Merck (NYSE:MRK), known as MSD outside of the United States and
Canada, today announced the presentation of results from two Phase
3 clinical trials evaluating ZEPATIER™ (elbasvir and grazoprevir)
50mg/100mg tablets in chronic hepatitis C (HCV) patients with
inherited blood disorders (C-EDGE IBLD) and in patients with a
history of intravenous drug use who are receiving opioid agonist
therapy (C-EDGE CO-STAR), respectively. Results from C-EDGE IBLD
demonstrated high rates of sustained virologic response (SVR) 12
weeks after the completion of treatment (SVR12, considered
virologic cure) and a safety profile consistent with that observed
in prior studies (abstract #SAT-128). Findings from C-EDGE CO-STAR
showed a high rate of SVR 24 weeks after completion of treatment
(SVR24) for the baseline chronic HCV infection and provided
insights into the incidence of reinfection in this high risk
population (abstract #SAT-163). The SVR24 data confirm the C-EDGE
CO-STAR SVR12 results unveiled at The Liver Meeting® in November
2015. ZEPATIER – Merck’s once-daily, fixed-dose combination tablet
indicated with or without ribavirin (RBV) for the treatment of
chronic HCV genotype (GT) 1 or GT4 infection in adults – was
approved by the U.S. Food and Drug Administration in January 2016,
based in part on prior studies from the Phase 3 program. Data from
these additional Phase 3 studies were presented today at The
International Liver CongressTM 2016 (ILC).
“To reduce the global burden and potential spread of chronic
hepatitis C, it is important that we develop evidence about
meaningful options for those patients for whom treatment may be
challenging,” said Dr. Eliav Barr, vice president, infectious
diseases, Merck Research Laboratories. “These data from Merck’s
broad clinical development program underscore the company’s
commitment to evaluating ZEPATIER in historically underserved and
understudied chronic hepatitis C populations, such as patients with
inherited blood disorders or those receiving opioid agonist
therapy.”
C-EDGE IBLD Overview and Findings
C-EDGE IBLD is a Phase 3 randomized, double-blind,
placebo-controlled study evaluating treatment with ZEPATIER
(elbasvir and grazoprevir) in patients with chronic HCV GT1, GT4 or
GT6 infection and inherited blood disorders, including hemophilia
A/B, von Willebrand disease, beta thalassemia and sickle cell
anemia. Patients were randomized in a 2:1 ratio to either an
immediate treatment group (ITG; 12 weeks of ZEPATIER) or deferred
treatment group (DTG; 12 weeks of placebo as control arm, followed
by 12 weeks of open-label ZEPATIER). The primary efficacy endpoint
for the study was the proportion of patients in the ITG who
achieved SVR12. Safety and tolerability were evaluated by comparing
subjects receiving ZEPATIER in the ITG (n=107) to those receiving
placebo in the DTG (n=52).
Following 12 weeks of treatment with ZEPATIER, 93 percent of
patients in the ITG (100/107) achieved SVR12 (virologic cure). Six
patients relapsed following twelve weeks of treatment; five of
these patients (3 GT1a, 1 GT1b and 1 GT4) had detectable NS5A
resistance-associated polymorphisms at baseline.1 The study did not
evaluate other ZEPATIER-based dosage regimens or durations.
The most common (greater than 10%) adverse events (AEs) among
patients receiving ZEPATIER for 12 weeks in C-EDGE IBLD, compared
with those receiving placebo, were headache (21%, 12%) and fatigue
(17%, 8%). No patient receiving ZEPATIER discontinued due to AEs,
compared with one patient receiving placebo. Three patients (3%)
receiving ZEPATIER and six patients (12%) receiving placebo
reported a total of 12 serious AEs. Treatment did not affect
pre-defined hematological parameters and did not interfere with the
management of underlying blood disorders.
C-EDGE CO-STAR Overview and Findings
C-EDGE CO-STAR is a Phase 3 double-blind, placebo-controlled
study evaluating treatment with ZEPATIER in patients with chronic
HCV GT1, GT4 and/or GT6 infection who are on opioid agonist therapy
(i.e., methadone, buprenorphine). Efficacy (SVR12) and safety
results from the trial were previously presented at The Liver
Meeting® in November 2015. Results presented at ILC this week
included secondary efficacy endpoint (SVR24) and reinfection
analyses. A separate analysis of health-related quality of life
data from C-EDGE CO-STAR was also presented this week at ILC.
The study included an immediate treatment group (ITG) that
received blinded ZEPATIER (elbasvir and grazoprevir) for 12 weeks
(n=201) and a deferred treatment group (DTG) that received 12 weeks
of placebo (control arm) (n=100), followed by 12 weeks of
open-label ZEPATIER (n=95). The secondary efficacy analysis
evaluated SVR24 in the modified full analysis set (n=271), which
included patients from both treatment groups who received ZEPATIER
for 12 weeks and completed 24 weeks of follow up, excluding those
who discontinued for non-treatment related reasons. An additional
analysis evaluated the reinfection incidence among all patients who
completed active study therapy (n=296).
Following 12 weeks of treatment with ZEPATIER, 94 percent
(175/186) and 96 percent (82/85) of patients achieved SVR24 in the
ITG (blinded) and DTG (open-label), respectively. The analysis of
296 patients showed six probable HCV reinfections occurred,2
including five through follow up week 12 (FU12) in the ITG and one
additional by FU24 in the DTG. These results represent a
reinfection incidence of 8.4 cases (95% CI: 3.1, 18.5) per 100
person years after 24 weeks of follow up. Patients in the trial
will be evaluated regularly for three years following the 24-week
period.
An analysis of AEs during the initial treatment period and first
two weeks of follow-up showed the most common AEs among patients
receiving blinded ZEPATIER or placebo were fatigue (16%, 20%),
headache (13%, 14%), nausea (11%, 9%) and diarrhea (10%, 9%),
respectively. Reported AEs in the open-label treatment group were
similar to the blinded group (fatigue, 14%; headache, 13%; nausea,
7%; diarrhea, 8%). One patient receiving ZEPATIER and one patient
receiving placebo reported serious treatment-related AEs. In
addition, one patient receiving ZEPATIER and one patient receiving
placebo discontinued due to AEs.
“Injection drug use is one of the leading contributors to the
spread of hepatitis C infection around the world. Many current or
former injection drug users with chronic hepatitis C infection are
on opioid agonist therapy, but historically there has been
reluctance to treat these patients due to concerns about
reinfection and compliance with treatment,” said Dr. Barr. “These
results from C-EDGE CO-STAR help contribute to our understanding of
the incidence of hepatitis C reinfection in these patients
following treatment with ZEPATIER.”
Selected Safety Information about ZEPATIER (elbasvir and
grazoprevir)
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 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 ribavirin (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 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 (elbasvir and grazoprevir) 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/100 mg
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 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 (elbasvir and
grazoprevir) 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 Any variant at amino acid position 28, 30, 31 or 93, as
determined by population sequencing.
2 Reinfection determined by virologic failure with a different
genotype, subtype or viral strain compared to baseline virus.
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MerckMedia:Pamela Eisele, 267-305-3558Sarra Herzog,
201-669-6570orInvestors:Teri Loxam, 908-740-1986Amy Klug,
908-740-1898
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