Interim Phase II Data of Merck’s Investigational MK-5172 in Combination Therapy in Chronic Hepatitis C Virus Genotype 1 Infection to be Presented at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting
November 10, 2012 9:00 am ET
Merck (NYSE: MRK), known as MSD outside of the United States and Canada,
announced interim results from a Phase II, multi-center, randomized,
dose-ranging study (n=332) assessing the safety and antiviral activity
of MK-5172, an investigational, once-daily, oral NS3/4A protease
inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype
1 infection in combination therapy in treatment-naïve patients. These
data will be presented this week at the American Association for the
Study of Liver Diseases Annual Meeting (AASLD).
The primary efficacy endpoint of the study was to evaluate the complete
early viral response (cEVR) of four regimens of MK-5172 in combination
with peginterferon alfa-2b and ribavirin (PR) compared to the control
arm in which patients received a 4-week lead-in of PR followed by the
addition of VICTRELIS® (boceprevir) 200 mg Capsules. cEVR was
assessed by the proportion of patients who achieved undetectable virus
(HCV RNA) at treatment week (TW) 12 in the investigational arms and at
TW 16 in the control arm. The MK-5172 regimens had rates of cEVR ranging
from 82.8 to 93 percent, versus the control of 74.2 percent.
In the initial cohort, termed the “Vanguard Cohort,” (n=136), 96 percent
of patients (25/26) who received a regimen containing 100 mg QD of
MK-5172 with PR achieved sustained virologic response (SVR) 12, defined
as having undetectable virus (HCV RNA) 12 weeks after treatment ended,
compared to 54 percent of patients (13/24) in the control arm.
“We are excited by these interim results evaluating MK-5172 in
combination therapy,” said Eliav Barr, M.D., vice president, Infectious
Diseases, Project Leadership and Management, Merck Research
Laboratories. “Our commitment to chronic hepatitis C remains steadfast.
We look forward to continuing our studies of MK-5172, including in
interferon-free regimens.”
Currently planned studies evaluating interferon-free regimens with
MK-5172 will be dosed at 100 mg QD.
Other data to be presented on MK-5172 at AASLD include results from a
preclinical study evaluating the antiviral activities of MK-5172 in
combination with MK-8742, an oral HCV NS5A inhibitor in Phase I
development.
Indications and Usage for VICTRELIS (boceprevir)
VICTRELIS is indicated for the treatment of chronic hepatitis C virus
(HCV) genotype 1 (G1) infection, in combination with peginterferon alfa
and ribavirin (PR), in adult patients (18 years and older) with
compensated liver disease, including cirrhosis, who are previously
untreated or who have failed previous interferon and ribavirin therapy.
The following points should be considered when initiating VICTRELIS for
treatment of chronic HCV infection:
-
VICTRELIS must not be used as monotherapy and should only be used in
combination with PR. -
VICTRELIS efficacy has not been studied in patients who have
previously failed therapy with a treatment regimen that includes
VICTRELIS or other HCV NS3/4A protease inhibitors. -
VICTRELIS in combination with PR has not been studied in patients
documented to be historical null responders [less than a 2 log10
HCV-RNA decline by treatment week (TW) 12] during prior therapy with
PR. The clinical studies included patients who were poorly interferon
responsive. Patients with less than 0.5 log10 HCV-RNA
decline in viral load at TW 4 with PR alone are predicted to have a
null response (less than a 2 log10 viral load decline by TW
12) to PR therapy. -
Poorly interferon responsive patients who were treated with VICTRELIS
in combination with PR have a lower likelihood of achieving a
sustained virologic response (SVR), and higher rate of detection of
resistance-associated substitutions upon treatment failure, compared
to patients with a greater response to PR.
About the Study
This Phase II, multi-center, double-blind, randomized,
active-controlled, dose ranging, response-guided therapy (RGT) study is
designed to examine the safety and antiviral activity of MK-5172
administered with peginterferon alfa-2b (1.5 µg/kg/week) and an
investigational, weight-based dose of ribavirin (600-1,400 mg/day) (PR)
in non-cirrhotic, treatment-naïve, adult patients with chronic HCV
genotype 1 infection. In the study, 332 patients were enrolled in two
cohorts: the Vanguard Cohort of 136 patients, followed by a Second
Cohort of 196 patients. In both cohorts, patients were randomized to one
of four MK-5172 treatment arms (100 mg QD, 200 mg QD, 400 mg QD, 800 mg
QD). All patients received MK-5172 in combination with PR for 12 weeks
followed by PR for 12 or 36 weeks, depending on treatment response at TW
4. If the patient’s virus (HCV RNA) was target not detected (TND; <10
IU/mL) at TW 4, then the patient was able to stop all therapy at TW 24.
If the patient's virus was target detected unquantifiable (TD(u); <25
IU/mL) or target detected quantifiable (TD(q)) at TW 4, then the patient
stopped all therapy at TW 48. In the control arm, patients received a
4-week lead-in of PR followed by the addition of VICTRELIS (boceprevir)
administered per the U.S. Prescribing Information.
After the primary TW 12 analysis of the MK-5172 arms in the Vanguard
cohort, patients receiving the 400 mg and 800 mg doses in the Second
Cohort were down-dosed due to elevated liver transaminases and began to
receive 100 mg in an open-label fashion between weeks 3 and 12 of
MK-5172 therapy.
Current Status of Study
All patients in both cohorts of the study (termed the Combined Cohort
when analyzed together) have reached the primary endpoint of the study,
cEVR, or have discontinued early. cEVR values reflect both those
patients with both undetectable (TND) and detectable unquantifiable
(TD(u)) HCV RNA. In the Second Cohort, 134 of 156 patients randomized
into the MK-5172 arms are receiving PR (n=17) or are in the follow-up
phase (n=117) of the study. All patients in the Vanguard Cohort who
received MK-5172 are in the follow-up phase of the study or have
discontinued early.
Of the patients randomized to the MK-5172 arms, 2.3 percent (6/266) met
the protocol-defined criteria for virologic failure: one (1) patient was
re-infected with genotype 3 infection; and four patients had no
detectable (n=3) or low (n=1) levels of MK-5172 at time of failure and
for a period of time prior. The primary efficacy analysis
included the full analysis set (FAS) of all randomized patients who
received at least one dose of study treatment.
SVR12 Results in the Vanguard Cohort
In the Vanguard Cohort, higher SVR12 rates were achieved across all
MK-5172 arms compared to control (FAS) – 96.2 percent (25/26) in the
MK-5172 100 mg arm; 86.7 percent (26/30) in the MK-5172 200 mg arm; 87.0
percent (20/23) in the MK-5172 400 mg arm; and 81.5 percent (22/27) in
the MK-5172 800 mg arm; versus 54.2 percent (13/24) in the control arm.
In these results, all patients had undetectable (TND) HCV RNA.
Safety Findings
In the MK-5172 arms of the study, there were two transient liver
abnormalities observed – early elevations in total bilirubin before TW
4, associated with normalization of alanine aminotransferase/aspartate
aminotransferase (ALT/AST) levels, and late elevations in liver
transaminases (ALT/AST) occurring after TW 4.
Patients with Early Total Bilirubin Elevations
| Arm 1 | Arm 2 | Arm 3 (N=67) | Arm 4 (N=65) | Arm 5 | ||||||||||
| MK-5172 | MK-5172 | VC | SC* | VC | SC* | BOC | ||||||||
|
100 mg |
200 mg |
MK-5172 |
MK-5172 | MK-5172 | MK-5172 |
800 mg tid |
||||||||
|
|
|
400 mg |
400 mg |
800 mg |
800 mg |
|
||||||||
| (n=66) | (n=68) | (n=24) | (n=43) | (n=29) | (n=36) | (n=66) | ||||||||
|
Total |
1 (1.5%) | 8 (11.8%) | 2 (8.3%) | 4 (9.3%) | 2 (6.9%) | 7 (19.2%) | 2 (3.0%) | |||||||
PR, peginterferon alfa-2b + ribavirin; ULN, upper limit of normal.
BOC, boceprevir; PR, peginterferon alfa-2b + ribavirin; SC, second
cohort; VC, vanguard cohort.
*Patients receiving the 400 mg and 800 mg doses in the SC were
down-dosed to receive 100 mg in an open-label fashion. Down dosing
occurred in the SC at various time points while on MK-5172. No patients
were dosed down in the VC.
Of those patients with bilirubin elevation, 92 percent (22/24) occurred
within the first seven to 23 days of therapy, and their bilirubin levels
decreased from peak levels despite continued dosing.
Patients With Late ALT/AST Elevations
| Arm 1 | Arm 2 | Arm 3 (N=67) | Arm 4 (N=65) | Arm 5 | ||||||||||
| Parameter | MK-5172 | MK-5172 | VC | SC* | VC | SC* | MK-5172 | |||||||
|
100 mg |
200 mg |
MK-5172 | MK-5172 | MK-5172 | MK-5172 | |||||||||
|
400 mg |
400 mg |
800 mg |
800 mg |
100 mg |
||||||||||
| (n=66) | (n=68) | (n=24) | (n=43) | (n=29) | (n=36) | (n=66) | ||||||||
|
Patients |
1 (2%) | 6 (9%) | 5 (21%) | 8 (19%) | 7 (24%) | 8 (22%) | 1 (2%) | |||||||
ALT, alanine aminotransferase; AST, aspartate aminotransferase; PR,
peginterferon alfa-2b + ribavirin; ULN, upper limit of normal.
*Patients receiving the 400 mg and 800 mg doses in the SC were
down-dosed to receive 100 mg in an open-label fashion. Down dosing
occurred in SC at various time points while on MK-5172. No patients were
down-dosed in the VC.
The frequency and severity of ALT/AST elevations after TW 4 were dose
dependent. The frequencies of ALT/AST elevations in the MK-5172 100 mg
arm and the control arm after TW 4 were comparable at 2 percent each,
(1/66) and (1/66), respectively. The frequency of ALT/AST
elevations observed in the MK-5172 200 mg, MK-5172 400 mg and MK-5172
800 mg arms after TW 4 were higher.
One patient in the MK-5172 800 mg arm experienced a serious adverse
event due to elevated ALT and total bilirubin levels, which returned to
normal after discontinuation of all therapy.
Important Safety Information about VICTRELIS (boceprevir)
All contraindications to PR also apply since VICTRELIS must be
administered with PR. Because ribavirin may cause birth defects and
fetal death, VICTRELIS in combination with PR is contraindicated in
pregnant women and in men whose female partners are pregnant. Avoid
pregnancy in female patients and female partners of male patients.
Patients must have a negative pregnancy test prior to therapy; have
monthly pregnancy tests; and use two or more forms of effective
contraception, including intrauterine devices and barrier methods,
during treatment and for at least 6 months after treatment has
concluded. Systemic hormonal contraceptives may not be as effective in
women while taking VICTRELIS (boceprevir). VICTRELIS is contraindicated
in coadministration with drugs that are highly dependent on CYP3A4/5 for
clearance, and for which elevated plasma concentrations are associated
with serious and/or life-threatening events.
VICTRELIS also is contraindicated in coadministration with potent
CYP3A4/5 inducers, where significantly reduced VICTRELIS plasma
concentrations may be associated with reduced efficacy. Drugs that are
contraindicated with VICTRELIS (boceprevir) include: alfuzosin,
carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine,
ergonovine, ergotamine, methylergonovine, cisapride, St. John’s Wort
(hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio®
(sildenafil) or Adcirca® (tadalafil) (when used for the
treatment of pulmonary arterial hypertension), pimozide, triazolam, and
orally administered midazolam.
Anemia and/or Neutropenia — The addition of VICTRELIS (boceprevir) to
PR is associated with an additional decrease in hemoglobin
concentrations compared to PR alone and/or may result in worsening of
neutropenia associated with PR therapy alone. Dose reduction or
discontinuation of peginterferon alfa and/or ribavirin may be required.
Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be
administered in the absence of PR.
Complete blood counts (with white blood cell differential counts) must
be conducted in all patients prior to initiating combination therapy
with VICTRELIS. Complete blood counts should be obtained at TW 4, 8 and
12, and should be monitored closely at other time points, as clinically
appropriate.
The most commonly reported adverse reactions (greater than 35 percent)
in clinical trials in adult patients receiving the combination of
VICTRELIS with PR were fatigue, anemia, nausea, headache and dysgeusia.
Of these commonly reported adverse reactions, fatigue, anemia, nausea,
and dysgeusia occurred at rates greater than or equal to 5 percent above
the rates for PR alone in either clinical study. The incidence of these
adverse reactions in previously untreated patients who were treated with
combination therapy with VICTRELIS compared with these adverse reactions
in previous treatment-failure patients who were treated with combination
therapy with VICTRELIS compared with PR alone were: fatigue (55 vs. 50
percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and
dysgeusia (44 vs. 11 percent), respectively.
VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by
CYP3A4/5. The potential for drug-drug interactions must be considered
prior to and during therapy.
Please see U.S. Prescribing Information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf
Merck’s Global Commitment to Advancing Hepatitis Therapy
Merck is committed to building on its strong legacy in the field of
viral hepatitis by continuing to discover, develop and deliver vaccines
and medicines to help prevent and treat viral hepatitis. In hepatitis
C, company researchers developed the first approved therapy for chronic
HCV in 1991 and the first combination therapy in 1998. In addition to
ongoing studies with VICTRELIS (boceprevir), extensive research efforts
are underway to develop additional oral therapies for viral hepatitis
treatment.
About Merck
Today’s Merck is a global healthcare leader working to help the world be
well. Merck is known as MSD outside the United States and Canada.
Through our prescription medicines, vaccines, biologic therapies, and
consumer care and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
healthcare through far-reaching policies, programs and partnerships. For
more information, visit www.merck.com
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but are not limited to, statements about the benefits of the merger
between Merck and Schering-Plough, including future financial and
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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.
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Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.
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