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

[Guest guest]

http://www.mdlinx.com/gastroenterology/template_cms.cfm?rec_rep= & int_ind=0 & quiz_\

id=2611 & m_id=50114 & rep_id=4311 & gi=#currQ FDA Approves Merck's VICTRELIS™

(boceprevir), First-in-Class Oral Hepatitis C Virus (HCV) Protease

InhibitorWHITEHOUSE STATION, N.J., May 13, 2011 — 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

CVICTRELIS 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

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 alonePrimary 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 8Secondary 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

respondersTreatment-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 populationsThe 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

studiesSerious 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

insightsInterferon-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

VICTRELISThe 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

VICTRELISAll 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. '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 treated 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 and

http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202258lbl.pdf.Dosing

and administrationVICTRELIS 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.<CUT>Please see

attached Prescribing Information for VICTRELIS. The Prescribing Information is

also available at:

http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and

http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202258lbl.pdf.VICTRELIS

is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse

Station, N.J., USA.

[Guest guest]

http://www.mdlinx.com/gastroenterology/template_cms.cfm?rec_rep= & int_ind=0 & quiz_\

id=2611 & m_id=50114 & rep_id=4311 & gi=#currQ FDA Approves Merck's VICTRELIS™

(boceprevir), First-in-Class Oral Hepatitis C Virus (HCV) Protease

InhibitorWHITEHOUSE STATION, N.J., May 13, 2011 — 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

CVICTRELIS 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

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 alonePrimary 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 8Secondary 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

respondersTreatment-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 populationsThe 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

studiesSerious 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

insightsInterferon-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

VICTRELISThe 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

VICTRELISAll 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. '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 treated 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 and

http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202258lbl.pdf.Dosing

and administrationVICTRELIS 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.<CUT>Please see

attached Prescribing Information for VICTRELIS. The Prescribing Information is

also available at:

http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and

http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202258lbl.pdf.VICTRELIS

is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse

Station, N.J., USA.