THOUSAND OAKS, Calif.,
Nov. 15, 2016 /PRNewswire/
-- Amgen (NASDAQ:AMGN) today announced that adding
Repatha® (evolocumab) to optimized statin therapy
resulted in statistically significant regression of atherosclerosis
in patients with coronary artery disease (CAD). The detailed
results from the GLAGOV Phase 3 coronary intravascular ultrasound
imaging trial were presented at a Late-Breaking Clinical Trials
Session of the American Heart Association (AHA) Scientific Sessions
2016 and simultaneously published in the Journal of the American
Medical Association.
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The GLAGOV study evaluated whether Repatha, a proprotein
convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the
treatment of certain patients with elevated low-density lipoprotein
cholesterol (LDL-C), would modify atherosclerotic plaque build-up
in the coronary arteries of patients already treated with optimized
statin therapy, as measured by intravascular ultrasound (IVUS) at
baseline and week 78.
"The cardiovascular community began conducting imaging studies
with LDL-C therapies to measure slowing of atherosclerotic disease
progression. This study shows that maximal LDL-C reduction with
Repatha can actually regress coronary atherosclerotic disease
compared to statins alone," said Sean E.
Harper, M.D., executive vice president of Research and
Development at Amgen. "In fact, nearly two-thirds of patients on
Repatha in this trial, the vast majority of whom were already on
high to moderate intensity statin therapy at baseline, experienced
a reduction in plaque burden."
The study met its primary objective showing that treatment with
Repatha resulted in a statistically significant regression from
baseline in percent atheroma volume (PAV), which is the proportion
of arterial lumen occupied by plaque. Patients in the Repatha arm
experienced a 0.95 percent decrease versus baseline in PAV compared
with an increase of 0.05 percent versus baseline in patients
receiving optimized statin therapy plus placebo (Repatha arm
p<0.0001; placebo arm p=0.78). The difference
between the two comparators was statistically significant
(p<0.0001). In addition, adding Repatha yielded plaque
regression in PAV for a greater percentage of patients than for
those receiving placebo (64.3 percent versus 47.3 percent,
respectively, p<0.0001). At baseline, 98 percent of
patients in both arms were on high to moderate intensity statin
therapy.
Patients in the Repatha arm experienced a mean decrease in
normalized total atheroma volume (TAV), which is a measure of
plaque volume, of 5.8mm³ compared with 0.9mm³ seen in the placebo
arm (Repatha arm p<0.0001; placebo arm p=0.45).
The difference between the two comparators was statistically
significant (p<0.0001). Additionally, adding Repatha
yielded plaque regression in TAV for a greater percentage of
patients than placebo (61.5 percent versus 48.9 percent,
respectively, p=0.0002).
"Based on previous studies, we did not know if GLAGOV would show
additional plaque regression at LDL-C levels below 60 mg/dL," said
Stephen J. Nicholls, M.D., Ph.D.,
professor of Cardiology and deputy director, South Australian
Health & Medical Research Institute, Adelaide, Australia. "One of the most
compelling results from GLAGOV is the continued reduction of plaque
at LDL-C levels well below commonly accepted thresholds."
At baseline, patients had a mean LDL-C of 92.5 mg/dL across both
treatment arms. During 78 weeks of treatment, the time-weighted
mean LDL-C level was 36.6 mg/dL in the Repatha arm, which
represents a reduction of 59.8 percent, compared with 93.0 mg/dL in
the placebo arm. At week 78, the mean LDL-C in the Repatha arm was
29 mg/dL, which represents a 68.0 percent decrease from baseline,
and in the placebo arm was 90 mg/dL.
An exploratory analysis evaluated the level of plaque reduction
achieved in the 144 patients with baseline LDL-C levels below 70
mg/dL (the lowest treatment target among the current global
guidelines). In this analysis, these patients experienced the
greatest decrease in plaque burden from baseline (change in PAV)
with Repatha compared with placebo (-1.97 percent versus -0.35
percent, respectively, p<0.0001). In addition, more than
80 percent of patients in this subset experienced plaque regression
(by change in PAV) with Repatha (81.2 percent Repatha; 48.0 percent
placebo, p<0.0001).
No new safety concerns were identified in the GLAGOV trial. The
incidence of treatment-emergent adverse events was comparable among
both groups (67.9 percent Repatha; 79.8 percent placebo). Adverse
events of clinical importance reviewed in this study included
myalgia (7.0 percent Repatha; 5.8 percent placebo), new diagnosis
of diabetes mellitus (3.6 percent Repatha; 3.7 percent placebo),
neurocognitive events (1.4 percent Repatha; 1.2 percent placebo)
and injection site reactions (0.4 percent Repatha; 0.0 percent
placebo). In the GLAGOV study, binding antibodies were rarely
observed (0.2 percent [1 patient] in the Repatha-treated arm) and
no patients tested positively for neutralizing antibodies.
Although the study was not powered to assess effects on
cardiovascular events, an exploratory analysis revealed that
positively-adjudicated major cardiovascular events occurred in 12.2
percent of patients receiving Repatha and 15.3 percent in those
receiving placebo. The majority of adjudicated events were coronary
revascularizations (10.3 percent Repatha; 13.6 percent placebo),
followed by myocardial infarction (2.1 percent Repatha; 2.9 percent
placebo). All other adjudicated cardiovascular events occurred in
≤0.8 percent of patients in each treatment group.
Harper continued, "The compelling data from GLAGOV remove any
scientific doubt about the ability of Repatha to lower LDL-C and
the impact it has on the critical underlying disease process. We
remain concerned that many patients are experiencing barriers to
accessing Repatha, despite their physician's treatment
recommendations. We look forward to our outcomes study, FOURIER,
and will continue to work with payers to improve access for
patients who need additional LDL-C lowering."
GLAGOV Study Design
GLAGOV (GLobal Assessment of Plaque ReGression with a PCSK9
AntibOdy as Measured by IntraVascular Ultrasound) is a Phase 3,
multicenter, double-blind, randomized, placebo-controlled trial
designed to evaluate the effect of Repatha on the change in burden
of CAD in 968 patients undergoing clinically indicated coronary
angiogram and on optimized background statin therapy.
Patients were required to have been treated with a stable statin
dose for at least four weeks and to have a LDL-C ≥80 mg/dL or
between 60 and 80 mg/dL with one major cardiovascular risk factor
(defined as non-coronary atherosclerotic vascular disease,
myocardial infarction or hospitalization for unstable angina in the
preceding two years or type 2 diabetes mellitus) or three minor
cardiovascular risk factors (defined as current cigarette smoking,
hypertension, low levels of HDL cholesterol, family history of
premature coronary heart disease, high sensitivity C-reactive
protein (hs-CRP) ≥2 mg/L or age ≥50 years in men and 55 years in
women).
Patients were randomized 1:1 into two treatment groups to either
receive monthly Repatha 420 mg or placebo subcutaneous injections.
Optimized statin therapy was defined as at least atorvastatin 20 mg
daily or equivalent, titrated to achieve LDL-C reduction per
regional guidelines. Highly effective statin therapy
(equivalent to atorvastatin 40 mg daily or higher) was recommended
for all patients. Those patients with LDL-C >100 mg/dL (2.6
mmol/L) not taking highly effective statin therapy, required
investigators' attestation as to why such doses were not
appropriate. The primary endpoint was change in PAV from baseline
to week 78 compared to placebo, as determined by IVUS. IVUS is a
high-resolution imaging tool that allows for the quantification of
coronary atheroma in the coronary arteries.
Secondary endpoints included PAV regression (any reduction from
baseline); change in TAV from baseline to week 78; and regression
(any reduction from baseline) in TAV.
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
The FOURIER outcomes trial is designed to evaluate whether
treatment with Repatha or placebo on top of optimized statin
therapy, reduces the risk of cardiovascular events in patients with
clinically evident atherosclerotic disease. The trial completed
patient enrollment in June 2015. The
primary endpoint for the FOURIER trial is major cardiovascular
events defined as the composite of cardiovascular death, myocardial
infarction (MI), stroke, hospitalization for unstable angina or
coronary revascularization. The key secondary endpoint is the
composite of cardiovascular death, MI or stroke. The trial is
planned to continue until at least 1,630 patients experience the
secondary endpoint, thereby providing 90 percent power to detect a
relative reduction of 15 percent in this endpoint. Top-line results
from the approximately 27,500-patient event-driven FOURIER study
are anticipated in the first quarter of 2017.
Repatha is approved in more than 40 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 August 2016.
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SOURCE Amgen