Merck Announces Results From Phase 3 Studies of ZEPATIER™ (Elbasvir and Grazoprevir) in Chronic Hepatitis C Patient Populations at The International Liver Congress™


April 16, 2016 12:00 am ET

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside of the United States and Canada,
today announced the presentation of results from two Phase 3 clinical
trials evaluating ZEPATIER™ (elbasvir and grazoprevir) 50mg/100mg
tablets in chronic hepatitis C (HCV) patients with inherited blood
disorders (C-EDGE
) and in patients with a history of intravenous drug
use who are receiving opioid agonist therapy (C-EDGE
), respectively. Results from C-EDGE IBLD
demonstrated high rates of sustained virologic response (SVR) 12 weeks
after the completion of treatment (SVR12, considered virologic cure) and
a safety profile consistent with that observed in prior studies
(abstract #SAT-128). Findings from C-EDGE CO-STAR showed a high
rate of SVR 24 weeks after completion of treatment (SVR24) for the
baseline chronic HCV infection and provided insights into the incidence
of reinfection in this high risk population (abstract #SAT-163). The
SVR24 data confirm the C-EDGE
SVR12 results
unveiled at The
Liver Meeting®
in November 2015. ZEPATIER
Merck’s once-daily, fixed-dose combination tablet indicated with or
without ribavirin (RBV) for the treatment of chronic HCV genotype (GT) 1
or GT4 infection in adults was approved by the U.S. Food and
Drug Administration in January 2016, based in part on prior studies from
the Phase 3 program. Data from these additional Phase 3 studies were
presented today at The
International Liver CongressTM 2016

“To reduce the global burden and potential spread of chronic hepatitis
C, it is important that we develop evidence about meaningful options for
those patients for whom treatment may be challenging,” said Dr. Eliav
Barr, vice president, infectious diseases, Merck Research Laboratories.
“These data from Merck’s broad clinical development program underscore
the company’s commitment to evaluating ZEPATIER in historically
underserved and understudied chronic hepatitis C populations, such as
patients with inherited blood disorders or those receiving opioid
agonist therapy.”

C-EDGE IBLD Overview and Findings

C-EDGE IBLD is a Phase 3 randomized, double-blind,
placebo-controlled study evaluating treatment with ZEPATIER (elbasvir
and grazoprevir) in patients with chronic HCV GT1, GT4 or GT6 infection
and inherited blood disorders, including hemophilia A/B, von Willebrand
disease, beta thalassemia and sickle cell anemia. Patients were
randomized in a 2:1 ratio to either an immediate treatment group (ITG;
12 weeks of ZEPATIER) or deferred treatment group (DTG; 12 weeks of
placebo as control arm, followed by 12 weeks of open-label ZEPATIER).
The primary efficacy endpoint for the study was the proportion of
patients in the ITG who achieved SVR12. Safety and tolerability were
evaluated by comparing subjects receiving ZEPATIER in the ITG (n=107) to
those receiving placebo in the DTG (n=52).

Following 12 weeks of treatment with ZEPATIER, 93 percent of patients in
the ITG (100/107) achieved SVR12 (virologic cure). Six patients relapsed
following twelve weeks of treatment; five of these patients (3 GT1a, 1
GT1b and 1 GT4) had detectable NS5A resistance-associated polymorphisms
at baseline.1 The study did not evaluate other ZEPATIER-based
dosage regimens or durations.

The most common (greater than 10%) adverse events (AEs) among patients
receiving ZEPATIER for 12 weeks in C-EDGE IBLD, compared with
those receiving placebo, were headache (21%, 12%) and fatigue (17%, 8%).
No patient receiving ZEPATIER discontinued due to AEs, compared with one
patient receiving placebo. Three patients (3%) receiving ZEPATIER and
six patients (12%) receiving placebo reported a total of 12 serious AEs.
Treatment did not affect pre-defined hematological parameters and did
not interfere with the management of underlying blood disorders.

C-EDGE CO-STAR Overview and Findings

C-EDGE CO-STAR is a Phase 3 double-blind, placebo-controlled
study evaluating treatment with ZEPATIER in patients with chronic HCV
GT1, GT4 and/or GT6 infection who are on opioid agonist therapy (i.e.,
methadone, buprenorphine). Efficacy (SVR12) and safety results from the
trial were previously presented at The Liver Meeting® in
November 2015. Results presented at ILC this week included secondary
efficacy endpoint (SVR24) and reinfection analyses. A separate analysis
of health-related quality of life data from C-EDGE CO-STAR was
also presented this week at ILC.

The study included an immediate treatment group (ITG) that received
blinded ZEPATIER (elbasvir and grazoprevir) for 12 weeks (n=201) and a
deferred treatment group (DTG) that received 12 weeks of placebo
(control arm) (n=100), followed by 12 weeks of open-label ZEPATIER
(n=95). The secondary efficacy analysis evaluated SVR24 in the modified
full analysis set (n=271), which included patients from both treatment
groups who received ZEPATIER for 12 weeks and completed 24 weeks of
follow up, excluding those who discontinued for non-treatment related
reasons. An additional analysis evaluated the reinfection incidence
among all patients who completed active study therapy (n=296).

Following 12 weeks of treatment with ZEPATIER, 94 percent (175/186) and
96 percent (82/85) of patients achieved SVR24 in the ITG (blinded) and
DTG (open-label), respectively. The analysis of 296 patients showed six
probable HCV reinfections occurred,2 including five through
follow up week 12 (FU12) in the ITG and one additional by FU24 in the
DTG. These results represent a reinfection incidence of 3.4 cases (95%
CI: 1.3, 7.5) per 100 person years after 24 weeks of follow up. Patients
in the trial will be evaluated regularly for three years following the
24-week period.

An analysis of AEs during the initial treatment period and first two
weeks of follow-up showed the most common AEs among patients receiving
blinded ZEPATIER or placebo were fatigue (16%, 20%), headache (13%,
14%), nausea (11%, 9%) and diarrhea (10%, 9%), respectively. Reported
AEs in the open-label treatment group were similar to the blinded group
(fatigue, 14%; headache, 13%; nausea, 7%; diarrhea, 8%). One patient
receiving ZEPATIER and one patient receiving placebo reported serious
treatment-related AEs. In addition, one patient receiving ZEPATIER and
one patient receiving placebo discontinued due to AEs.

“Injection drug use is one of the leading contributors to the spread of
hepatitis C infection around the world. Many current or former injection
drug users with chronic hepatitis C infection are on opioid agonist
therapy, but historically there has been reluctance to treat these
patients due to concerns about reinfection and compliance with
treatment,” said Dr. Barr. “These results from C-EDGE CO-STAR
help contribute to our understanding of the incidence of hepatitis C
reinfection in these patients following treatment with ZEPATIER.”

Selected Safety Information about ZEPATIER (elbasvir and grazoprevir)

ZEPATIER (elbasvir and grazoprevir) is not for use in patients with
moderate or severe hepatic impairment (Child Pugh B or C). ZEPATIER is
also not for use with organic anion transporting polypeptides 1B1/3
(OATP1B1/3) inhibitors (e.g., atazanavir, darunavir, lopinavir,
saquinavir, tipranavir, cyclosporine), strong cytochrome P450 3A (CYP3A)
inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort),
and efavirenz. If ZEPATIER is administered with ribavirin (RBV),
healthcare professionals should refer to the prescribing information for
RBV as the contraindications, warnings and precautions, adverse
reactions and dosing for RBV also apply to this combination regimen.

Elevations of alanine transaminase (ALT) to greater than 5 times the
upper limit of normal (ULN) occurred in 1% of subjects, generally at or
after treatment week 8. These late ALT elevations were typically
asymptomatic and most resolved with ongoing or completion of therapy.
Healthcare professionals should perform hepatic lab testing on patients
prior to therapy, at treatment week 8, and as clinically indicated. For
patients receiving 16 weeks of therapy, additional hepatic lab testing
should be performed at treatment week 12.

Patients should be instructed to consult their healthcare professional
without delay if they have onset of fatigue, weakness, lack of appetite,
nausea and vomiting, jaundice or discolored feces. Healthcare providers
should consider discontinuing ZEPATIER if ALT levels remain persistently
greater than 10 times ULN. ZEPATIER should be discontinued if ALT
elevation is accompanied by signs or symptoms of liver inflammation or
increasing conjugated bilirubin, alkaline phosphatase, or international
normalized ratio.

The concomitant use of ZEPATIER with certain drugs may lead to possible
clinically significant adverse reactions from greater exposure to
ZEPATIER or concomitant drugs. Coadministration of ZEPATIER is not
recommended with certain strong CYP3A inhibitors (e.g., ketoconazole or
the cobicistat-containing regimens of
elvitegravir/cobicistat/emtricitabine/tenofovir [disoproxil fumarate or
alafenamide]). Healthcare professionals should not exceed atorvastatin
20mg/daily or rosuvastatin 10mg/daily when given with ZEPATIER. If
ZEPATIER is given with fluvastatin, lovastatin or simvastatin,
healthcare professionals should give the lowest statin dose necessary
and closely monitor for statin-associated adverse events. If ZEPATIER
and tacrolimus are coadministered, frequent monitoring of tacrolimus
whole blood concentrations, changes in renal function and
tacrolimus-associated adverse events is recommended.

The concomitant use of ZEPATIER and certain drugs may cause significant
decrease of elbasvir and grazoprevir plasma concentrations, which may
lead to reduced therapeutic effect of ZEPATIER (elbasvir and
grazoprevir) and possible development of resistance. Coadministration of
ZEPATIER is not recommended with moderate CYP3A inducers (e.g.,
nafcillin, bosentan, etravirine, modafinil).

In subjects receiving ZEPATIER for 12 weeks, the most commonly reported
adverse reactions of all intensity (greater than or equal to 5% in
placebo-controlled trials) were fatigue, headache and nausea. In
subjects receiving ZEPATIER with RBV for 16 weeks, the most commonly
reported adverse reactions of moderate or severe intensity (greater than
or equal to 5%) were anemia and headache.

About ZEPATIER™ (elbasvir and grazoprevir) 50mg/100 mg Tablets

ZEPATIER is a fixed-dose combination product containing elbasvir, a
hepatitis C virus (HCV) NS5A inhibitor, and grazoprevir, an HCV NS3/4A
protease inhibitor, and is indicated with or without ribavirin (RBV) for
treatment of chronic HCV genotype (GT) 1 or GT4 infection in adults. The
dosing regimens and durations for treatment with once-daily ZEPATIER for
chronic HCV GT1 or GT4 infection in patients with or without cirrhosis,
HIV-1 co-infection or renal impairment are as follows:

  • Twelve weeks of treatment with ZEPATIER is recommended for:
    GT1a-infected patients who are treatment-naïve or who failed prior
    treatment with peginterferon alfa plus RBV (PegIFN/RBV-experienced)
    without baseline NS5A resistance-associated polymorphisms (amino acid
    positions 28, 30, 31 or 93); GT1b-infected patients who are
    treatment-naïve or PegIFN/RBV-experienced; and GT4-infected patients
    who are treatment-naïve.
  • Twelve weeks of treatment with ZEPATIER in combination with RBV is
    recommended for GT1a- or GT1b-infected patients who failed prior
    treatment with PegIFN/RBV + a HCV NS3/4A protease inhibitor (PI)
    (boceprevir, simeprevir or telaprevir). For GT1a-infected
    PegIFN/RBV/PI-experienced patients with one or more baseline NS5A
    resistance-associated polymorphisms, the optimal ZEPATIER-based
    treatment regimen and duration of therapy has not been established.
  • Sixteen weeks of treatment with ZEPATIER in combination with RBV is
    recommended for: GT1a-infected patients who are treatment-naïve or
    PegIFN/RBV-experienced with baseline NS5A resistance-associated
    polymorphisms; and GT4-infected patients who are

For patients with chronic HCV GT1a infection, testing for the presence
of NS5A resistance-associated polymorphisms is recommended prior to
starting treatment with ZEPATIER (elbasvir and grazoprevir) to determine
the optimal dosage regimen and duration.

Merck’s Commitment to HCV

For nearly 30 years, Merck has been at the forefront of the response to
the HCV epidemic. Merck employees are dedicated to applying their
scientific expertise, resources and global reach to develop and deliver
innovative healthcare solutions to support people living with chronic
HCV worldwide.

About Merck

For 125 years, Merck has been a global health care 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 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
health care through far-reaching policies, programs and partnerships.
For more information, visit
and connect with us on Twitter,
and LinkedIn.

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Commission (SEC) available at the SEC’s Internet site (

Please see Prescribing Information for ZEPATIER (elbasvir and
grazoprevir) at
and the Patient Information for ZEPATIER at


1 Any variant at amino acid position 28, 30, 31 or 93, as
determined by population sequencing.

2 Reinfection determined by virologic failure with a
different genotype, subtype or viral strain compared to baseline virus.

Pamela Eisele, 267-305-3558
Sarra Herzog, 201-669-6570
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898

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