Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced that the investigational IMPROVE-IT study
met its primary and all secondary composite efficacy endpoints. In
IMPROVE-IT, patients taking the LDL-cholesterol-lowering medicine
VYTORIN® (ezetimibe/simvastatin) – which combines simvastatin with
the non-statin ZETIA® (ezetimibe) -- experienced significantly
fewer major cardiovascular events (as measured by a composite of
cardiovascular death, non-fatal myocardial infarction, non-fatal
stroke, re-hospitalization for unstable angina or coronary
revascularization occurring at least 30 days after randomization)
than patients treated with simvastatin alone. The results from this
18,144-patient study of high-risk patients presenting with acute
coronary syndromes were presented today during the late-breaking
clinical trials session at the American Heart Association 2014
Scientific Sessions.
Because high-risk patients treated with statins, including those
on treatment with low levels of LDL-cholesterol (LDL-C), continue
to be at increased cardiovascular risk, IMPROVE-IT was designed to
address whether lowering LDL-C to well under 70 mg/dL by adding
ezetimibe to a statin further reduced cardiovascular events. In
IMPROVE-IT, at seven years, 32.7 percent of patients taking VYTORIN
experienced a primary endpoint event compared to 34.7 percent of
patients taking simvastatin alone (hazard ratio of 0.936, p=0.016).
Based on the LDL-C range compared in the study’s treatment arms (at
one year, a mean LDL-C of 53 mg/dL versus 70 mg/dL, respectively),
the 6.4 percent relative risk reduction observed in the VYTORIN arm
in IMPROVE-IT was consistent with the treatment effect that had
been projected based on prior studies of statins.
Merck plans to submit the data from IMPROVE-IT to the U.S. Food
and Drug Administration in mid-2015 to support a new indication for
reduction of major cardiovascular events for VYTORIN and ZETIA.
VYTORIN and ZETIA are currently indicated for use along with a
healthy diet to reduce elevated LDL cholesterol in patients with
hyperlipidemia. The current U.S. Prescribing Information for both
products states that the effect of ezetimibe on cardiovascular
morbidity and mortality, alone or incremental to statin therapy,
has not been determined.
“In IMPROVE-IT, the addition of ezetimibe to a statin resulted
in a further reduction in cardiovascular events compared to statin
therapy alone, which is the first time this has been directly shown
in a study of a non-statin cholesterol-lowering medicine,” said
study co-chairs, Drs. Eugene Braunwald of Harvard Medical School
and Robert Califf of Duke University. “The IMPROVE-IT data also
address an important scientific question about lowering LDL-C to
very low levels.”
VYTORIN (ezetimibe/simvastatin) should not be taken with strong
CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole,
voriconazole, HIV protease inhibitors, boceprevir, telaprevir,
erythromycin, clarithromycin, telithromycin, nefazodone, and
cobicistat-containing products); or with gemfibrozil, cyclosporine,
or danazol. VYTORIN also should not be taken by anyone with active
liver disease, unexplained persistent elevations of hepatic
transaminase levels, or hypersensitivity to the product; or by
women who are pregnant, nursing or may become pregnant. ZETIA
(ezetimibe) should not be taken by people with hypersensitivity to
any component of the medication. Statin contraindications also
apply when ZETIA is used with these drugs: statins are
contraindicated in patients with active liver disease, unexplained
persistent elevations in hepatic transaminase levels and in
pregnant and nursing women. Refer to individual statin labels for
details about who should not take that statin.
IMPROVE-IT compared very low LDL-C levels -- a range at or
below 70 mg/dL
In IMPROVE-IT (IMProved Reduction of Outcomes: VYTORIN Efficacy
International Trial), the LDL-C levels compared were very low. At
one year, the mean LDL-C level was 53 mg/dL in the VYTORIN group
and 70 mg/dL in the simvastatin group, with a between-group
difference of 17 mg/dL. When the IMPROVE-IT study was initiated in
2005, the optional recommended target LDL-C level in the United
States for acute coronary syndrome patients and other groups
considered to be at very high risk for cardiovascular events was
<70 mg/dL. Prior cardiovascular outcomes studies of statins have
not compared treatments at such low LDL-C levels (see Table).
Table: LDL-C Comparison Ranges
Between Treatment Arms in Selected Trials*
Trial IDEAL
(2005)
TNT
(2005)
PROVE-IT(2004) A to
Z(2004) IMPROVE-IT
(2014)
LDL-C
Comparison Range
(mg/dL)§
104vs.81 101vs.77 95vs.62 77vs.63
70vs.53 *Blazing, et al. Am H J 2014; 168:
205-212.
§All values are expressed as means except
PROVE-IT and A to Z, which are expressed as medians.
At the start of the study, the average baseline LDL-C was
approximately 95 mg/dL. Among treatment-naïve patients (about
two-thirds of those in the study), the mean baseline LDL-C was 101
mg/dL. Among patients on prior lipid lowering therapy at
enrollment, the mean baseline LDL-C was 80 mg/dL.
Additional efficacy and safety results from
IMPROVE-IT
Patients in IMPROVE-IT were initially randomized to treatment
with VYTORIN (ezetimibe/simvastatin) 10/40 mg or simvastatin 40 mg.
Patients were followed for up to nine years, with a median clinical
follow-up of approximately six years. In this event-driven study,
5,314 primary endpoint events were reported.
In addition to the significant result on the primary composite
efficacy endpoint, patients taking VYTORIN experienced significant
reductions compared to patients taking simvastatin alone on the
three secondary composite efficacy endpoints, as follows:
- VYTORIN reduced the incidence of the
composite endpoint of death due to all causes, major coronary
events, and non-fatal stroke; this endpoint occurred in 38.7
percent of patients taking VYTORIN and 40.3 percent of patients
taking simvastatin only (hazard ratio of 0.948, p=0.034).
- VYTORIN reduced the incidence of the
composite endpoint of death due to coronary heart disease (CHD),
non-fatal myocardial infarction (MI), and urgent coronary
revascularization with either percutaneous coronary intervention
(PCI) or coronary artery bypass graft (CABG) occurring at least 30
days after randomization; this endpoint occurred in 17.5 percent of
patients taking VYTORIN and 18.9 percent of patients taking
simvastatin only (hazard ratio of 0.912, p=0.016).
- VYTORIN reduced the incidence of the
composite endpoint of cardiovascular death, non-fatal MI,
documented unstable angina that requires admission into a hospital,
all revascularization (including both coronary and non-coronary)
occurring at least 30 days after randomization, and non-fatal
stroke; this endpoint occurred in 34.5 percent of patients taking
VYTORIN and 36.2 percent of patients taking simvastatin only
(hazard ratio of 0.945, p=0.035).
There were no significant differences between treatment groups
in adverse events of special interest, which included myopathy and
rhabdomyolysis, gallbladder adverse events, liver enzyme elevations
greater than or equal to three times the upper limit of normal
(ULN) and cancer. These safety findings from IMPROVE-IT were
generally consistent with current labeling for ezetimibe. Among
9,067 patients in the ezetimibe/simvastatin group vs. 9,077
patients in the simvastatin group, myopathy was reported in 0.2
percent vs. 0.1 percent of patients, respectively; rhabdomyolysis
was reported in 0.1 percent vs. 0.2 percent; gallbladder-related
adverse events were reported in 3.1 percent vs. 3.5 percent;
cholecystectomy was reported in 1.5 percent vs. 1.5 percent; and
alanine aminotransferase (ALT) and/or aspartate transaminase (AST)
elevations (greater than or equal to three times ULN, consecutive)
were reported in 2.5 percent vs. 2.3 percent of patients. Over
seven years, cancer was reported in 10.2 percent of patients in
both treatment groups.
“We believe that the IMPROVE-IT study makes an important
scientific contribution to the body of evidence relating
LDL-cholesterol levels to cardiovascular risk,” said Dr. Roger
Perlmutter, president, Merck Research Laboratories. “We are
grateful to our collaborators at Harvard and Duke who led the
study, their fellow investigators, and to the thousands of patients
around the world who participated in this study for their
efforts.”
About VYTORIN® (ezetimibe/simvastatin)
VYTORIN contains ezetimibe and simvastatin. VYTORIN is indicated
as adjunctive therapy to diet for the reduction of total
cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and
non–HDL cholesterol, and to increase HDL cholesterol in patients
with primary (heterozygous familial and nonfamilial) hyperlipidemia
or mixed hyperlipidemia when diet alone is not enough.
The Prescribing Information for VYTORIN states that no
incremental benefit of VYTORIN on cardiovascular morbidity and
mortality over and above that demonstrated for simvastatin has been
established. VYTORIN is not indicated to reduce cardiovascular
events in patients who have presented with acute coronary
syndromes.
Selected cautionary information about VYTORIN
All patients starting therapy with VYTORIN, or whose dose of
VYTORIN is being increased, should be advised of the risk of
myopathy, including rhabdomyolysis, and told to promptly report any
unexplained muscle pain, tenderness, or weakness particularly if
accompanied by malaise or fever or if muscle signs and symptoms
persist after discontinuing VYTORIN. VYTORIN should be discontinued
immediately if markedly elevated creatine kinase (CK) levels occur
or myopathy is diagnosed or suspected. VYTORIN contains
simvastatin, which occasionally causes myopathy manifested as
muscle pain, tenderness, or weakness with CK levels above 10 times
ULN. Myopathy sometimes takes the form of rhabdomyolysis with or
without acute renal failure secondary to myoglobinuria, and rare
fatalities have occurred. Predisposing factors for myopathy include
advanced age (≥65 years), female gender, uncontrolled
hypothyroidism, and renal impairment. The risk of myopathy,
including rhabdomyolysis, is dose related.
The 10/80 mg dose of VYTORIN should not be started in new
patients. The risk of myopathy, including rhabdomyolysis, is
greater in patients taking simvastatin 80 mg compared with other
statin therapies with similar or greater LDL cholesterol lowering
efficacy, and with lower doses of simvastatin. The 10/80 mg dose of
VYTORIN (ezetimibe/simvastatin) should be used only in patients who
have been taking that dose chronically (e.g., for 12 months or
more) without evidence of muscle toxicity. If a patient who is
currently tolerating the 10/80 mg dose needs to be initiated on an
interacting drug that is contraindicated or is associated with a
dose cap for simvastatin, that patient should be switched to an
alternative statin or statin-based regimen with less potential for
the drug-drug interaction. Please read Warnings and Precautions in
the Prescribing Information for additional information.
In addition to drugs that are contraindicated because of an
increased risk of myopathy/rhabdomyolysis, grapefruit juice should
be avoided. Use caution when prescribing VYTORIN with a
fenofibrate, and immediately discontinue both drugs if myopathy is
diagnosed or suspected. Cases of myopathy, including
rhabdomyolysis, have been reported with simvastatin coadministered
with colchicine, and caution should be used when prescribing
VYTORIN with colchicine.
The dose of VYTORIN should not exceed 10/10 mg daily in patients
receiving verapamil, diltiazem or dronedarone, and 10/20 mg daily
in patients receiving amiodarone, amlodipine or ranolazine. For
patients with homozygous familial hypercholesterolemia (HoFH)
taking lomitapide, the dose should not exceed 10/20 mg/day (or
10/40 mg/day for patients who have previously taken simvastatin 80
mg/day chronically, e.g., for 12 months or more, without evidence
of muscle toxicity); patients initiating lomitapide should have
their dose of VYTORIN reduced by 50%. The benefits of combined use
of VYTORIN with these drugs, other fenofibrates, or niacin (≥1
g/day) should be carefully weighed against the potential risk of
myopathy/rhabdomyolysis. Caution should be used when Chinese
patients taking niacin (≥1 g/day) are coadministered doses of
VYTORIN exceeding 10/20 mg/day; Chinese patients should not receive
VYTORIN 10/80 mg with niacin.
Persistent elevations in hepatic transaminase can occur. Liver
function tests should be performed at treatment initiation and
thereafter when clinically indicated. If serious liver injury with
clinical symptoms and/or hyperbilirubinemia or jaundice occurs
during treatment, therapy should be interrupted promptly and not
restarted unless an alternate etiology is found.
Increases in HbA1c and fasting serum glucose levels have been
reported with statins, including simvastatin.
In clinical trials, the most commonly reported side effects,
regardless of cause, included headache (5.8 percent), increased ALT
(3.7 percent), myalgia (3.6 percent), upper respiratory tract
infection (3.6 percent), and diarrhea (2.8 percent).
VYTORIN tablets contain ezetimibe and simvastatin: 10 mg of
ezetimibe and 10, 20, 40, or 80 mg of simvastatin (VYTORIN 10/10,
10/20, 10/40, or 10/80 mg, respectively). The usual dosage range is
10/10 mg/day to 10/40 mg/day; patients should not be titrated to
the restricted 10/80-mg dose.
About ZETIA (ezetimibe)
ZETIA, administered alone or in combination with a statin, is
indicated as adjunctive therapy to diet for the reduction of
elevated total cholesterol, LDL cholesterol, apolipoprotein B, and
non-HDL cholesterol in patients with primary (heterozygous familial
and non-familial) hyperlipidemia when diet alone is not enough.
The Prescribing Information for ZETIA states that the effect of
ZETIA on cardiovascular morbidity and mortality has not been
determined. ZETIA is not indicated for use with a statin to further
reduce cardiovascular events in patients who have presented with
acute coronary syndromes.
Selected cautionary information about ZETIA
When using ZETIA with a statin, also follow the label
recommendations for that specific statin.
When ZETIA was coadministered with a statin, consecutive
elevations in hepatic transaminase levels (greater than or equal to
3 times ULN) were slightly higher (1.3 percent) than those of
statins alone (0.4 percent). Liver function tests should be
performed when ZETIA is added to statin therapy and according to
statin recommendations. Should an increase in ALT or AST greater
than or equal to 3 times ULN persist, consider withdrawal of ZETIA
and/or the statin.
Patients should be advised to promptly report muscle pain,
tenderness, or weakness. Risk for skeletal muscle toxicity
increases with higher statin doses, advanced age (>65),
hypothyroidism, renal impairment, and depending on the statin used,
concomitant use of other drugs. Discontinue drug if myopathy is
diagnosed or suspected.
ZETIA is not recommended in patients with moderate to severe
hepatic impairment.
The coadministration of ZETIA with fibrates other than
fenofibrate is not recommended until use in patients is adequately
studied. Exercise caution when using ZETIA and cyclosporine
concomitantly because exposure to both drugs is increased.
Cyclosporine concentrations should be monitored in these
patients.
ZETIA should be used in pregnant or nursing women only if the
benefit outweighs the risk.
In clinical trials, regardless of causality assessment, the most
frequent side effects for ZETIA coadministered with a statin versus
a statin alone included nasopharyngitis (3.7 percent vs 3.3
percent), myalgia (3.2 percent vs 2.7 percent), upper respiratory
tract infection (2.9 percent vs 2.8 percent), arthralgia (2.6
percent vs 2.4 percent), and diarrhea (2.5 percent vs 2.2 percent);
for ZETIA administered alone vs placebo: upper respiratory tract
infection (4.3 percent vs 2.5 percent), diarrhea (4.1 percent vs
3.7 percent), arthralgia (3.0 percent vs 2.2 percent), sinusitis
(2.8 percent vs 2.2 percent), pain in extremity (2.7 percent vs 2.5
percent), and fatigue (2.4 percent vs 1.5 percent).
Additional information about the IMPROVE-IT study
IMPROVE-IT was an international, multi-center, randomized,
double-blind active comparator trial of 18,144 high-risk patients
presenting with acute coronary syndromes (ACS), including unstable
angina (UA), non-ST-segment elevation acute myocardial infarction
(NSTEMI), and ST-segment elevation acute myocardial infarction
(STEMI). The study assessed the incidence of major cardiovascular
events, as measured by a composite of cardiovascular death,
non-fatal MI, non-fatal stroke, re-hospitalization for ACS, or
coronary revascularization (occurring 30 days or more after the
initial event), in patients treated with ezetimibe/simvastatin
(VYTORIN) compared with patients treated with simvastatin
alone.
All patients in the trial were started at doses of
ezetimibe/simvastatin 10/40 mg or simvastatin 40 mg. Prior to a
2011 protocol amendment, the dose could be titrated to
ezetimibe/simvastatin 10/80 mg or simvastatin 80 mg if successive
LDL-C values exceeded 79 mg/dL. The study enrolled patients within
10 days of ACS hospitalization who had sufficient risk as defined
in the protocol and who had an initial LDL-C of ≤125 mg/dL if
lipid-lowering drug naïve or <100 mg/dL if on a prior
prescription lipid-lowering therapy identified as no more potent
than simvastatin 40 mg/day. The LDL-C entry limitations were
designed to enroll patients reasonably anticipated to achieve LDL-C
levels of 70 mg/dL or less in the simvastatin only cohort, which
was the optional recommended target set in the 2004 update to the
Adult Treatment Panel (ATP) III guidelines.
For additional information about the study, please see the
accompanying study timeline.
About Merck
Today's Merck is a global healthcare 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 healthcare through far-reaching policies, programs and
partnerships. For more information, visit www.merck.com and connect
with us on Twitter, Facebook and YouTube.
Merck Forward-Looking Statement
This news release includes “forward-looking statements” within
the meaning of the safe harbor provisions of the United States
Private Securities Litigation Reform Act of 1995. These statements
are based upon the current beliefs and expectations of Merck’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 conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and healthcare
legislation in the United States and internationally; global trends
toward healthcare cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; Merck’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 Merck’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
Merck 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 Merck’s 2013 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 VYTORIN
(ezetimibe/simvastatin) at
http://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_pi.pdf
and the Patient Information for VYTORIN at
http://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_ppi.pdf.
Please see Prescribing Information for ZETIA (ezetimibe)
at
http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf
and the Patient Information for ZETIA at
http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_ppi.pdf.
MerckMedia Contact:Pam Eisele, 267-305-3558orInvestor
Contact:Joe Romanelli, 908-423-5185
Merck (NYSE:MRK)
Historical Stock Chart
From Mar 2024 to Apr 2024
Merck (NYSE:MRK)
Historical Stock Chart
From Apr 2023 to Apr 2024