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November 17, 2014 11:45 am ET

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)§

104 vs. 81

101 vs. 77

95 vs. 62

77 vs. 63

70 vs. 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

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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
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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.

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