment week 12 of prior treatment (null responders). If treated, these patients should receive 4 weeks of peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS in combination with peginterferon alfa and ribavirin.

Patients with compensated cirrhosis should receive 4 weeks peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS in combination with peginterferon alfa and ribavirin.

Patients who have HCV-RNA results greater than or equal to 100 IU/mL at treatment week 12 discontinue the three-medicine regimen. Patients who have confirmed detectable HCV-RNA at treatment week 24 discontinue the three-medicine regimen.

The wholesale acquisition cost (WAC) of VICTRELIS per week is $1,100.

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The Prescribing Information and Medication Guide are available at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.

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¹ SVR, the protocol specified primary efficacy endpoint of the pivotal studies, 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^™ is a trademark 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.