Phase 2 Data Presentations at The Liver
Meeting® Detail SVR12 Rates from Two Studies as Well
as SVR8 Rates in Patients for Whom Direct-Acting Antiviral
Treatment Previously Failed
Merck (NYSE:MRK), known as MSD outside of the United States and
Canada, today announced the presentation of results from three
Phase 2 clinical trials evaluating MK-3682B
(MK-3682/grazoprevir/ruzasvir1), the company’s investigational
all-oral, triple-combination regimen for the treatment of chronic
hepatitis C (HCV) infection (informally referred to as MK3).
Results from Part B of C-CREST 1 & 2 demonstrated high rates of
sustained virologic response2 (SVR) 12 weeks after the completion
of therapy (SVR12, considered virologic cure) in patients with
chronic HCV genotype (GT) 1 or GT3 infection who received eight
weeks of treatment with MK-3682B. Findings from C-CREST 1 & 2
Part B also demonstrated high rates of SVR12 in GT1, GT2 and
GT3-infected patients who received MK3 for 12 or 16 weeks. Findings
from Part C of C-CREST 1 & 2 and interim results from the
ongoing C-SURGE study showed high rates of SVR12 and SVR8,
respectively, in chronic HCV patients who had failed prior
treatment with investigational or approved direct-acting antiviral
regimens. These results will be announced in oral presentations at
The Liver Meeting® 2016 today (C-CREST 1 & 2 Parts B and C) and
tomorrow (C-SURGE).
“Across the chronic hepatitis C treatment landscape, incredible
progress has been made in a remarkably short amount of time, but
there remains a need for more options, particularly for patients
who do not achieve sustained virologic response with treatment
regimens available today,” said Dr. Eliav Barr, senior vice
president, global clinical development, infectious diseases and
vaccines, Merck Research Laboratories. “The strong findings
observed following treatment with MK-3682B are an encouraging step
towards Merck’s goal of developing and delivering a
shorter-duration, pan-genotypic next-generation treatment regimen
for more patients with chronic hepatitis C infection.”
C-CREST 1 & 2 Part B Overview and Findings
Part B of C-CREST 1 & 2 – ongoing, open-label Phase 2
clinical trials – was designed to evaluate the safety and efficacy
of MK-3682B in patients with chronic HCV GT1, GT2 or GT3 infection,
with or without cirrhosis. Patients with GT2 or GT3 infection
received MK-3682B with or without RBV. All patients with GT1 or GT2
infection were treatment-naïve. Fifty six percent (189/337) of
patients with GT3 infection were treatment naïve and 44 percent
(148/337) were previously treated with peginterferon/ribavirin
(RBV). The primary endpoint of the study was the proportion of
patients in each treatment arm who achieved SVR12.
Eight weeks of treatment with MK-3682B resulted in SVR12 rates
of 95 percent, 86 percent and 95 percent in GT1, GT2 and GT3
patients, respectively. A 12-week treatment duration resulted in
high SVR12 rates in all genotypes (GT1, 99%; GT2, 97%; GT3, 97%).
Efficacy was comparable in patients with and without cirrhosis.
There were no virologic failures in the patients with GT1 or GT2
infection who received 12 weeks of MK-3682B. Efficacy results are
presented in the table below. Results from Part A of C-CREST 1
& 2 were previously reported at The Liver Meeting® in November
2015.
Summary of SVR12 Findings
Population N
MK-3682B
+/- RBV
8 weeks
MK-3682B
+/- RBV
12 weeks
MK-3682B
+/- RBV
16 weeks
GT1a 90 93% (39/42) 98%
(47/48) - GT1b 86 98%
(45/46) 100% (40/40) - GT2
151 86% (54/63) 97% (60/62)
100% (26/26) GT3* 337 95%
(98/103) 97% (155/159) 96% (72/75)
*28 percent (29/103), 36 percent (58/159)
and 81 percent (61/75)of patients with GT3 infection receiving
eight, 12 or 16 weeksof therapy, respectively, were previously
treated with peginterferon/RBV
Among patients who received at least one dose of MK-3682B with
or without RBV, the overall most common adverse events (AEs)
reported (greater than 10% incidence in either treatment arm) were
headache (22%), fatigue (19%) and nausea (13%). There were two
drug-related serious AEs, both considered related to RBV only. Nine
patients discontinued study drug due to AEs, four of whom
discontinued RBV only. One patient died due to AEs not related to
the study drug.
“As a scientist and physician who regularly treats patients with
chronic hepatitis C, the importance of continuing to research this
complex disease and its many complications is evident,” said Dr.
Eric Lawitz, vice president, scientific and research development,
The Texas Liver Institute and clinical professor of medicine, The
University of Texas Health Science Center, San Antonio. “The
virologic cure rates observed in Part B of C-CREST 1 & 2
clearly demonstrate the potential for MK3 and support further study
of this investigational regimen.”
C-SURGE Overview and Preliminary Findings
C-SURGE is an ongoing, open-label Phase 2 clinical trial
designed to evaluate MK-3682B with or without RBV in chronic HCV
GT1 patients who previously failed therapy with either
ledipasvir/sofosbuvir (LDV/SOF) or ZEPATIER™ (elbasvir and
grazoprevir). The study enrolled 94 patients randomized to receive
16 weeks of MK-3682B plus RBV (n=45) or 24 weeks of MK-3682B
without ribavirin (n=49); one patient in the 16 week arm withdrew
prior to starting treatment. Of the 93 patients who received
treatment in this study, 61 percent (57/93) had previously received
12 to 24 weeks of treatment with LDV/SOF; 15 percent (14/93) had
received 8 weeks of LDV/SOF; and 24 percent (22/93) had received 12
weeks of ZEPATIER. A majority of patients (84%, 78/93) had at least
one baseline NS5A resistance-associated variant (RAV) at positions
28, 30, 31 or 93.
Interim results from the modified full analysis set (mFAS),
which excludes one patient in the 16-week arm who withdrew due to
administrative reasons after receiving three doses of study
medication, show all patients (43/43) who have completed treatment
with MK-3862B plus RBV for 16 weeks achieved SVR8. All patients
(49/49) in the mFAS who received MK-3682B for 24 weeks have
completed treatment and remain subject to follow-up; the interim
results show of those in the 24-week arm who have reached follow-up
weeks four and eight, 100 percent have achieved SVR4 (38/38) and
SVR8 (30/30), respectively. SVR12 is the primary outcome measure of
this ongoing trial. Final results will be presented at a future
scientific congress.
Among patients who received at least one dose of MK-3682B with
or without RBV, the overall most common AEs reported were fatigue
(35%), headache (13%), diarrhea (9%), rash (9%) and pruritus (5%).
There were no drug-related serious AEs, and no patients
discontinued due to a drug-related AE.
C-CREST 1 & 2 Part C Overview and Findings
Part C of C-CREST 1 & 2 was designed to evaluate retreatment
with MK-3682B plus RBV for 16 weeks among patients who previously
failed an investigational triple-therapy regimen
(MK-3682/grazoprevir/ruzasvir or MK-3682/grazoprevir/elbasvir). The
study enrolled 24 patients with GT1 (n=2), GT2 (n=14) or GT3 (n=8)
infection. All patients (23/23) who completed treatment achieved
SVR12. One GT2 patient discontinued treatment after a single dose
due to drug-related serious AEs. Among patients who received at
least one dose of MK-3682B plus RBV, the most common AEs reported
(greater than 20% incidence) were headache (33%), fatigue (25%),
nausea (25%), rash (21%) and insomnia (21%).
About MK-3682B
MK-3682B (informally referred to as MK3) is Merck’s
investigational triple-combination therapy in Phase 2 development
for the treatment of chronic HCV infection. MK-3682B combines an
HCV nucleotide analogue NS5B polymerase inhibitor (MK-3682), an HCV
NS3/4A protease inhibitor (grazoprevir, MK-5172) and an HCV NS5A
inhibitor (ruzasvir, MK-8408).
About ZEPATIER™ (elbasvir and grazoprevir) 50 mg/100mg
tablets
ZEPATIER is a fixed-dose combination product containing
elbasvir, an HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A
protease inhibitor. ZEPATIER is indicated with or without ribavirin
(RBV) for treatment of chronic HCV genotypes 1 or 4 infection in
adults.
Selected Safety Information about ZEPATIER
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
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 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 MK-3682 is an HCV nucleotide analogue NS5B polymerase
inhibitor. Grazoprevir (MK-5172) is an HCV NS3/4A protease
inhibitor. Ruzasvir (MK-8408) is an HCV NS5A inhibitor.
2 Measured as HCV RNA less than 15 IU/mL.
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