Merck/Schering-Plough Pharmaceuticals comments on results of the ENHANCE study - Study presented at American College of Cardiology Scientific Sessions and published in on-line version of the New England Journal of Medicine



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    CHICAGO, IL, March 30 /CNW Telbec/ - Results of ENHANCE (Ezetimibe aNd
simvastatin in Hypercholesterolemia enhANces atherosClerosis rEgression), an
imaging trial in 720 patients with heterozygous familial hypercholesterolemia
(HeFH), a rare genetic condition that causes very high levels of LDL "bad"
cholesterol and greatly increases the risk for premature coronary artery
disease, were presented at the 57th Annual Scientific Sessions of the American
College of Cardiology and also were published on-line in The New England
Journal of Medicine(1).
    As previously reported on January 14, 2008, despite the fact that
ezetimibe 10 mg plus simvastatin 80 mg significantly lowered LDL "bad"
cholesterol more than simvastatin 80 mg alone, there was no significant
difference between treatment with ezetimibe plus simvastatin and simvastatin
alone on the pre-specified primary endpoint: a change in the thickness of
carotid artery walls over two years as measured by ultrasound. There also were
no significant differences between treatment with ezetimibe plus simvastatin
and simvastatin on the four pre-specified key secondary endpoints: per cent of
patients manifesting regression in the average carotid artery intima-media
thickness (CA IMT); proportion of patients developing new carotid artery
plaques (greater than)1.3 mm; changes in the average maximum CA IMT; and
changes in the average CA IMT plus changes in the average common femoral
artery IMT.
    In ENHANCE, when compared to simvastatin alone, ezetimibe plus
simvastatin significantly lowered LDL "bad" cholesterol, as well as
triglycerides and C-reactive protein (CRP). In the ENHANCE study, as
previously reported, the overall safety profile of ezetimibe plus simvastatin
in the study was generally consistent with their product labels.
    "While ENHANCE showed no statistical difference between treatment arms in
mean IMT, it did show once again that combining ezetimibe with simvastatin
lowers LDL-C significantly more than simvastatin alone," said Dr. Daniel
Gaudet, ENHANCE study investigator, Professor of Medicine at University of
Montreal and Director of research at the Chicoutimi University Hospital Lipid
Clinic. "Over 30 years of science have confirmed that elevated LDL-C is a
major risk factor for cardiovascular disease, and we must continue to treat
patients for high cholesterol in light of the strong body of evidence we
currently have."
    In the ENHANCE publication, the authors provided three theoretical
explanations why, despite ezetimibe plus simvastatin significantly lowering
LDL "bad" cholesterol more than simvastatin (56 per cent vs. 39 per cent,
p(less than)0.01), there was no significant difference between treatment
groups on the primary endpoint and four key secondary endpoints: (1) lowering
of LDL cholesterol with non-statin therapy, such as ezetimibe, might affect
IMT differently than statin therapy, (2) the imaging technology selected was
not sensitive enough to detect a difference, or (3) that these HeFH patients
were extensively pretreated with lipid-lowering therapy, thereby limiting the
amount that CA IMT could change with further LDL cholesterol-lowering therapy,
consequently limiting the ability to detect a differential response to the two
treatments. The authors concluded that the reason for the failure to observe
an incremental effect on CA IMT thickness in spite of a reduction in the level
of LDL cholesterol remains unknown.
    In the publication, the authors addressed the premise that the lack of a
difference in the change of mean CA IMT between ezetimibe plus simvastatin and
simvastatin alone, despite greater LDL cholesterol-lowering, could be
attributed to lipid-independent effects of statins on arteries. The authors
presented several facts that argued against this concept, including a
discussion of clinical studies involving statin and non-statin therapeutic
approaches that demonstrated cardiovascular risk reductions were associated
with the degree of LDL-cholesterol lowering. The authors suggested that
clinical outcomes data are needed to answer this question.
    As for the hypothesis that the results may reflect the imaging
technology, the authors noted this seems unlikely given the precision of the
imaging measurement results seen in the ENHANCE trial.
    With respect to the hypothesis that the ENHANCE results were due to the
characteristics of the patients studied, the authors pointed out that in an
earlier imaging study (extension of ASAP or Atorvastatin vs. Simvastatin on
Atherosclerosis Progression study) use of potent lipid-lowering therapy in
HeFH patients produced "regression" or "thinning" of CA IMT during the first
one to two years of therapy, but further decreases during the following two
years on the same therapy were not seen. In ENHANCE, approximately 80 per cent
of the enrolled patients reported taking statin treatment at the time of
screening for the study, and had a mean baseline CA IMT of 0.69 to 0.70 mm. In
another recent IMT study in HeFH patients (RADIANCE 1 or Rating
Atherosclerotic Disease Change by Imaging with A New CETP Inhibitor study),
the baseline CA IMT was also lower than in the earlier IMT study and similar
to ENHANCE and, importantly, the pattern of change in CA IMT in this IMT study
was very similar to that observed in both treatment groups in the ENHANCE
study.
    The authors noted that "these data raise the possibility that there may
be limits to the extent to which the lowering of LDL cholesterol levels can
result in a further decrease in the progression of intima-media thickness in
the context of previous statin therapy and a modest baseline intima-media
thickness (2)."
    "Although a definitive explanation is never possible with a finding like
this, we believe that the most likely explanation for the failure to see a
significant difference between treatment groups in ENHANCE relates to the
behavior of IMT in this population of HeFH patients," noted Thomas Musliner,
M.D., Executive Director, Cardiovascular Disease, Clinical Research, Merck
Research Laboratories. "The large majority of these patients were previously
treated with LDL cholesterol-lowering therapy and presumably experienced an
effect in CA IMT from that treatment, as reflected in the patients' relatively
low CA IMT values when they began the study. The findings of the ASAP
extension, RADIANCE 1 and ENHANCE suggest there are limits to how much IMT can
be decreased in HeFH study cohorts in the context of the widespread and
prolonged use of effective LDL cholesterol-lowering treatment starting at an
earlier age, which is now the standard of care for these patients."

    Endpoint Data and Cardiovascular Events

    ENHANCE investigators found no statistically significant difference
between the two treatment groups on the primary endpoint: the change in the
average CA IMT at three carotid artery locations. The change from baseline in
the mean (average) CA IMT in the ezetimibe plus simvastatin group was
0.0111 mm, which did not significantly differ from the simvastatin group's
change of 0.0058 mm (P=0.29). The median data for the primary endpoint, which
also showed no statistical difference between treatments, was 0.0058 mm in the
ezetimibe plus simvastatin group and 0.0095 mm for the simvastatin group. The
treatment groups also did not have statistically significant differences for
each of the three carotid artery locations that comprised the primary
endpoint: the common carotid, the internal carotid and the carotid bulb.
    The ENHANCE study was not designed nor powered to evaluate cardiovascular
clinical events. IMPROVE-IT is underway and is designed to provide
cardiovascular outcomes data for ezetimibe plus simvastatin in patients with
acute coronary syndrome. No incremental benefit of ezetimibe plus simvastatin
on cardiovascular morbidity and mortality over and above that demonstrated for
simvastatin has been established.

    Lipid Parameters of LDL Cholesterol, Triglycerides and HDL Cholesterol;
    and C-reactive Protein

    Over the two-year period of the ENHANCE study based upon the "last
observation carried forward" endpoint approach, the group treated with
ezetimibe plus simvastatin had a 56 per cent mean reduction of LDL cholesterol
(from a baseline of 319 mg/dL or 8.25 mmol/L) that was significantly greater
than the 39 per cent mean reduction of LDL cholesterol (from a baseline of
318 mg/dL or 8.22 mmol/L) in the group treated with simvastatin alone (P(less
than)0.01).
    In addition, by study completion, the ezetimibe plus simvastatin group
had a 30 per cent median reduction in triglycerides (from baseline 157 mg/dL
or 1.77 mmol/l), significantly more than the 23 per cent median reduction
(from baseline 160 mg/dL or 1.81 mmol/L) in the simvastatin group (P(less
than)0.01). Also, the ezetimibe plus simvastatin group had a 49 per cent
median reduction in CRP (from baseline 1.70 mg/L), significantly more than the
24 per cent median reduction in CRP (from baseline 1.70 mg/L) in the
simvastatin group (P(less than)0.01). The ezetimibe plus simvastatin group had
a 10 per cent increase (from baseline 46.7 mg/dL or 1.21 mmol/L) in HDL "good"
cholesterol; the simvastatin group had an 8 per cent increase from baseline
47.4 mg/dL or 1.23 mmol/L (P=0.05, no statistical significance).

    Tolerability Data

    As previously reported, the overall safety profiles of ezetimibe and
simvastatin were similar and generally consistent with their product labels.
Both medicines were generally well tolerated. Also, the overall incidence
rates of treatment-related adverse events were 34 per cent for ezetimibe plus
simvastatin (122/357) and 29 per cent (107/363) for simvastatin only; the
incidence rates for discontinuations due to adverse events were 8.1 per cent
for ezetimibe plus simvastatin (29/357) and 9.4 per cent for simvastatin only
(34/363).

    About the Study Design and Methodology

    The ENHANCE study was an international two-year, randomized,
double-blind, controlled trial in 720 HeFH patients between the ages of 30 to
75. All of the ENHANCE patients had HeFH, which affects approximately 0.2 per
cent of the population. The rationale for studying HeFH patients is that these
patients are known to be at increased risk for premature coronary artery
disease and, if untreated, exhibit increased IMT progression rates beginning
in childhood. Prior LDL cholesterol-lowering therapy of any kind was not an
exclusion criterion for ENHANCE, although such therapies were discontinued at
the start of the study. Also, there was not a minimum value for CA IMT
specified for inclusion in study. Following a six-week, single blind, placebo
lead-in/drug "wash-out" period, patients were randomized to receive either
daily ezetimibe 10 mg and simvastatin 80 mg (N=357) or daily simvastatin 80 mg
(N=363).
    ENHANCE investigators took digitized single-frame CA IMT images at the
three locations of the patients' right and left carotid arteries. These images
were taken at several time points: study baseline, 6, 12, 18 and 24 months.
    "Examination of the CA IMT collected during ENHANCE proved to be a far
more challenging process than originally anticipated when the study design was
drawn up. Therefore, preparation of the images for entry into a database took
significantly longer than expected, as the blinded investigators and CA IMT
evaluators took numerous steps in 2006 and 2007 to address image quality
control and finalize the analysis," said Enrico P. Veltri, M.D., co-author of
the ENHANCE study publication and group vice president, Cardiovascular and
Metabolic Disease, Clinical Research, Schering-Plough Research Institute. "Our
companies acted with integrity and good faith in connection with the trial,"
he said.

    About Merck Frosst/Schering Pharmaceuticals

    Merck Frosst/Schering Pharmaceuticals (MFSP) is a joint venture between
Merck Frosst Canada Ltd. and Schering-Plough Canada Inc., which was
established in December 2001 as part of a worldwide partnership (except Japan)
between the two companies. MFSP was formed to develop and market new
prescription medicines for the management of cholesterol.

    Merck Forward-Looking Statement

    This press release contains "forward-looking statements" as that term is
defined in the Private Securities Litigation Reform Act of 1995. These
statements are based on management's current expectations and involve risks
and uncertainties, which may cause results to differ materially from those set
forth in the statements. The forward-looking statements may include statements
regarding product development, product potential or financial performance. No
forward-looking statement can be guaranteed, and actual results may differ
materially from those projected. Merck undertakes no obligation to publicly
update any forward-looking statement, whether as a result of new information,
future events, or otherwise. Forward-looking statements in this press release
should be evaluated together with the many uncertainties that affect Merck's
business, particularly those mentioned in the cautionary statements in Item 1A
of Merck's Form 10-K for the year ended Dec. 31, 2007, and in its periodic
reports on Form 10-Q and Form 8-K, which the Company incorporates by
reference.

    Schering-Plough Disclosure Notice

    The information in this press release includes certain "forward-looking
statements" within the meaning of the U.S. Private Securities Litigation
Reform Act of 1995, including statements relating to potential market for
EZETROL(R) (ezetimibe). Forward-looking statements relate to expectations or
forecasts of future events. Schering-Plough does not assume the obligation to
update any forward-looking statement. Many factors could cause actual results
to differ materially from Schering-Plough's forward-looking statements,
including market forces, economic factors, product availability, patent and
other intellectual property protection, current and future branded, generic or
over-the-counter competition, the regulatory process, and any developments
following regulatory approval, among other uncertainties. For further details
about these and other factors that may impact the forward-looking statements,
see Schering-Plough's Securities and Exchange Commission filings, including
Part I, Item 1A. "Risk Factors" in the Schering-Plough's 2007 10-K/A.

    -----------------------------------------------

    (1) N Engl J Med 2008; 358: 1431-43.
    (2) N Engl J Med 2008; 358: 1431-43.




For further information:

For further information: Sheila Murphy, Merck Frosst Canada Ltd., Cell:
(954) 540-6620, sheila_murphy@merck.com; Dan Brennan, NATIONAL PharmaCom,
Cell: (514) 912-0682, dbrennan@national.ca


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