THOUSAND OAKS, Calif.,
Aug. 16, 2017 /PRNewswire/
-- Amgen (NASDAQ:AMGN) today announced that the New England
Journal of Medicine (NEJM) published results from the
Repatha® (evolocumab) cognitive function trial
(EBBINGHAUS), which was conducted in a subset of patients enrolled
in the randomized, placebo-controlled Repatha cardiovascular
outcomes study (FOURIER). The study demonstrated that Repatha was
non-inferior to placebo, with no significant difference in
cognitive function between the Repatha and placebo-treated
groups.
"In the first prospectively designed study of cognitive function
with a PCSK9 inhibitor using validated instruments, we showed that
there were no significant differences between patients taking
evolocumab and those on placebo," said Robert P. Giugliano, M.D., S.M., Brigham and
Women's Hospital, Boston and lead
study investigator. "These findings are reassuring for both
physicians and patients because they show that LDL cholesterol
levels can be lowered with evolocumab to levels well below current
treatment targets, with no negative effects on memory or other
cognitive domains."
The effect of Repatha on executive function (primary endpoint)
was non-inferior to placebo, and there was no statistical
difference between Repatha and placebo on the other cognitive
domains tested: working memory, memory function and psychomotor
speed (secondary endpoints).
"Historically, the clinical cardiology community has had
concerns that low LDL-C levels may impact cognitive function," said
Sean E. Harper, M.D., executive vice
president of Research and Development at Amgen. "Across our
comprehensive clinical trial program, thousands of patients have
been treated with Repatha, which has demonstrated a consistent
safety profile, even at very low LDL cholesterol levels. These
findings add to the body of evidence supporting the safety of
LDL-lowering with Repatha in patients with established
cardiovascular disease who need more than statin therapy
alone."
In the primary cohort of 1,204 patients, followed for a median
of 19 months, the change from baseline raw score of spatial working
memory strategy index of executive function was similar in the
Repatha and placebo groups (mean baseline score 17.8; mean change
from baseline -0.21 versus -0.29, respectively). The primary
endpoint was below the pre-specified margin, demonstrating
non-inferiority. The primary endpoint was assessed by the Cambridge
Neuropsychological Test Automated Battery (CANTAB) Spatial Working
Memory strategy index of executive function. CANTAB is an
established, language- and culture-independent, computerized,
tablet-based cognitive assessment tool that uses touchscreen
neuropsychological tests of cognition specifically designed to
assess central nervous system disorders and cognitive function
across a range of domains, including episodic and working memory,
executive function, psychomotor speed and attention.
Secondary endpoint results in the three cognitive domains of
working memory, memory function and psychomotor speed were
consistent with the primary endpoint result, and patients treated
with Repatha experienced changes from baseline similar to placebo
in all three cognitive domains tested. Changes from baseline in the
global composite score were also similar between treatment
arms.
In an exploratory analysis, results were consistent regardless
of achieved low-density lipoprotein cholesterol (LDL-C) levels and
did not show an association between LDL-C level and adverse
cognitive outcomes, including in the 661 patients with the
lowest-achieved LDL-C level (<25 mg/dL).
In the EBBINGHAUS study, neurocognitive adverse event rates were
similar between treatment arms (1.9 percent Repatha; 1.3 percent
placebo). The adverse events identified in EBBINGHAUS were
consistent with the adverse events identified in the 27,564-patient
Repatha cardiovascular outcomes study FOURIER.
The results were initially presented at a Late-Breaking Clinical
Trial Session at the American College of Cardiology 66th Annual
Scientific Session (ACC.17) in March 2017.
Repatha Cognitive Function (EBBINGHAUS) Study Design
EBBINGHAUS (Evaluating PCSK9 Binding antiBody Influence oN
coGnitive HeAlth in high cardiovascUlar risk Subjects) is a
double-blind, placebo-controlled, randomized non-inferiority trial
involving 1,974 patients with clinically evident atherosclerotic
cardiovascular disease enrolled in the Repatha cardiovascular
outcomes study (FOURIER). The primary non-inferiority assessment of
the primary endpoint of spatial working memory strategy index of
executive function (assessing executive function, or high-level
thinking and decision making) was performed on the primary cohort
of 1,204 patients who enrolled on or before the first dose of
investigational product and had at least one post-baseline CANTAB
assessment. The full cohort (1,974 patients) included all
randomized patients. The primary endpoint was assessed by comparing
the 95 percent confidence interval (CI) with the pre-specified
non-inferiority margin for the treatment difference between Repatha
and placebo. Secondary endpoints were the CANTAB Spatial Working
Memory between-errors score (assessing working memory, or the
ability to hold material in mind while that material is being
actively processed); the CANTAB Paired Associates Learning Total
Errors Adjusted (assessing memory function, or the ability to store
and retrieve information by associating an event with a time and
place); and the CANTAB Reaction Time Five-Choice Median Reaction
Time (assessing psychomotor speed, which is responsible for
detecting and responding to a stimulus). For all three secondary
endpoints, the 95 percent CI for the estimated treatment difference
between Repatha and placebo spanned equivalence.
Primary and secondary endpoints were assessed using a
tablet-based tool at baseline, week 24, yearly and at study end.
The primary analysis compared the mean change from baseline in
patients who had a baseline cognitive assessment on or prior to the
first day of study drug.
Repatha Cardiovascular Outcomes (FOURIER) Study
Design
The 27,564-patient Repatha cardiovascular outcomes
study, FOURIER (Further Cardiovascular OUtcomes Research
with PCSK9 Inhibition in Subjects
with Elevated Risk), was a multinational, Phase 3,
randomized, double-blind, placebo-controlled trial, designed to
evaluate whether treatment with Repatha in combination with statin
therapy compared to placebo plus statin therapy reduces
cardiovascular events. The hard major adverse cardiovascular event
(MACE) composite endpoint was time to cardiovascular death,
myocardial infarction or stroke (key secondary endpoint). The
extended MACE composite endpoint was the time to cardiovascular
death, myocardial infarction, stroke, hospitalization for unstable
angina, or coronary revascularization (primary endpoint).
Eligible patients with high cholesterol (LDL-C ≥70 mg/dL or
non-high-density lipoprotein cholesterol [non-HDL-C] ≥100 mg/dL)
and clinically evident atherosclerotic cardiovascular disease at
more than 1,300 study locations around the world were randomized to
receive Repatha subcutaneous 140 mg every two weeks or 420 mg
monthly plus optimized statin dose; or placebo subcutaneous every
two weeks or monthly plus optimized statin dose. Optimized statin
therapy was defined as at least atorvastatin 20 mg or equivalent
daily with a recommendation for at least atorvastatin 40 mg or
equivalent daily where approved. The study was event driven and
continued until at least 1,630 patients experienced a key secondary
endpoint.
About
Repatha® (evolocumab)
Repatha® (evolocumab)
is a human monoclonal antibody that inhibits proprotein convertase
subtilisin/kexin type 9 (PCSK9). Repatha binds to PCSK9 and
inhibits circulating PCSK9 from binding to the low-density
lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR
degradation and permitting LDLR to recycle back to the liver cell
surface. By inhibiting the binding of PCSK9 to LDLR, Repatha
increases the number of LDLRs available to clear LDL from the
blood, thereby lowering LDL-C levels.1
Repatha is approved in more than 50 countries, including the
U.S., Japan, Canada and in all 28 countries that are
members of the European Union. Applications in other countries
are pending.
Important U.S. Product Information
Repatha® is indicated as an adjunct to diet
and:
- Maximally tolerated statin therapy for treatment of adults with
heterozygous familial hypercholesterolemia (HeFH) or clinical
atherosclerotic cardiovascular disease (ASCVD), who require
additional lowering of low-density lipoprotein cholesterol
(LDL-C)
- Other LDL-lowering therapies (e.g., statins, ezetimibe, LDL
apheresis) in patients with homozygous familial
hypercholesterolemia (HoFH) who require additional lowering of
LDL-C
The effect of Repatha® on cardiovascular
morbidity and mortality has not been determined.
The safety and effectiveness of Repatha® have
not been established in pediatric patients with HoFH who are
younger than 13 years old.
The safety and effectiveness of Repatha® have
not been established in pediatric patients with primary
hyperlipidemia or HeFH.
Important U.S. Safety Information
Contraindication: Repatha® is
contraindicated in patients with a history of a serious
hypersensitivity reaction to Repatha®.
Allergic reactions: Hypersensitivity reactions (e.g.
rash, urticaria) have been reported in patients treated with
Repatha®, including some that led to discontinuation of
therapy. If signs or symptoms of serious allergic reactions occur,
discontinue treatment with Repatha®, treat according to
the standard of care, and monitor until signs and symptoms
resolve.
Adverse reactions: The most common adverse reactions
(>5% of Repatha®-treated patients and more common
than placebo) were: nasopharyngitis, upper respiratory tract
infection, influenza, back pain, and injection site reactions.
In a 52-week trial, adverse reactions led to discontinuation of
treatment in 2.2% of Repatha®-treated patients and 1% of
placebo-treated patients. The most common adverse reaction that led
to Repatha® treatment discontinuation and occurred
at a rate greater than placebo was myalgia (0.3% versus 0% for
Repatha® and placebo, respectively).
Adverse reactions from a pool of the 52-week trial and seven
12-week trials:
Local injection site reactions occurred in 3.2% and 3.0% of
Repatha®-treated and placebo-treated patients,
respectively. The most common injection site reactions were
erythema, pain, and bruising. The proportions of patients who
discontinued treatment due to local injection site reactions in
Repatha® -treated patients and placebo-treated
patients were 0.1% and 0%, respectively.
Allergic reactions occurred in 5.1% and 4.7% of
Repatha®-treated and placebo-treated patients,
respectively. The most common allergic reactions were rash (1.0%
versus 0.5% for Repatha® and placebo,
respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus
0.2%), and urticaria (0.4% versus 0.1%).
Neurocognitive events were reported in less than or equal to
0.2% in Repatha®-treated and placebo-treated
patients.
In a pool of placebo- and active-controlled trials, as well as
open-label extension studies that followed them, a total of 1,988
patients treated with Repatha® had at least one
LDL-C value <25 mg/dL. Changes to background lipid-altering
therapy were not made in response to low LDL-C values, and
Repatha® dosing was not modified or interrupted on
this basis. Although adverse consequences of very low LDL-C were
not identified in these trials, the long-term effects of very low
levels of LDL-C induced by Repatha® are
unknown.
Musculoskeletal adverse reactions were reported in 14.3% of
Repatha®-treated patients and 12.8% of placebo-treated
patients. The most common adverse reactions that occurred at a rate
greater than placebo were back pain (3.2% versus 2.9% for
Repatha® and placebo, respectively), arthralgia
(2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).
Homozygous Familial Hypercholesterolemia (HoFH): In
49 patients with homozygous familial hypercholesterolemia studied
in a 12-week, double-blind, randomized, placebo-controlled trial,
33 patients received 420 mg of
Repatha® subcutaneously once monthly. The adverse
reactions that occurred in at least 2 (6.1%)
Repatha®-treated patients and more frequently than in
placebo-treated patients, included upper respiratory tract
infection (9.1% versus 6.3%), influenza (9.1% versus 0%),
gastroenteritis (6.1% versus 0%), and nasopharyngitis (6.1% versus
0%).
Immunogenicity: Repatha® is a human
monoclonal antibody. As with all therapeutic proteins, there is a
potential for immunogenicity with Repatha®.
Please contact Amgen Medinfo at 800-77-AMGEN (800-772-6436)
or 844-REPATHA (844-737-2842) regarding
Repatha® availability or find more information,
including full Prescribing Information,
at www.amgen.com and www.Repatha.com.
About Amgen Cardiovascular
Building on more than three
decades of experience in developing biotechnology medicines for
patients with serious illnesses, Amgen is dedicated to
addressing important scientific questions to advance care and
improve the lives of patients with cardiovascular disease, the
leading cause of morbidity and mortality
worldwide.2 Amgen's research into
cardiovascular disease, and potential treatment options, is part of
a growing competency at Amgen that utilizes human
genetics to identify and validate certain drug targets. Through its
own research and development efforts, as well as
partnerships, Amgen is building a robust cardiovascular
portfolio consisting of several approved and investigational
molecules in an effort to address a number of today's important
unmet patient needs, such as high cholesterol and heart
failure.
About Amgen
Amgen is committed to
unlocking the potential of biology for patients suffering from
serious illnesses by discovering, developing, manufacturing and
delivering innovative human therapeutics. This approach begins by
using tools like advanced human genetics to unravel the
complexities of disease and understand the fundamentals of human
biology.
Amgen focuses on areas of high unmet medical need and
leverages its expertise to strive for solutions that improve health
outcomes and dramatically improve people's lives. A biotechnology
pioneer since 1980, Amgen has grown to be one of the
world's leading independent biotechnology companies, has reached
millions of patients around the world and is developing a pipeline
of medicines with breakaway potential.
For more information, visit www.amgen.com and follow
us on www.twitter.com/amgen.
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CONTACT: Amgen, Thousand
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REFERENCES
- Repatha® U.S. Prescribing Information. Amgen.
- World Health Organization. Cardiovascular diseases (CVDs) fact
sheet. http://www.who.int/mediacentre/factsheets/fs317/en/.
Accessed March 2017.
SOURCE Amgen