KENILWORTH, N.J., Jan. 28, 2016 /PRNewswire/ -- Merck (NYSE:
MRK), known as MSD outside the United
States and Canada, today
announced that the U.S. Food and Drug Administration (FDA) has
approved ZEPATIER™ (elbasvir and grazoprevir) for the
treatment of adult patients with chronic hepatitis C virus (HCV)
genotype (GT) 1 or GT4 infection, with or without ribavirin (RBV),
following priority review by the FDA. ZEPATIER (pronounced
ZEP-ah-teer) is a once-daily, fixed-dose combination tablet
containing the NS5A inhibitor elbasvir (50 mg) and the NS3/4A
protease inhibitor grazoprevir (100 mg). The FDA previously granted
two Breakthrough Therapy designations to ZEPATIER, for the
treatment of chronic HCV GT1 infection in patients with end stage
renal disease on hemodialysis, and for the treatment of patients
with chronic HCV GT4 infection. Breakthrough Therapy designation is
given to investigational medicines for serious or life-threatening
conditions that may offer substantial improvement over existing
therapies. Across multiple clinical studies, ZEPATIER achieved high
rates of sustained virologic response ranging from 94 to 97 percent
in GT1-infected patients, and 97 to 100 percent in GT4-infected
patients. Sustained virologic response is defined as HCV RNA levels
measuring less than the lower limit of quantification at 12 weeks
after the cessation of treatment (SVR12), indicating that a
patient's HCV infection has been cured.
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ZEPATIER is not for use in patients with moderate or severe
hepatic impairment (Child-Pugh B or C). ZEPATIER also is 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 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.
"Continued innovation is needed to help address the worldwide
epidemic of chronic hepatitis C virus infection," said Dr.
Roger M. Perlmutter, president,
Merck Research Laboratories. "Our clinical program was designed to
study a broad range of patients infected with the hepatitis C
virus, including difficult-to-treat patients such as those with
stage 4 or 5 chronic kidney disease. The approval of ZEPATIER is a
testament to Merck's unwavering commitment to improving therapy for
patients with hepatitis C virus infection, and we are eager to
bring this innovation to patients and physicians in the United States."
ZEPATIER was approved with a treatment duration of 12 or 16
weeks, depending on HCV genotype, prior treatment history and, for
patients with GT1a infection, the presence of certain baseline NS5A
polymorphisms. A 12-week, once-daily regimen is recommended for the
vast majority of patients for whom ZEPATIER is indicated.
Merck's broad clinical trial program supporting the efficacy of
ZEPATIER included six studies in 1,373 patients with chronic HCV
GT1 or GT4 infection. These studies assessed the rate of sustained
virologic response 12 weeks after the completion of treatment with
ZEPATIER (SVR12). The clinical development program for ZEPATIER
enrolled diverse groups of HCV GT1- and GT4-infected patients,
including treatment-naïve patients and those who had failed prior
therapy with peginterferon alfa (PegIFN) and RBV, as well as
patients suffering with meaningful co-morbidities and health
complications, such as compensated cirrhosis and HIV-1
co-infection. GT1-infected patients with severe renal impairment on
hemodialysis and those who previously failed therapy with PegIFN
and RBV in combination with an HCV NS3/4A protease inhibitor
(boceprevir, simeprevir or telaprevir) also were studied.
The following table provides a summary of clinical data that
contributed to the efficacy assessment of ZEPATIER. The primary
endpoint in each study was SVR12. Please see section entitled
Summary of Study Designs below for additional study design
information, including treatment arms and baseline
characteristics.
Clinical Studies Supporting Efficacy of ZEPATIER
(elbasvir and grazoprevir):
Clinical
Trial(s)
|
Population
|
SVR12
(n/N)
|
Treatment
Regimen and
Duration
|
GT1
|
|
|
|
C-EDGE TN
(double blind, placebo
controlled)
|
TN +/-
cirrhosis
|
95%
(273/288)
|
ZEPATIER
12 weeks
|
C-EDGE
CO-INFXN (open-label, single
arm)
|
TN +/- cirrhosis +
HIV-1
co-infection
|
95%
(179/189)
|
C-SURFER (double blind,
placebo
controlled)
|
TN/TEa +/-
cirrhosis +
severe renal impairment
|
94%
(115/122)
|
C-EDGE
TEd (open-label,
comparative)
|
TEb +/-
cirrhosis +/- HIV-
1 co-infection
|
94%
(90/96)
97%
(93/96)
|
ZEPATIER
12 weeks
ZEPATIER
+ RBV
16 weeks
|
C-SALVAGE
(open-label, single arm)
|
TEc +/-
cirrhosis
|
96%
(76/79)
|
ZEPATIER
+ RBV
12 weeks
|
GT4
|
|
|
|
C-SCAPE
(open-label)
C-EDGE
TN
C-EDGE
CO-INFXN
|
TN without
cirrhosis
TN +/-
cirrhosis
TN +/- cirrhosis +
HIV-1
co-infection
|
97%
(64/66)
|
ZEPATIER
12 weeks
|
C-EDGE
TE
|
TEb +/-
cirrhosis
|
100% (8/8)
|
ZEPATIER
+ RBV
16 weeks
|
TE, treatment-experienced; TN, treatment-naïve.
a Failed prior IFN or PegIFN +/- RBV.
b Failed prior PegIFN + RBV.
c Failed prior PegIFN + RBV + HCV NS3/4A protease
inhibitor (PI): boceprevir, simeprevir or telaprevir.
d C-EDGE TE treatment outcomes for ZEPATIER with
RBV for 12 weeks (n=104) or without RBV for 16 weeks (n=101) not
shown because these regimens are not recommended in PegIFN +
RBV-experienced GT1 patients.
Selected Safety Information about ZEPATIER (elbasvir and
grazoprevir)
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.
Recommended Dosage Regimens and Durations for ZEPATIER
(elbasvir and grazoprevir)
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:
Patient
Population
|
Treatment
|
Duration
|
GT1a:
Treatment-naïve or
PegIFN/RBV-experienced*
without baseline NS5A polymorphisms†
|
ZEPATIER
|
12 weeks
|
GT1a:
Treatment-naïve or
PegIFN/RBV-experienced*
with baseline NS5A polymorphisms†
|
ZEPATIER with
RBV
|
16 weeks
|
GT1b:
Treatment-naïve or
PegIFN/RBV-experienced*
|
ZEPATIER
|
12 weeks
|
GT1a or GT1b:
PegIFN/RBV/PI-experienced§
|
ZEPATIER with
RBV
|
12 weeks
|
GT4:
Treatment-naïve
|
ZEPATIER
|
12 weeks
|
GT4:
PegIFN/RBV-experienced*
|
ZEPATIER with
RBV
|
16 weeks
|
*Patients who have failed treatment with PegIFN + RBV.
†NS5A resistance-associated polymorphisms at amino acid
positions 28, 30, 31 or 93.
§Patients who have failed treatment with PegIFN/RBV +
HCV NS3/4A PI: boceprevir, simeprevir or telaprevir. For
GT1a-infected PegIFN/RBV/PI-experienced patients with one or more
baseline NS5A resistance-associated polymorphisms (positions 28,
30, 31 or 93), the optimal ZEPATIER-based treatment regimen and
duration of therapy has not been established.
In patients with GT1a infection, some hepatitis C viruses may
contain mutations that can confer resistance to treatment. These
are called resistance-associated polymorphisms, also referred to as
resistance-associated variants (RAVs). GT1a infection accounts for
46 percent of U.S. HCV cases. To help as many patients as possible
to achieve SVR12, testing for NS5A resistance-associated
polymorphisms (positions 28, 30, 31 or 93) is recommended for
GT1a-infected patients prior to starting treatment with ZEPATIER to
determine the optimal dosage regimen and duration. In clinical
trials of ZEPATIER, 12 percent (37/309) of GT1a-infected U.S. study
participants had these NS5A resistance-associated polymorphisms at
baseline. A 16-week regimen of ZEPATIER with RBV is recommended for
GT1a-infected patients with these baseline NS5A polymorphisms as
described in the above table.
"This approval provides patients and physicians with an
additional treatment option that has the potential to cure many
patients with chronic hepatitis C in the
United States," said Dr. Ira
Jacobson, site chair, department of medicine, Mount Sinai
Beth Israel, New York. "ZEPATIER
is a once-daily, single-tablet direct-acting antiviral that has
demonstrated high cure rates in genotype 1 and in genotype 4,
including treatment-naïve and treatment-experienced patients with
or without compensated cirrhosis and those with chronic kidney
disease."
The company anticipates that ZEPATIER will be available for
shipping to wholesalers within seven business days.
"Chronic hepatitis C is a potentially devastating illness that
can cause serious long-term health consequences for patients,
including reduced liver function, liver failure or liver cancer,"
said Michael Ninburg, executive
director, Hepatitis Education Project, Seattle. "Today, chronic hepatitis C is a
curable condition for many patients, and we are fortunate to have
multiple therapeutic tools that can mitigate its impact."
Selected Safety Information about ZEPATIER (elbasvir and
grazoprevir) (continued)
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 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.
Pricing Designed to Enable Broad Patient Access to ZEPATIER
(elbasvir and grazoprevir)
The latest innovations in
chronic HCV treatment that have become available over the past
three years, now including ZEPATIER, provide the U.S. with an
unprecedented opportunity to significantly reduce the burden of
HCV. The scientific community believes that control of HCV
infection may be possible and is actively working to achieve that
goal by 2030. A significant medical need remains: it is estimated
that less than one in five patients with chronic HCV infection are
currently treated, with thousands of new cases each year.
ZEPATIER, which received two Breakthrough Therapy designations
(for GT1 patients with end stage renal disease on hemodialysis and
for GT4 patients) and was thereafter approved by the FDA following
priority review, offers a highly effective option for a broad range
of adult patients with chronic HCV GT1 or GT4 infection. Public
reports indicate that net prices for the most commonly used
direct-acting antiviral regimens are substantially lower than the
list prices. However, the majority of patients with chronic HCV
have not yet been treated, in some cases due to cost
constraints. After considering these factors, Merck has
established a list price of $54,600
for a 12-week regimen, which the company believes to be in the
range of net prices for other commonly used HCV direct-acting
antiviral regimens at 12 weeks of therapy. Merck anticipates
that this price, as well as our comprehensive access strategy to
seek broad coverage across commercial and public segments, will
help broaden and accelerate patient access to treatment and move us
closer to our shared goal of reducing the burden of chronic HCV in
the U.S.
"Merck's decades-long commitment in chronic hepatitis C -- and
infectious diseases overall -- has been to both scientific
innovation and access," said Robert
McMahon, president, U.S. Market, Global Human Health, Merck.
"We are embracing this opportunity to partner with payers and
physicians to enable as many appropriate patients to be treated as
possible, as quickly as possible."
Financial Assistance Programs for Those Who Need Help With
the Cost of Their Medicine
Merck also anticipates that the
list price of ZEPATIER will result in lower out-of-pocket
medication costs for some patients. Lower out-of-pocket costs alone
do not necessarily reflect a cost advantage in the outcome of the
condition treated, because there are other variables that affect
relative costs. The direct out-of-pocket costs to patients
will vary, depending on an individual's insurance
plan.
Privately insured patients who have difficulty affording the
co-pay set by their insurance plan may be eligible for significant
co-pay assistance and may pay as little as $5 for each prescription. Maximum savings
are limited and terms and conditions apply. Information is
available at www.merckaccessprogram-ZEPATIER.com. Merck
anticipates that the website for ZEPATIER will be accessible within
24 hours of FDA approval.
Merck also offers assistance to patients who cannot afford
ZEPATIER through Merck's 50-year-old Patient Assistance
Program. The Merck PAP provides certain Merck medicines free
of charge to eligible patients. The Merck PAP for ZEPATIER is
designed primarily for the uninsured who, without our assistance,
could not afford their medication. Additionally, for those
patients whose insurance plan covers ZEPATIER, but who still cannot
afford their medication, a request for an exception may be made if
they meet certain financial, medical, and/or insurance
criteria. For more information about the Merck PAP, please
visit www.merckhelps.com or call the Merck Patient Assistance
Program at 1-800-405-5810.
Summary of Study Designs
Clinical Trials for GT1
HCV
C-EDGE TN was a randomized, double-blind,
placebo-controlled trial in treatment-naïve patients with GT1 or
GT4 infection with or without cirrhosis. Patients were randomized
in a 3:1 ratio to: ZEPATIER for 12 weeks (immediate treatment
group) (N=306) or placebo for 12 weeks followed by open-label
treatment with ZEPATIER for 12 weeks (deferred treatment group)
(N=102). Among patients with GT1 infection randomized to the
immediate treatment group, the median age was 55 years (range: 20
to 78); 56% of the patients were male; 61% were white; 20% were
black or African American; 8% were Hispanic or Latino; mean body
mass index was 26 kg/m2; 72% had baseline HCV RNA levels
greater than 800,000 IU per mL; 24% had cirrhosis; 67% had non-C/C
IL28B alleles (CT or TT); and 55% had GT1a and 45% had GT1b chronic
HCV infection.
C-EDGE COINFECTION (CO-INFXN) was an open-label, single-arm
trial in treatment-naïve HIV-1/HCV co-infected patients with GT1 or
GT4 infection with or without cirrhosis. Patients received ZEPATIER
for 12 weeks (N=217). Among patients with GT1 infection, the median
age was 50 years (range: 21 to 71); 85% of the patients were male;
75% were white; 19% were black or African American; 6% were
Hispanic or Latino; mean body mass index was 25 kg per
m2; 59% had baseline HCV RNA levels greater than 800,000
IU per mL; 16% had cirrhosis; 65% had non-C/C IL28B alleles (CT or
TT); and 76% had GT1a, 23% had GT1b, and 1% had GT1-Other chronic
HCV infection.
C-SURFER was a randomized, double-blind, placebo-controlled
trial in patients with GT1 infection, with or without cirrhosis,
with chronic kidney disease (CKD) Stage 4 (eGFR 15-29 mL/min/1.73
m2) or CKD Stage 5 (eGFR <15 mL/min/1.73
m2), including patients on hemodialysis, who were
treatment-naïve or who had failed prior therapy with IFN or PegIFN
± RBV therapy. Patients were randomized in a 1:1 ratio to one of
the following treatment groups: elbasvir 50 mg once daily +
grazoprevir 100 mg once daily for 12 weeks (N=111) (immediate
treatment group) or placebo for 12 weeks followed by open-label
treatment with elbasvir + grazoprevir for 12 weeks (N=113)
(deferred treatment group). In addition, 11 patients received
open-label elbasvir + grazoprevir for 12 weeks (intensive
pharmacokinetic [PK] group). Patients randomized to the immediate
treatment group and intensive PK group had a median age of 58 years
(range: 31 to 76); 75% of the patients were male; 50% were white;
45% were black or African American; 11% were Hispanic or Latino;
57% had baseline HCV RNA levels greater than 800,000 IU/mL; 6% had
cirrhosis; and 72% had non-C/C IL28B alleles (CT or TT).
C-EDGE TE was a randomized, open-label comparative trial in
patients with GT1 or GT4 infection, with or without cirrhosis, with
or without HCV/HIV-1 co-infection, who had failed prior therapy
with PegIFN + RBV therapy. Patients were randomized in a 1:1:1:1
ratio to one of the following treatment groups: ZEPATIER for 12
weeks (N=105), ZEPATIER + RBV for 12 weeks (N=104), ZEPATIER for 16
weeks (N=101), or ZEPATIER + RBV for 16 weeks (N=104). Among
patients with GT1 infection, the median age was 57 years (range: 19
to 77); 64% of the patients were male; 67% were white; 18% were
black or African American; 9% were Hispanic or Latino; mean body
mass index was 28 kg/m2; 78% had baseline HCV RNA levels
greater than 800,000 IU/mL; 34% had cirrhosis; 79% had non-C/C
IL28B alleles (CT or TT); and 60% had GT1a, 39% had GT1b, and 1%
had GT1-Other chronic HCV infection.
C-SALVAGE was an open-label single-arm trial in patients with
GT1 infection, with or without cirrhosis, who had failed prior
treatment with boceprevir, simeprevir, or telaprevir in combination
with PegIFN + RBV. Patients received elbasvir 50 mg once daily +
grazoprevir 100 mg once daily + RBV for 12 weeks (N=79). Patients
had a median age of 55 years (range: 23 to 75); 58% of the patients
were male; 97% were white; 3% were black or African American; 15%
were Hispanic or Latino; mean body mass index was 28
kg/m2; 63% had baseline HCV RNA levels greater than
800,000 IU/mL; 43% had cirrhosis; and 97% had non-C/C IL28B alleles
(CT or TT); 46% had baseline NS3 resistance-associated
substitutions.
Clinical Trials for GT4 HCV
The efficacy of ZEPATIER
in patients with GT4 chronic HCV infection was demonstrated in
C-EDGE TN, C-EDGE CO-INFXN, C-EDGE TE, and C-SCAPE. C-SCAPE was a
randomized, open-label trial which included treatment-naïve
patients with GT4 infection without cirrhosis. Patients were
randomized in a 1:1 ratio to elbasvir 50 mg once daily +
grazoprevir 100 mg once daily for 12 weeks (N=10) or elbasvir 50 mg
once daily + grazoprevir 100 mg once daily + RBV for 12 weeks
(N=10). In these combined studies in patients with GT4 infection,
64% were treatment-naïve; 66% of the patients were male; 87% were
white; 10% were black or African American; 22% had cirrhosis; and
30% had HIV-1/HCV co-infection.
About Merck
Today's Merck is 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 www.merck.com and connect with us on Twitter,
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Kenilworth, NJ, USA
This
news release of Merck & Co., Inc., Kenilworth, NJ, USA (the "company") includes
"forward-looking statements" within the meaning of the safe harbor
provisions of the U.S. Private Securities Litigation Reform Act of
1995. These statements are based upon the current beliefs and
expectations of the company's management and are subject to
significant risks and uncertainties. There can be no guarantees
with respect to pipeline products that the products will receive
the necessary regulatory approvals or that they will prove to be
commercially successful. If underlying assumptions prove inaccurate
or risks or uncertainties materialize, actual results may differ
materially from those set forth in the forward-looking
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Risks and uncertainties include, but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
legislation in the United States
and internationally; global trends toward health care cost
containment; technological advances, new products and patents
attained by competitors; challenges inherent in new product
development, including obtaining regulatory approval; the company's
ability to accurately predict future market conditions;
manufacturing difficulties or delays; financial instability of
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The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company's 2014
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Securities and Exchange Commission (SEC) available at the SEC's
Internet site (www.sec.gov).
Please see Prescribing Information for ZEPATIER (elbasvir and
grazoprevir) at
http://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf
and the Patient Information for ZEPATIER at
http://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_ppi.pdf
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