- Bempedoic acid is an oral, once-daily ATP Citrate Lyase
(ACL) Inhibitor that reduces cholesterol and fatty acid synthesis
in the liver
- Study 1 is the largest of a comprehensive five Phase 3 study
programme investigating the benefits of bempedoic acid in patients
requiring additional low-density lipoprotein cholesterol (LDL-C)
lowering
- Over 52-weeks, bempedoic acid was observed to be
well-tolerated, and did not lead to higher overall adverse events
compared with placebo
- Treated patients showed lower rates of new-onset or
worsening of diabetes compared with those on
placebo[1]
- Research by Professor Kausik
Ray published in the 14 March
2019 The New England Journal of Medicine (NEJM)
MUNICH, Germany and
ANN ARBOR, Michigan, March 14, 2019 /PRNewswire/ -- Daiichi
Sankyo Europe GMbH (hereafter, 'Daiichi Sankyo') and Esperion
Therapeutics (NASDAQ: ESPR) announced today that results from the
2,230 patient, 52-week, Phase 3 long-term safety study of bempedoic
acid were published in NEJM. The paper can be found
online here.
Bempedoic acid is being developed as a convenient, once-daily,
oral therapy for the treatment of patients with elevated
LDL-C. Bempedoic acid and the bempedoic acid / ezetimibe
combination are currently undergoing regulatory review for
marketing authorisation by the European Medicines Agency (EMA). A
decision is expected during the first half of 2020.
Study 1, also known as CLEAR Harmony (Cholesterol Lowering via
BEmpedoic Acid, an ACL-inhibiting Regimen) is the largest study in
the five Phase 3 study CLEAR research programme, designed to
deliver significant evidence on the benefits of bempedoic acid in
patients in need of additional LDL-C lowering. Study 1 evaluated
the long-term safety, tolerability and efficacy of bempedoic acid
180 mg versus placebo in 2,230 high-risk patients with
atherosclerotic cardiovascular disease (ASCVD) that are
inadequately controlled with current lipid-modifying therapies,
including maximally tolerated statins.
The NEJM publication highlights results from
the primary endpoint of adverse event rates over 52-weeks along
with key efficacy endpoints at 12-weeks, including that bempedoic
acid:[1]
- significantly lowered LDL-C by 18.1% (p<0.001) on background
maximally tolerated statin therapy
- significantly reduced hsCRP, an important marker of the
underlying inflammation associated with cardiovascular disease by
22%
- treated patients showed lower rates of new-onset or worsening
of diabetes compared with those on placebo (3.3% vs 5.4%)
- did not lead to higher overall adverse events compared with
placebo (78.5% vs 78.7%), and the proportion of patients with
reported serious adverse events was small and similar compared with
placebo (14.5% vs 14.0%)
- did not lead to increased discontinuation rates due to
muscle-related adverse events of importance, myalgia and muscle
weakness compared to placebo (2.1% vs 1.9%)
- showed fewer adjudicated major adverse cardiac events compared
with placebo (4.6% vs 5.7%)
- was observed to be well-tolerated.
"The publication of the largest bempedoic acid study to date
further confirms what leading experts have said, that bempedoic
acid is well-tolerated and efficacious potential treatment option
that can significantly lower LDL-C as well as reduce hsCRP. The
results of this study further support Daiichi Sankyo Europe's
long-term commitment to cardiovascular care," said Wolfgang Zierhut, MD, Executive Director Medical
Affairs and Head Thrombosis and Cardiovascular at Daiichi Sankyo
Europe.
"The latest study shows that bempedoic acid could be another
addition to the arsenal of once-daily, oral cholesterol-lowering
treatments available to patients. Overall, these latest studies
show that not only is the treatment generally well-tolerated, being
comparable with placebo but that when added to high intensity
statin treatment it can help to further reduce LDL-C levels," said
Professor Kausik Ray,
Imperial College London's School of Public Health, who
led the study. "Whilst this was not an outcomes study, the
parallel paper in the same issue of the journal comparing the
mechanism of cholesterol lowering with bempedoic acid with statins
using genetics suggests that we can hope to expect similar benefit
to statins per mmol/L lowering of LDL-C. The ongoing trial, 'CLEAR
OUTCOMES', is specially testing even longer-term safety and whether
this approach reduces cardiovascular disease risk in addition to
lowering cholesterol."
Design of Global Pivotal Phase 3 Study 1
The 52-week, global, pivotal Phase 3 randomised, double-blind,
placebo-controlled, multicenter study evaluated the long-term
safety and tolerability of bempedoic acid 180 mg/day versus placebo
in high-risk patients with ASCVD and/or heterozygous familial
hypercholesterolemia (HeFH) with LDL-C levels of at least 70 mg/dL
(1.8 mmol/L) who are inadequately controlled with current
lipid-modifying therapies, including maximally tolerated statin
therapy. The study was conducted at 117 sites in the U.S.,
Canada and Europe. A total of 2,230 patients were
randomised 2:1 to receive bempedoic acid or placebo. The secondary
objective was to assess the 12-week LDL-C lowering efficacy of
bempedoic acid versus placebo. Tertiary objectives were to assess
the effect of bempedoic acid on other lipid parameters and risk
markers, including hsCRP.
An open-label extension study (1002-050) was initiated in early
2017 and is fully enrolled with 1,462 patients.
Bempedoic Acid / Ezetimibe Fixed Dose Combination
Tablet
Through the complementary mechanisms of action of inhibition of
cholesterol synthesis (bempedoic acid) and inhibition of
cholesterol absorption (ezetimibe), the bempedoic acid / ezetimibe
fixed dose combination tablet is a non-statin, orally available,
once-daily, LDL-C lowering therapy. Inhibition of ATP Citrate Lyase
(ACL) by bempedoic acid reduces cholesterol biosynthesis and lowers
LDL-C by up-regulating the LDL receptor. Inhibition of Niemann-Pick
C1-Like 1 (NPC1L1) by ezetimibe results in reduced absorption of
cholesterol from the gastrointestinal tract, thereby reducing
delivery of cholesterol to the liver, which in turn upregulates the
LDL receptors. Phase 3 data demonstrated that this well
tolerated combination results in a 35% lowering of LDL-C when used
with maximally tolerated statins, a 43% lowering of LDL-C when used
as a monotherapy, and a 34% reduction in high sensitivity
C-reactive protein (hsCRP). Rates of treatment-emergent adverse
events, muscle-related adverse events and discontinuations were
similar in the bempedoic acid and placebo treatment
groups.[2]
Bempedoic Acid
With a targeted mechanism of action, bempedoic acid is a
first-in-class, complementary, oral, once-daily ATP Citrate Lyase
(ACL) inhibitor that reduces cholesterol and fatty acid
biosynthesis and lowers LDL-C by up-regulating the LDL receptor.
Similar to statins, bempedoic acid also reduces high sensitivity
C-reactive protein (hs-CRP), a key marker of inflammation
associated with cardiovascular
disease.[3] Bempedoic acid is a prodrug that
requires activation by the very long-chain acyl-CoA synthetase-1
(ACSVL1). Furthermore, it was demonstrated that the absence of
ACSVL1 in skeletal muscle provides a mechanistic basis for
bempedoic acid to potentially avoid the myotoxicity associated with
statin therapy.[4] Completed Phase 2 and Phase 3
studies conducted in almost 4,800 patients, and approximately 3,100
patients treated with bempedoic acid, have produced an additional
20% LDL-C lowering when used with maximally tolerated statins, up
to 30% LDL-C lowering as monotherapy, 35% LDL-C lowering in
combination with ezetimibe when used with maximally tolerated
statins and up to 48% LDL-C lowering in combination with ezetimibe
as monotherapy.[5] Rates of treatment-emergent
adverse events, muscle-related adverse events and discontinuations
were similar in the bempedoic acid and placebo treatment
groups.[3]
The effect of bempedoic acid on cardiovascular morbidity and
mortality has not yet been determined. The company initiated a
global cardiovascular outcomes trial (CVOT) to assess the effects
of bempedoic acid on the occurrence of major cardiovascular events
in patients with, or at high risk for, cardiovascular disease (CVD)
who are only able to tolerate less than the lowest approved daily
starting dose of a statin and considered "statin intolerant." The
CVOT — known as CLEAR Outcomes — is an event-driven, randomised,
double-blind, placebo-controlled study expected to enroll
approximately 12,600 patients with hypercholesterolemia and high
CVD risk at over 1,000 sites in approximately 30
countries.[6]
About Daiichi Sankyo
Daiichi Sankyo Group is dedicated to the creation and supply of
innovative pharmaceutical products to address diversified, unmet
medical needs of patients in both mature and emerging markets. With
over 100 years of scientific expertise and a presence in more than
20 countries, Daiichi Sankyo and its 15,000 employees around the
world draw upon a rich legacy of innovation and a robust pipeline
of promising new medicines to help people. In addition to a strong
portfolio of medicines for hypertension and thrombotic disorders,
under the Group's 2025 Vision to become a "Global Pharma Innovator
with Competitive Advantage in Oncology", Daiichi Sankyo research
and development is primarily focused on bringing forth novel
therapies in oncology, including immuno-oncology, with additional
focus on new horizon areas, such as pain management,
neurodegenerative diseases, heart and kidney diseases, and other
rare diseases. For more information, please
visit: www.daiichisankyo.com.
Esperion's Commitment to Patients with
Hypercholesterolemia
High levels of LDL-C can lead to a build-up of fat and
cholesterol in and on artery walls (known as atherosclerosis),
potentially leading to cardiovascular events, including heart
attack or stroke. In the U.S., 96 million people, or more than 37%
of the adult population have elevated LDL-C. There are
approximately 18 million people in the U.S. with atherosclerotic
cardiovascular disease (ASCVD) who live with elevated levels of
LDL-C despite taking maximally tolerated lipid-modifying therapy —
including individuals considered statin intolerant — leaving them
at high risk for cardiovascular events. More than 50% of ASCVD
patients who are not able to reach their LDL-C goals with statins
alone, need less than a 40% reduction to reach their LDL-C
threshold.
Esperion's mission as the Lipid Management Company is to deliver
once-daily, oral therapies that complement existing oral drugs to
provide the additional LDL-C lowering that these patients need.
The Lipid Management Company
Esperion is the Lipid Management Company passionately committed
to developing and commercializing complementary, cost-effective,
convenient, once-daily, oral therapies for the treatment of
patients with elevated LDL-C. Through scientific and clinical
excellence, and a deep understanding of cholesterol biology, the
experienced Lipid Management Team at Esperion is committed to
developing new LDL-C lowering therapies that will make a
substantial impact on reducing global cardiovascular disease; the
leading cause of death around the world. Bempedoic acid and the
company's lead product candidate, the bempedoic acid / ezetimibe
combination tablet, are targeted therapies that have been shown to
significantly lower elevated LDL-C levels in patients with
hypercholesterolemia, including patients inadequately treated with
current lipid-modifying therapies. For more information, please
visit www.esperion.com and follow us on Twitter
at https://twitter.com/EsperionInc.
Forward Looking Statement: Esperion
This press release contains forward-looking statements that are
made pursuant to the safe harbor provisions of the federal
securities laws, including statements regarding the regulatory
approval pathway for the bempedoic acid / ezetimibe combination
tablet and bempedoic acid and the therapeutic potential of,
clinical development plan for, the bempedoic acid / ezetimibe
combination tablet and bempedoic acid, including Esperion's timing,
designs, plans and announcement of results regarding its CLEAR
Outcomes study and other ongoing clinical studies for bempedoic
acid and the bempedoic acid / ezetimibe combination tablet,
Esperion's expectations for the market for therapies to lower
LDL-C, including the market adoption of bempedoic acid and the
bempedoic acid / ezetimibe combination tablet, if approved, the
expected upcoming milestones described in this press release, and
Esperion's cash position and financial outlook. Any express or
implied statements contained in this press release that are not
statements of historical fact may be deemed to be forward-looking
statements. Forward-looking statements involve risks and
uncertainties that could cause Esperion's actual results to differ
significantly from those projected, including, without limitation,
delays or failures in Esperion's studies, that positive results
from a clinical study of bempedoic acid may not be sufficient for
FDA or EMA approval or necessarily be predictive of the results of
future or ongoing clinical studies, that notwithstanding the
completion of Esperion's Phase 3 clinical development program for
LDL-C lowering, the FDA or EMA may require additional development
in connection with seeking regulatory approval, that DSE is able to
successfully commercialize the bempedoic acid / ezetimibe
combination tablet and bempedoic acid, if approved, that existing
cash resources may be used more quickly than anticipated, and the
risks detailed in Esperion's filings with the Securities and
Exchange Commission. Esperion disclaims any obligation or
undertaking to update or revise any forward-looking statements
contained in this press release, other than to the extent required
by law.
Product Communications Contact:
Lydia Worms
Daiichi Sankyo Europe GmbH
+49(89)-7808751
lydia.worms@daiichi-sankyo.eu
Investor Contact:
Alex Schwartz
Esperion
734-249-3386
aschwartz@esperion.com
[1] Ray K, et al. Safety and Efficacy of
Bempedoic Acid. N Engl J Med 2019; 380:1022-1032. DOI:
10.1056/NEJMoa1803917
[2] Top-Line Results from the Bempedoic Acid /
Ezetimibe Combination Pill Phase 3 Study. Esperion Investor
Presentation. Aug 27, 2018. Available
at https://investor.esperion.com/static-files/1639de53-9494-4299-98a5-0b6f1317678a.
Last accessed March 8, 2019.
[3] Phase 3 Top-Line Results from Study 2 &
Cumulative Phase 3 Program Results. Esperion Investor Presentation.
Oct 29, 2018. Available
at https://investor.esperion.com/static-files/32936da0-96f9-40e5-a12b-bd00ece6698d.
Last accessed March 8, 2019.
[4] Pinkosky L et al. Liver-specific
ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and
attenuates atherosclerosis. Nature. 2016: 10.1038.
[5] Thompson PD, et al. Treatment
with ETC-1002 alone and in combination with ezetimibe lowers LDL
cholesterol in hypercholesterolemic patients with or without statin
intolerance. J Clin Lipidol (2016) 10,
556–567.
[6] Evaluation of Major Cardiovascular Events in
Patients With, or at High Risk for, Cardiovascular Disease Who Are
Statin Intolerant Treated with Bempedoic Acid (ETC-1002) or Placebo
(CLEAR Outcomes). Available
at https://clinicaltrials.gov/ct2/show/NCT02993406?term=bempedoic+acid&rank=4.
Last accessed December 12, 2018.
March 2019 Job Code:
BEM/19/0002
