Real-World Observational Study in the U.S. Veterans Affairs System Evaluating Use of Merck’s ZEPATIER® (Elbasvir and Grazoprevir) Shows High Sustained Virologic Response Rates in Patients with Chronic Hepatitis C

Study Evaluated VA Population with High Incidence of Co-Morbidities

KENILWORTH, N.J.--(BUSINESS WIRE)--$MRK #MRK--Merck (NYSE: MRK), known as MSD outside of the United States and Canada,
today announced the presentation of findings from a retrospective
database analysis of patients with chronic hepatitis C virus (HCV)
infection who were administered ZEPATIER® in the U.S.
Department of Veterans Affairs (VA) healthcare system. For the evaluable
population (n=2,436), 95.6 percent of veterans treated with ZEPATIER
achieved the primary outcome of sustained virologic response (SVR),
defined as undetectable HCV RNA at least twelve weeks after the end of
treatment. For patients with no HCV RNA measurements at or after 12
weeks (19% of the study cohort), the analysis used HCV RNA measurements
available at least four and less than 12 weeks after the end of
treatment. The response rates in the real-world setting of the VA
supplement the overall findings from the controlled
clinical studies
of ZEPATIER. These findings will be presented today
in an oral session (abstract #PS-095) at The International Liver
Congress™ 2017 being held in Amsterdam, the Netherlands.


In the United States, ZEPATIER is indicated for the treatment of chronic
HCV GT1 or GT4 infection in adults. ZEPATIER is indicated for use with
ribavirin (RBV) in certain patient populations. The U.S. Prescribing
Information for ZEPATIER includes a Boxed Warning about the risk of
hepatitis B virus (HBV) reactivation in patients co-infected with HCV
and HBV. In controlled clinical studies of ZEPATIER, SVR was the primary
endpoint defined as HCV RNA less than lower limit of quantification
(LLOQ) at 12 weeks after the cessation of treatment (SVR12).

U.S. veterans are three times more likely to have chronic hepatitis C
compared to the general U.S. population and a high proportion suffer
co-morbid conditions that can make treatment challenging,” said Jennifer
Kramer, investigator, Michael E. DeBakey VA Medical Center, Houston,
Texas, and assistant professor of medicine, department of medicine,
Baylor College of Medicine. “

This study shows that chronic hepatitis C
antiviral treatment can result in a high rate of sustained virologic
response in U.S. veterans.”

This retrospective database analysis included patients with chronic HCV
treated with ZEPATIER (elbasvir and grazoprevir) in the VA healthcare
system between February 1, 2016 and August 1, 2016. Study outcomes
include real-world utilization and SVR rates. Please see additional
information about the design, methodology and limitations of this
observational study below.

After applying study exclusion criteria, 2,436 patients were included in
the evaluable population cohort. The mean age of subjects was 63.5
years. The prevalence of co-morbidities as determined by ICD-9 and CPT
codes as recorded in the VA database was as follows: cirrhosis (33.2%),
diabetes (53.2%), depression (57.2%) and HIV co-infection (3%).
Additionally, more than half of the patients had a history of drug
(53.9%) or alcohol (60.5%) abuse. The population included 1,988
previously untreated patients and 448 treatment-experienced patients
(322 of whom previously received an interferon-based regimen with or
without an NS3/4A HCV protease inhibitor, and 126 of whom previously
received an interferon-free direct-acting antiviral regimen).

A total of 95.6 percent (2,328/2,436) of patients in the evaluable
population achieved SVR following treatment with ZEPATIER. The SVR rates
by genotype (GT) were as follows: all GT1, 95.4 percent (2218/2324);
GT1a, 93.4 percent (788/844); GT1b, 96.6 percent (1379/1428); and GT4,
96.9 percent (62/64). The SVR rates by baseline viral load (BVL) were as
follows: BVL greater than 800,000 IU/ml, 94.7 percent (1497/1580); and
BVL less than or equal to 800,000 IU/ml, 97.3 percent (726/746).

The SVR rates by baseline patient characteristics were as follows: male,
95.5 percent (2,245/2,350); female, 96.5 percent (83/86); African
American, 95.9 percent (1,342/1,400); Hispanic, 95.1 percent (77/81);
White, 95.0 percent (783/824); previously untreated, 96.1 percent
(1,910/1,988); treatment-experienced, 93.3 percent (418/448); cirrhosis,
95.5 percent (772/808); without cirrhosis, 95.6 percent (1556/1628);
stage 3 chronic kidney disease (CKD) (eGFR 30 to 59 mL/min/1.73m2),
96.7 percent (380/393); stage 4-5 CKD (eGFR less than 30 mL/min/1.73m2),
96.3 percent (392/407); HIV positive, 98.6 percent (73/74); HIV
negative, 95.5 percent (2255/2362); history of alcohol abuse, 95.9
percent (1412/1473); no history of alcohol abuse, 95.1 percent
(916/963); history of drug abuse, 95.3 percent (1251/1313); no history
of drug abuse, 95.9 percent (1077/1123).

Adverse event data were not collected as part of this real-world data
analysis.

Analysis of data from real-world medical settings can provide useful
insights to supplement knowledge gained from randomized clinical
trials,” said Susan Shiff, senior vice president, center for
observational and real-world evidence, Merck. “

These data from a
real-world VA setting add to the body of evidence on ZEPATIER (elbasvir
and grazoprevir) and help deepen scientific understanding of the
treatment of this complex disease affecting diverse, sometimes difficult
to treat, patient populations.”

Study Methodology

Patients with chronic HCV treated with ZEPATIER from February 1 to
August 1, 2016 were identified from the VA Corporate Data Warehouse, a
national repository of VA electronic medical records. Inclusion criteria
specified initiation of ZEPATIER therapy, at least 18 years of age,
positive HCV RNA, and at least one inpatient or outpatient visit within
a one-year period prior to treatment initiation (n=2,985). Patients were
excluded if they had RBV added greater than one month after treatment
initiation (n=23). Patients without SVR data or on-treatment HCV RNA
data (n=494), or those treated with ZEPATIER for greater than seventeen
weeks (n=32), were excluded as well. The total number of patients in the
evaluable population was 2,436.

SVR was assessed based on undetectable HCV RNA at least twelve weeks
after the end of treatment. For patients with no HCV RNA measurements at
or after 12 weeks, the analysis used HCV RNA measurements available at
least four and less than 12 weeks after the end of treatment. SVR was
evaluated based on HCV RNA measurement at least 12 weeks post treatment
in 81 percent of the study population.

About Real-World Data Analyses and Associated Limitations

Real-world studies analyze data generated outside of randomized clinical
trials, such as through analyses of electronic medical records or claims
databases, to provide insight into how medicines perform or are used
from a clinical and economic viewpoint in real-world clinical settings.
Information from real-world analyses alone does not provide sufficient
evidence to validate efficacy or safety of a therapeutic regimen and
does not provide a substitute for evidence obtained from randomized
controlled clinical trials.

This study is subject to certain limitations. The VA population may not
be generalizable to the entire U.S. population, due in part to the
potential for a differing demographic make-up and/or risk factors. Bias
may exist as diagnoses and co-morbidities were identified through ICD-9
and CPT codes. Treatment completion was identified through prescription
records which may not reflect adherence. Database analyses are also
prone to errors in coding and missing data, including unavailable SVR
data at or after the 12-week post-treatment time point. Additionally,
some laboratory data including data on the presence of baseline NS5A
resistance associated substitutions was not available at the time of
this analysis.

About the VA Corporate Data Warehouse (CDW)

The Department of Veterans Affairs Veterans Healthcare Administration
(VHA) is supported by one of the largest integrated healthcare
information systems in the United States. The VHA's Corporate Data
Warehouse (CDW) was developed in 2006 to accommodate the massive amounts
of data being generated from more than 20 years of use and to streamline
the process of knowledge discovery to application.

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

ZEPATIER is a fixed-dose combination product containing elbasvir, a HCV
NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. In
the United States, ZEPATIER is indicated for the treatment of chronic
HCV GT1 or 4 infection in adults. ZEPATIER is indicated for use with
ribavirin (RBV) in certain patient populations. The efficacy of ZEPATIER
has not been established in patients who have previously failed
treatment with other regimens that included an NS5A inhibitor.

Selected Safety Information about ZEPATIER

The US Prescribing Information for ZEPATIER contains a Boxed Warning
about the risk of hepatitis B virus (HBV) reactivation in patients
coinfected with HCV and HBV. Healthcare professionals should test all
patients for evidence of current or prior HBV infection by measuring
hepatitis B surface antigen (HBsAg) and hepatitis B core antibody
(anti-HBc) before initiating treatment with ZEPATIER. HBV reactivation
has been reported in HCV/HBV coinfected patients who were undergoing or
had completed treatment with HCV direct-acting antivirals and were not
receiving HBV antiviral therapy. Some cases have resulted in fulminant
hepatitis, hepatic failure, and death. Healthcare professionals should
monitor HCV/HBV coinfected patients for clinical and laboratory signs of
hepatitis flare or HBV reactivation during HCV treatment and
post-treatment follow-up. Healthcare professionals should initiate
appropriate patient management for HBV infection as clinically indicated.

HBV reactivation has been reported in HBsAg positive patients and also
in patients with serologic evidence of resolved HBV infection (ie, HBsAg
negative and anti-HBc positive). The risk of HBV reactivation may be
increased in patients receiving some immunosuppressant or
chemotherapeutic agents. HBV reactivation is characterized as an abrupt
increase in HBV replication manifesting as a rapid increase in serum HBV
DNA level. In patients with resolved HBV infection, reappearance of
HBsAg can occur. Reactivation of HBV replication may be accompanied by
hepatitis, ie, increases in aminotransferase levels and, in severe
cases, increases in bilirubin levels, liver failure, and death can occur.

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 inhibitors of organic anion transporting
polypeptides 1B1/3 (OATP1B1/3) that are known or expected to
significantly increase grazoprevir plasma concentrations (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
(elbasvir and grazoprevir) 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 (elbasvir and grazoprevir) 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 adverse
reactions or reduced therapeutic effect due to drug interactions.
Certain strong CYP3A inhibitors may increase the plasma concentration of
ZEPATIER, leading to possibly clinically significant adverse reactions.
Moderate CYP3A inducers may decrease the plasma concentration of
ZEPATIER, leading to reduced therapeutic effect and possible development
of resistance. Coadministration of ZEPATIER with these drugs is not
recommended. Physicians should consult the Prescribing Information for
potential drug interactions.

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.

Selected Dosage and Administration Information for ZEPATIER®
(elbasvir and grazoprevir)

ZEPATIER is a single tablet taken once daily. The recommended dosing is
12 or 16 weeks with or without RBV, depending on HCV genotype, prior
treatment history and, for patients with genotype 1a infection, presence
of certain baseline NS5A resistance-associated polymorphisms. See
Prescribing Information for ZEPATIER for specific dosage regimens and
durations. Refer to RBV prescribing information for RBV dosing and
dosage modifications when ZEPATIER is given with RBV. To determine
dosage regimen and duration of ZEPATIER for genotype 1a patients,
testing for the presence of virus with one or more baseline NS5A
resistance-associated polymorphisms at positions 28, 30, 31, or 93 is
recommended prior to initiating treatment.

Merck’s Commitment to HCV

For more than 30 years, Merck has been at the forefront of the response
to the HCV epidemic. Merck’s chronic HCV clinical development programs
have included more than 135 clinical trials in approximately 40
countries and have enrolled nearly 10,000 participants. As part of our
longstanding leadership in infectious diseases, Merck collaborates with
the scientific and patient communities to develop and deliver innovative
solutions to support people living with chronic HCV worldwide.

About Merck

For more than a century, Merck, a leading global biopharmaceutical
company known as MSD outside of the United States and Canada, has been
bringing forward medicines and vaccines for many of the world's most
challenging diseases. 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.
Today, Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer's disease and infectious
diseases including HIV and Ebola. For more information, visit www.merck.com
and connect with us on TwitterFacebookInstagram,
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and LinkedIn.

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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. 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
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United States and internationally; global trends toward health care cost
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by competitors; challenges inherent in new product development,
including obtaining regulatory approval; the company’s ability to
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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 2016 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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