Results From C-EDGE Head-to-Head Study in
Patients with Chronic Hepatitis C Genotypes 1 or 4 Infection
Presented at The International Liver Congress™ 2016
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced the presentation of results from C-EDGE
Head-to-Head, the company’s comparative, Phase 3, open-label
clinical trial evaluating the efficacy and safety of ZEPATIER™
(elbasvir and grazoprevir) 50mg/100mg tablets versus a regimen of
sofosbuvir 400mg tablets plus peginterferon and ribavirin
(pegIFN/RBV) in treatment-naïve and pegIFN/RBV
treatment-experienced patients with chronic hepatitis C (HCV)
genotype (GT) 1 or GT4 infection (abstract #PS002). In this study,
ZEPATIER demonstrated superiority on efficacy and safety endpoints
compared to sofosbuvir plus pegIFN/RBV, based on pre-specified
analyses. In the full analysis set (FAS) (n=255), the efficacy
endpoint of sustained virologic response (SVR) 12 weeks after the
completion of therapy (SVR12, considered virologic cure) was
achieved in 99 percent (128/129) of patients receiving ZEPATIER for
12 weeks versus 90 percent (114/126) of patients receiving
sofosbuvir plus pegIFN/RBV for 12 weeks. The study’s safety
endpoint was the frequency of pre-specified (Tier 1) safety events
focusing on tolerability, hematologic side effects, and
liver-related laboratory abnormalities.1 ZEPATIER – Merck’s
once-daily, fixed-dose combination tablet indicated with or without
RBV for the treatment of chronic HCV GT1 or GT4 infection in adults
– was approved by the U.S. Food and Drug Administration (FDA) on
Jan. 28, 2016, based in part on prior studies from the Phase 3
program. The results of C-EDGE Head-to-Head will be featured today
in the official press program at The International Liver Congress™
2016.
“Overall in this study, the elbasvir and grazoprevir regimen
showed superior SVR rates and improvement on pre-specified safety
endpoints compared to the sofosbuvir plus peginterferon and
ribavirin regimen in these genotype 1- or 4-infected patients,”
said Dr. Jan Sperl, Department of Hepatogastroenterology, Institute
for Clinical and Experimental Health, Prague, Czech Republic and
lead study investigator. “Sofosbuvir in combination with
peginterferon and ribavirin continues to be a prescribed treatment
regimen in many regions, and this comparative study versus
combination treatment with elbasvir and grazoprevir provides
interesting and important insights.”
C-EDGE Head-to-Head is a comparative Phase 3, randomized,
open-label, parallel-group trial conducted at multiple sites in the
European Union, Norway and Turkey, and was designed to evaluate the
efficacy and safety of 12 weeks of ZEPATIER (elbasvir and
grazoprevir) versus a 12 week treatment regimen of sofosbuvir plus
pegIFN/RBV. The trial enrolled treatment-naïve and pegIFN/RBV
treatment-experienced patients, with or without cirrhosis, with
chronic HCV GT1 or GT4 infection. Investigators were to enroll only
patients whom, in their opinion, were appropriate candidates for 12
weeks of pegIFN/RBV-based therapy; this assessment included
consideration of factors associated with lower response rates to
interferon-based therapies (e.g., advanced fibrosis/cirrhosis, high
baseline viral concentrations, black race, IL28B non-CC genotype,
or prior null-response to pegIFN/RBV therapy). The study randomized
255 GT1- or GT4-infected patients to 12 weeks of treatment with
either ZEPATIER (elbasvir and grazoprevir) 50mg/100mg tablets
(n=129) or sofosbuvir 400mg tablets plus pegIFN/RBV (n=126).
Overall, at baseline, 17 percent of patients had compensated
cirrhosis; 67 percent had HCV RNA greater than 800,000 IU/mL; 99
percent were white; 78 percent had IL28B non-CC genotype; and
approximately 25 percent had failed prior treatment with pegIFN/RBV
(10% prior null-responders, 5% prior partial-responders, 10% prior
relapsers).
In the FAS (n=255), the efficacy analyses demonstrated
superiority of ZEPATIER compared to sofosbuvir plus pegIFN/RBV, as
measured by SVR12. 2 Higher SVR rates were observed among those
receiving ZEPATIER (elbasvir and grazoprevir) in subgroups of
patients who had previously experienced a non-response to
pegIFN/RBV therapy and in those with cirrhosis, higher baseline
viral load, or IL28B non-CC genotype. Efficacy results for the
overall population as well as those for selected subgroups are
shown in Table 1. In the ZEPATIER group, one patient (1%)
discontinued from the trial after completing treatment. There were
no virologic failures in the ZEPATIER group. In the sofosbuvir plus
pegIFN/RBV group, virologic failure occurred in 11 patients (9%)
and one patient (1%) discontinued from the trial after the first
week of treatment.
Table 1: Summary of Efficacy (SVR12) Findings in FAS, Overall
and Selected Subgroups
Population ZEPATIER
(n=129)
Sofosbuvir + PegIFN/RBV
(n=126)
All Patients 99% (128/129)
90% (114/126)
Genotype
GT1a 100%
(18/18) 100% (17/17) GT1b
99% (104/105) 90% (94/104) GT4
100% (6/6) 60% (3/5)
Cirrhotic/Non-cirrhotic
Non-cirrhotic 99%
(106/107) 93% (98/105) Cirrhotic
100% (22/22) 76% (16/21)
Prior
Treatment Experience
Treatment-naïve 99% (99/100)
96% (87/91) PegIFN/RBV Null-response
100% (11/11) 50% (7/14)
PegIFN/RBV Partial-response 100% (6/6)
88% (7/8) PegIFN/RBV Relapse
100% (12/12) 100% (13/13)
The primary safety analysis compared the incidence of adverse
events (AEs) of special relevance (Tier 1 AEs) between the ZEPATIER
and sofosbuvir plus pegIFN/RBV treatment groups. Additional AEs
(Tier 2 AEs) also were recorded. Safety results are shown in Table
2. Overall, the incidence of Tier 1 AEs, including those commonly
associated with pegIFN and/or RBV such as hematological side
effects of decreased hemoglobin and decreased neutrophil count,
were lower in the ZEPATIER treatment group versus the sofosbuvir
plus pegIFN/RBV treatment group. In the ZEPATIER (elbasvir and
grazoprevir) treatment group, headache was the only AE reported at
a frequency of greater than 10 percent. In the sofosbuvir plus
pegIFN/RBV treatment group, AEs reported in greater than 10 percent
of patients were pyrexia, headache, fatigue, asthenia,
influenza-like illness, chills, myalgia, decreased appetite,
anemia, nausea and cough. No grade three or four abnormalities of
alanine aminotransferase (ALT), aspartate aminotransferase (AST) or
hemoglobin were observed in the ZEPATIER group. In the sofosbuvir
plus pegIFN/RBV group, one patient had a grade three ALT
abnormality and five patients had grade three or four hemoglobin
reduction.
Table 2: Summary of Safety Findings
ZEPATIER
(n=129)
Sofosbuvir + PegIFN/RBV
(n=126)
Tier 1 Adverse Events 1% (1/129)
28% (35/126) Serious Drug Related Adverse Events
(DRAEs) 0% (0/129) 2%
(3/126) Discontinuations due to DRAE 0%
(0/129) 1% (1/126) Neutrophil Count <0.75 x
109/L 0% (0/129) 13%
(16/126) Hemoglobin <10 g/dL 1% (1/129)
14% (18/126)
Tier 2 Adverse Events
52% (67/129) 93%
(117/126) One or more adverse events 52%
(67/129) 93% (117/126) One or more drug
related adverse events 25% (32/129)
90% (114/126) Serious adverse events
1% (1/129) 4% (5/126)
Other Safety
Events
ALT Grade 3 or 4: >5.1 x ULN (IU/L) 0%
(0/129) 1% (1/126) AST Grade 3 or 4: >5.1
xULN (IU/L) 0% (0/129) 0%
(0/126) Hemoglobin Grade 3 or 4: <9.0 (mg/dL)
0% (0/129) 4% (5/126)
“Treatment regimens containing peginterferon and ribavirin are
associated with certain serious side effects,” said Dr. Jan
Gerstoft, Clinic for Infectious Diseases and Rheumatology,
Copenhagen, Denmark. “This study provides evidence for the clinical
potential of elbasvir and grazoprevir in chronic HCV genotype 1- or
4-infection as compared with a regimen containing peginterferon and
ribavirin along with sofosbuvir.”
Selected Safety Information about ZEPATIER (elbasvir and
grazoprevir)
ZEPATIER 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 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 (elbasvir and
grazoprevir) 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.
About ZEPATIER™ (elbasvir and grazoprevir) 50mg/100mg
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 (elbasvir and grazoprevir) 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
PegIFN/RBV-experienced.
For patients with chronic HCV GT1a infection, testing for the
presence of NS5A resistance-associated polymorphisms is recommended
prior to starting treatment with ZEPATIER 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
www.merck.com and connect with us on Twitter, Facebook, YouTube and
LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
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
litigation, including patent litigation, and/or regulatory
actions.
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 2015
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
___________________________
1 See Table 2
2 Per the trial protocol, in the FAS all randomized patients
received at least one (1) dose of study medication. Superiority was
concluded if the lower bound of the two-sided 95% CI for the
difference between SVR12 rates in the treatment groups was greater
than zero.
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