ZEPATIER Achieves High Cure Rates
(SVR12) in Broad Range of Patients with Chronic Hepatitis C
Infection, Including Those with Compensated Cirrhosis, Renal
Impairment of Any Degree and HIV-1/HCV Co-infection
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.
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,
placebocontrolled)
TN +/- cirrhosis 95% (273/288)
ZEPATIER
12 weeks
C-EDGE CO-INFXN(open-label, single arm)
TN +/- cirrhosis + HIV-1co-infection
95% (179/189)
C-SURFER(double blind,
placebocontrolled)
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
+ RBV12 weeks
GT4
C-SCAPE (open-label)
C-EDGE TN
C-EDGE CO-INFXN
TN without cirrhosisTN +/- cirrhosisTN +/-
cirrhosis + HIV-1co-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. cFailed
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.
ForGT1a-infected PegIFN/RBV/PI-experienced patients with one or
more baseline NS5A resistance-associatedpolymorphisms (positions
28, 30, 31 or 93), the optimal ZEPATIER-based treatment regimen and
duration of therapyhas 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, Facebook, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co. Inc.,
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 statements.
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 international economies and sovereign risk;
dependence on the effectiveness of the company’s patents and other
protections for innovative products; and the exposure to
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The company undertakes no obligation to publicly update any
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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
Annual Report on Form 10-K and the company’s other filings with the
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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