Item 8.01. Other Events.
On
November 10, 2018, the Company announced primary results from its
REDUCE-IT
study.
REDUCE-IT
met its primary endpoint demonstrating a 25% relative risk reduction,
or RRR, to a high degree of statistical significance (p<0.001), in first occurrence of major adverse CV events, or MACE, in the
intent-to-treat
patient population
with use of Vascepa 4 grams/day as compared to placebo. Patients qualified to enroll in
REDUCE-IT
had LDL-C between
41-100
mg/dL (median baseline LDL-C 75 mg/dL)
controlled by statin therapy and various cardiovascular risk factors including persistent elevated triglycerides between
135-499 mg/dL
(median baseline 216 mg/dL) and either established cardiovascular
disease (secondary prevention cohort) or age 50 or more with diabetes mellitus and at least one other CV risk factor (primary prevention cohort). Approximately 59% of the patients had diabetes at baseline and approximately 71% of the patients had
established cardiovascular disease at time of enrollment.
REDUCE-IT
also showed a 26% RRR in its key secondary composite endpoint of cardiovascular death, heart attacks and stroke (p<0.001). On
November 10, 2018,
REDUCE-IT
results were published in
The New England Journal of Medicine
and presented as late-breaking clinical results at the 2018 Scientific Sessions of the American Heart
Association, or AHA. The Company commenced the REDUCE-IT trial in 2011 and has expended more than $300 million to fund its completion.
Number needed to treat, or NNT, was 21 for the first occurrence of MACE in the
5-point
primary
composite endpoint. The NNT is a statistical concept intended to provide a measurement of the impact of a medicine or therapy by estimating the number of patients that need to be treated in order to have an impact on one person.
An additional seven secondary endpoints were achieved below the key secondary endpoint, in order of sequential statistical testing within the
prespecified hierarchy:
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Cardiovascular death or nonfatal heart attack: 25% RRR (p<0.001)
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Fatal or nonfatal heart attack: 31% RRR (p<0.001)
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Urgent or emergent revascularization: 35% RRR (p<0.001)
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Cardiovascular death: 20% RRR (p=0.03)
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Hospitalization for unstable angina: 32% RRR (p=0.002)
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Fatal or nonfatal stroke: 28% RRR (p=0.01)
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Total mortality, nonfatal heart attack or nonfatal stroke: 23% RRR (p<0.001)
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The next prespecified secondary endpoint in the hierarchy was the only such endpoint that did not achieve statistical significance:
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Total mortality, which includes mortality from
non-cardiovascular
and
cardiovascular events: 13% RRR (p=0.09)
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Positive
REDUCE-IT
results were
consistent across various patient subgroups, including female/male,
diabetic/non-diabetic
and secondary/primary prevention. Vascepa was well tolerated with a safety profile generally consistent with clinical
experience associated with
omega-3
fatty acids and current
FDA-approved
labeling of such products. Excluding the MACE results described above, overall adverse event
rates in
REDUCE-IT
were similar across the statin plus Vascepa and the statin plus placebo treatment groups. There were no significant differences between treatments in the overall rate of treatment emergent
adverse events or serious adverse events leading to withdrawal of study drug. The one serious adverse event occurring at a frequency of >2% was pneumonia which occurred at a numerically higher rate in the statin plus placebo treatment group
(2.9%) than in the statin plus Vascepa treatment group (2.6%). Adverse events occurring in 5% or greater of patients and more frequently with Vascepa than placebo were peripheral edema (6.5% Vascepa patients versus 5.0% placebo patients),
constipation (5.4% Vascepa patients versus 3.6% placebo patients), and atrial fibrillation (5.3% Vascepa patients versus 3.9% placebo patients). There were numerically more serious adverse events related to bleeding in the statin plus Vascepa
treatment group although overall rates were low with no fatal bleeding observed in either group and no significant difference in adjudicated hemorrhagic stroke or serious central nervous system or gastrointestinal bleeding events between treatments.
In the
REDUCE-IT
trial, cardiovascular benefits appeared not to be influenced significantly
by TG levels at baseline (above or below 150 mg/dL baseline range) or as achieved at one year, potentially suggesting mechanisms at work with use of Vascepa that are independent of baseline TG levels or therapy-driven reduction
in TG levels. Mechanisms responsible for the benefit shown in
REDUCE-IT
were not the focus of
REDUCE-IT.
As summarized from the primary results of
REDUCE-IT
in
The New England Journal of Medicine,
potential Vascepa mechanisms of action at work in
REDUCE-IT
may include TG reduction, anti-thrombotic
effects, antiplatelet or anticoagulant effects, membrane-stabilizing effects, effects on stabilization and/or regression of coronary plaque and inflammation reduction, each as supported by earlier stage mechanistic studies. In addition, the median
change in LDL cholesterol levels from baseline was higher in the placebo group versus the Vascepa group (difference of 5.0 mg/dL; p < 0.001). However, a
post hoc
analysis of
REDUCE-IT
data published in
The
New England Journal of Medicine
showed no material difference in each of the primary and key secondary cardiovascular risk composite
endpoint event rates for placebo patients that experienced an increase in LDL-C at one year versus those with no change or a decrease, and also suggested a similar relative risk reduction regardless of whether there was an
increase in LDL cholesterol level among the patients in the placebo group. Moreover, as the authors of the paper published in
The New England Journal of Medicine
noted, the relatively small differences in LDL-C levels between the groups would
not be likely to explain the 25% lower MACE risk observed with Vascepa and the Japan open-label EPA Lipid Intervention Study (JELIS), an over 18,000 patient cardiovascular outcomes study in Japan of a highly-pure EPA product similar to Vascepa,
previously demonstrated a 19% risk reduction without a mineral oil placebo.
Following the announcement of
REDUCE-IT
topline results, the Company has begun promoting
REDUCE-IT
results to healthcare professionals in the United States based on what the Company believes is its
continuing obligation under its First Amendment settlement to ensure that its promotion of Vascepa remains truthful and
non-misleading.
This effort continued after November 10, 2018 as more data became
available with
REDUCE-IT
primary results. The Company is also developing Vascepa for FDA approval of additional indications based on
REDUCE-IT.
The
REDUCE-IT
study was designed under a special protocol assessment agreement, or SPA, with the FDA.
The Company intends to submit an sNDA to the FDA in early 2019 seeking approval to expand the label for Vascepa based on the cardioprotective effect of Vascepa demonstrated in the
REDUCE-IT
study. The
FDAs determination of standard or priority review will be made when the sNDA is submitted. At this time, the Company is planning for a standard review with potential approval anticipated in late 2019.
Forward-Looking Statements
This report
contains forward-looking statements, including expectations regarding planned regulatory filings and the nature of FDAs review and related timing thereof; expectations that
REDUCE-IT
results could lead
to a new treatment paradigm in the patient population studied; and plans for sales force, international and insurance coverage expansion. These forward-looking statements are not promises or guarantees and involve substantial risks and
uncertainties. In addition, the Companys ability to effectively commercialize Vascepa will depend in part on its ability to continue to effectively finance its business, efforts of third parties, its ability to create market demand for Vascepa
through education, marketing and sales activities, to achieve market acceptance of Vascepa, to receive adequate levels of reimbursement from third-party payers, to develop and maintain a consistent source of commercial supply at a competitive price,
to comply with legal and regulatory requirements in connection with the sale and promotion of Vascepa and to maintain patent protection for Vascepa. Among the factors that could cause actual results to differ materially from those described or
projected herein include the following: uncertainties associated generally with research and development, clinical trials and related regulatory approvals; the risk that sales may not meet expectations and related cost may increase beyond
expectations; the risk that patents may not be upheld in patent litigation and applications may not result in issued patents sufficient to protect the Vascepa franchise. A further list and description of these risks, uncertainties and other risks
associated with an investment in the Company can be found in the Companys filings with the U.S. Securities and Exchange Commission, including its most recent quarterly report on Form
10-Q.
Existing and
prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. The Company undertakes no obligation to update or revise the information contained in this press release,
whether as a result of new information, future events or circumstances or otherwise.