Very low LDL-C Levels <20 mg/dL Were Well
Tolerated With no new Safety Signals and Were Associated With a
Reduced Risk of Cardiovascular Outcomes
Data Reinforces Long-Term Efficacy and
Consistent Safety Profile of Repatha Observed in
FOURIER-OLE
THOUSAND
OAKS, Calif., Nov. 7,
2022 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today presented a
new analysis from the Phase 3 FOURIER and FOURIER open label
extension (OLE) studies of Repatha® (evolocumab) in
adults with atherosclerotic cardiovascular disease (ASCVD) during
the Nov. 7 Late-Breaking Science Session of the American Heart
Association (AHA) Scientific Sessions 2022 in Chicago, Illinois. These data
demonstrated that achieving and sustaining a low-density
lipoprotein cholesterol (LDL-C) level of <20 mg/dL was
associated with improved cardiovascular (CV) outcomes, including
the composite endpoint of cardiovascular death, myocardial
infarction (MI) and stroke, with no evidence of an increased
incidence of safety events for up to 8.6 years of
follow-up.1
"The current analysis further supports that achieving very
low LDL-C long-term is not associated with any new safety signals
and correlates with the reduction in cardiovascular events in
patients with atherosclerotic cardiovascular disease,"
said David M. Reese, M.D., executive vice president of
Research and Development at Amgen. "Repatha continues to be at
the forefront of PCSK9i research, with the longest safety and
efficacy trial data among PCSK9i treatments for cardiovascular
disease, providing crucial information for patients and doctors
managing this disease."
This pre-specified exploratory analysis examined the association
between achievement of different LDL-C levels with the incidence of
cardiovascular and safety outcomes for up to 8.6 years of follow
up.1 Between the parent FOURIER and FOURIER-OLE studies,
over 3,500 patients (13%) achieved LDL-C levels of <20 mg/dL and
over 10,000 (39%) achieved LDL-C levels of <40
mg/dL.1 This analysis found that over the course of
77,470 patient-years of follow-up there was a monotonic
relationship between lower LDL-C levels – down to very low LDL-C
levels <20 mg/dL – and a lower risk of the efficacy endpoint
from FOURIER of CV death, MI, stroke, coronary revascularization or
hospital admission for unstable angina (see Figure
1).1
A similar relationship was observed between achieved LDL-C
levels and the risk of the key secondary efficacy endpoint from
FOURIER of CV death, MI or stroke (P for trend<0.0001) (see
Figure 2).1 There were no significant associations
between lower achieved LDL-C and the risk of serious adverse
events, neurocognitive events, the development of new onset
diabetes, cataract-related adverse events, new or progressive
malignancy, the occurrence of hemorrhagic stroke, muscle-related
events or non-cardiovascular death.1
"Until now, there was a gap in the medical knowledge of the
long-term efficacy and safety implications of a very low LDL-C
level <20 mg/dL," said Marc S.
Sabatine, MD, Chair of the TIMI Study Group at Brigham and
Women's Hospital and senior investigator for this study. "These
data fill that gap by demonstrating that a lower LDL-C level was
associated with improved cardiovascular outcomes with a similar
safety profile, down to very low LDL-C levels. Furthermore, these
data substantiate the use of a PCSK9 inhibitor to reduce LDL-C
below the threshold of 55 mg/dL for very high-risk ASCVD patients,
as recommended in the recently published ACC 2022 Expert Consensus
Decision Pathway on the Role of Nonstatin Therapies for LDL-C
Lowering in the Management of ASCVD Risk."
Prolonged LDL-C reduction with Repatha is also being
studied in 12,301 patients without a prior heart attack or stroke
in the ongoing VESALIUS-CV (NCT03872401) outcomes trial.
About Cardiovascular Disease (CVD)
CVD remains the
leading cause of global mortality and a major contributor to
disability and rising healthcare costs.2,3 LDL-C is a
key modifiable risk factor for the development of CVD, yet nearly
half of post-MI patients fail to achieve guideline recommended
LDL-C goals, including those taking high-intensity statins, leaving
many patients at risk for another cardiovascular
event.4,5 Nearly one in five patients who have had a
heart attack will have another cardiovascular event within one
year, so it's important that patients get their LDL-C to guideline
recommended levels.6 The American College of
Cardiology's recent Expert Consensus Decision Pathway reinforces
the criticality of lowering LDL-C in an update to the previous
guidelines, including a lower threshold of 55 mg/dL for very
high-risk ASCVD patients, and underscores the important role that
PCSK9 inhibitor mAbs, like Repatha, play in helping to prevent
cardiovascular events, like heart attack and
stroke.7
Repatha® FOURIER and FOURIER-OLE Study
Design
FOURIER (20110118) 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 reduced
cardiovascular events. The primary endpoint was the time to first
occurrence of cardiovascular death, myocardial infarction, stroke,
hospitalization for unstable angina, or coronary revascularization.
The key secondary endpoint was the time to first occurrence of
cardiovascular death, myocardial infarction or stroke.
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 ASCVD 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 effective statin
dose; or placebo subcutaneous every two weeks or monthly plus
effective 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.
FOURIER-OLE were multicenter, open-label extension studies
designed to assess the extended long-term safety of evolocumab in
subjects who completed the FOURIER study. The FOURIER-OLE was
composed of studies 20130295 and 20160250, which enrolled 5,035 and
1,600 subjects who completed the FOURIER study to receive
open-label evolocumab and were followed up for a median of 5 and
4.6 years, respectively. All patients in the extension program
were treated with open label evolocumab resulting in no concurrent
placebo arm during this period. Although not all patients
participated in FOURIER-OLE, baseline characteristics were broadly
comparable between the originally randomized treatment arms,
thereby allowing for reasonably unconfounded exploratory
comparisons between groups.
Total of 26,389 patients had an early achieved LDL-C available,
19,960 of whom were in FOURIER alone with a median follow-up of 2.0
years and 6,429 of whom also participated in FOURIER-OLE with a
median follow-up of ~7 years and a maximum follow-up of 8.6
years.
PROFICIO Program
FOURIER and its extension studies are
part of Amgen's PROFICIO (Program to Reduce
LDL-C and
cardiovascular Outcomes Following Inhibition of
PCSK9 In different populations) program of clinical studies
investigating the impact of Repatha® on LDL-C and
CVD across multiple populations at high CV risk, including those
managed by statins, statin-intolerant patients, those with genetic
disorders and patients with atherosclerosis. To date,
the PROFICIO program consists of 50 trials including more
than 51,000 patients worldwide.
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.
Amgen is one of the 30 companies that comprise the Dow Jones
Industrial Average and is also part of the Nasdaq-100 index. In
2022, Amgen was named one of the "World's Best Employers" by Forbes
and one of "America's 100 Most Sustainable Companies" by
Barron's.
For more information, visit Amgen.com and follow us on Twitter,
LinkedIn, Instagram, TikTok and YouTube.
About
Repatha® (evolocumab)
Repatha 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. The clinical
benefits and safety of Repatha have been studied for 12 years in 50
clinical trials with over 47,000 patients. This vast body of
evidence demonstrates that Repatha works rapidly.
Repatha is approved in more than 75 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 Information8
Repatha is a PCSK9 (proprotein convertase subtilisin/kexin type
9) inhibitor antibody indicated:
- in adults with established cardiovascular disease to reduce the
risk of myocardial infarction, stroke, and coronary
revascularization
- as an adjunct to diet, alone or in combination with other
low-density lipoprotein cholesterol (LDLC)-lowering therapies, in
adults with primary hyperlipidemia, including heterozygous familial
hypercholesterolemia (HeFH), to reduce LDL-C
- as an adjunct to diet and other LDL-C-lowering therapies in
pediatric patients aged 10 years and older with HeFH, to reduce
LDL-C
- as an adjunct to other LDL-C-lowering therapies in adults and
pediatric patients aged 10 years and older with homozygous familial
hypercholesterolemia (HoFH), to reduce LDL-C
The safety and effectiveness of Repatha have not been
established in pediatric patients with HeFH or HoFH who are younger
than 10 years old or in pediatric patients with other types of
hyperlipidemia or HeFH.
Important U.S. Safety Information8
INDICATIONS
Repatha® is indicated:
- In adults with established cardiovascular disease to
reduce the risk of myocardial infarction, stroke, and coronary
revascularization
- As an adjunct to diet, alone or in combination with other
low-density lipoprotein cholesterol (LDL-C)–lowering therapies, in
adults with primary hyperlipidemia, including heterozygous familial
hypercholesterolemia (HeFH), to reduce LDL–C
- As an adjunct to diet and other LDL-C-lowering therapies in
pediatric patients aged 10 years and older with HeFH, to reduce
LDL-C
- As an adjunct to other LDL–C-lowering therapies in adults
and pediatric patients aged 10 years and older with homozygous
familial hypercholesterolemia (HoFH), to reduce LDL–C
The safety and effectiveness of Repatha® have not been
established in pediatric patients with HeFH or HoFH who are younger
than 10 years old or in pediatric patients with other types of
hyperlipidemia.
IMPORTANT SAFETY INFORMATION
- Contraindication: Repatha® is contraindicated in
patients with a history of a serious hypersensitivity reaction to
evolocumab or any of the excipients in Repatha®. Serious
hypersensitivity reactions including angioedema have occurred in
patients treated with Repatha®.
- Hypersensitivity Reactions: Hypersensitivity reactions,
including angioedema, have been reported in patients treated with
Repatha®. If signs or symptoms of serious hypersensitivity
reactions occur, discontinue treatment with Repatha®, treat
according to the standard of care, and monitor until signs and
symptoms resolve.
- Adverse Reactions in Adults with Primary Hyperlipidemia:
The most common adverse reactions (>5% of patients treated with
Repatha® and more frequently than placebo) were: nasopharyngitis,
upper respiratory tract infection, influenza, back pain, and
injection site 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. Hypersensitivity reactions occurred in 5.1% and 4.7% of
Repatha®-treated and placebo-treated patients, respectively. The
most common hypersensitivity 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%).
- Adverse Reactions in the Cardiovascular Outcomes Trial:
The most common adverse reactions (>5% of patients treated with
Repatha® and more frequently than placebo) were: diabetes mellitus
(8.8% Repatha®, 8.2% placebo), nasopharyngitis (7.8% Repatha®, 7.4%
placebo), and upper respiratory tract infection (5.1% Repatha®,
4.8% placebo).
Among the 16,676 patients without diabetes mellitus at baseline,
the incidence of new-onset diabetes mellitus during the trial was
8.1% in patients treated with Repatha® compared with 7.7% in
patients that received placebo.
- Adverse Reactions in Pediatric Patients with HeFH: The
most common adverse reactions (>5% of patients treated with
Repatha® and more frequently than placebo) were: nasopharyngitis,
headache, oropharyngeal pain, influenza, and upper respiratory
tract infection.
- Adverse Reactions in Adults and Pediatric Patients with
HoFH: In a 12-week study in 49 patients, the adverse reactions
that occurred in at least two patients treated with Repatha® and
more frequently than placebo were: upper respiratory tract
infection, influenza, gastroenteritis, and nasopharyngitis. In an
open-label extension study in 106 patients, including 14 pediatric
patients, no new adverse reactions were observed.
- Immunogenicity: Repatha® is a human monoclonal antibody.
As with all therapeutic proteins, there is potential for
immunogenicity with Repatha®.
Please see full Prescribing
Information.
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.
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References
- Sabatine, Marc (2022, November
5-7). Long-Term Efficacy of Very Low LDL-Cholesterol
Levels With the PCSK9 Inhibitor Evolocumab: Analysis of the FOURIER
and FOURIER-OLE Studies [Conference Presentation]. American
Heart Association Scientific Sessions, Chicago, Illinois.
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(2022, February 10). Retrieved
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in post-myocardial infarction patients: nationwide real world data
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- Lloyd-Jones, D. M., Morris, P. B., & Ballantyne, C. M., et
al. (2022). 2022 ACC expert consensus decision pathway on the role
of nonstatin therapies for LDL-cholesterol lowering in the
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https://doi.org/10.1016/j.jacc.2022.07.006.
- Repatha® U.S. Prescribing Information; Amgen,
Thousand Oaks, CA, 2021.
CONTACT: Amgen, Thousand Oaks
Jessica Akopyan, 805-440-5721
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