Merck Receives FDA Approval of ZEPATIER™ (elbasvir and grazoprevir) for the Treatment of Chronic Hepatitis C Virus Genotype 1 or 4 Infection in Adults Following Priority Review
January 28, 2016 6:59 pm ET
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 |
|||||||||
| Clinical Trial(s) | Population | SVR12 (n/N) |
Treatment Regimen and Duration |
||||||
| GT1 | |||||||||
|
C-EDGE TN |
TN +/- cirrhosis | 95% (273/288) |
ZEPATIER
12 weeks |
||||||
|
C-EDGE CO-INFXN (open-label, single arm) |
TN +/- cirrhosis + HIV-1 |
95% (179/189) | |||||||
|
C-SURFER |
TN/TEa +/- cirrhosis + |
94% (115/122) | |||||||
|
C-EDGE TEd (open-label, comparative) |
TEb +/- cirrhosis +/- HIV- |
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 |
||||||
| GT4 | |||||||||
|
C-SCAPE (open-label)
C-EDGE TN C-EDGE CO-INFXN |
TN without cirrhosis |
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* |
ZEPATIER | 12 weeks | ||||
|
GT1a:
Treatment-naïve or PegIFN/RBV-experienced* |
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 + |
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
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be well. Merck is known as MSD outside the United States and Canada.
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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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