- Late-Breaking Presentation of Final Results of Bempedoic Acid Pivotal Phase 3 CLEAR Wisdom at the American College of Cardiology (ACC) 2019 Scientific Sessions
- Over 52-Weeks, Bempedoic Acid was Observed to be Safe, Well-Tolerated and Adverse Event Profile was Similar to that of Placebo
- Bempedoic Acid is an Oral, Once-Daily ATP Citrate Lyase (ACL) Inhibitor that Reduces Cholesterol and Fatty Acid Synthesis in the Liver
MUNICH and ANN ARBOR, Michigan, March 19, 2019 /PRNewswire/ -- Daiichi Sankyo Europe GMbH (hereafter, 'Daiichi Sankyo') and Esperion today announced that the Phase 3 results from CLEAR Wisdom of first-in-class, oral, once-daily ATP citrate lyase (ACL) inhibitor, bempedoic acid, were presented at the ACC Scientific Sessions & Expo in New Orleans. Bempedoic acid is being developed as a complementary, convenient, once-daily, oral therapy for the treatment of patients with elevated low-density lipoprotein cholesterol (LDL-C). Bempedoic acid and the bempedoic acid / ezetimibe combination tablet new drug applications have been submitted to the United States Food and Drug Administration (FDA), and are under regulatory review for marketing authorisation by the European Medicines Agency (EMA).
The late-breaking presentation, titled "Efficacy and Safety of Bempedoic Acid Added to Maximally Tolerated Statins in Patients with Hypercholesterolemia and High Cardiovascular Risk: The CLEAR Wisdom Trial", was delivered by Anne C. Goldberg MD, FACP, FAHA, FNLA, Professor of Medicine, Division of Endocrinology, Metabolism and Lipid Research at Washington University, St. Louis.
The presentation highlighted results from the primary endpoint of LDL-C lowering at 12-weeks and key secondary endpoint of safety and tolerability over 52-weeks, including that bempedoic acid:1
-- significantly lowered LDL-C by 17% on background maximally tolerated
statin therapy, and maintained significant reductions in LDL-C for 52
-- significantly lowered high sensitivity C-reactive protein (hsCRP), an
important marker of the underlying inflammation associated with
cardiovascular disease, by 19%;
-- had an adverse event profile that was similar to that of placebo (70.1%
vs 70.8%) and serious adverse event profile that was generally similar
to that of placebo (20.3% vs 18.7%);
-- showed no worsening of glycemic measurements in patients with a history
of diabetes, including a 12-week reduction in haemoglobin A1c of 0.21%.
There is a significant need for additional treatment options for the large number of patients in Europe with hypercholesterolemia who are not at their target LDL-C level. Even in very high-risk patients, only 32% are at their target LDL-C level. Bempedoic acid has a liver specific mode of action and therefore has the potential to avoid the muscle related adverse drug reactions associated with statin therapy. Bempedoic acid can be used in combination with other lipid lowering drugs and will offer an oral, once-daily option for patients not at target.
"In the CLEAR Wisdom Trial, bempedoic acid was shown to be safe and well-tolerated and also provided significant lowering of LDL-C in patients on background maximally tolerated statin therapy," said Anne C. Goldberg MD, FACP, FAHA, FNLA, Professor of Medicine, Division of Endocrinology, Metabolism and Lipid Research at Washington University, St. Louis and lead study author. "These results show that bempedoic acid could be an important new, oral treatment option for high-risk patients who require additional LDL-C lowering."
"CLEAR Wisdom was the final clinical study in the five Phase 3 study research programme, designed to deliver significant evidence on the benefits of bempedoic acid in patients in need of additional LDL-C lowering. We are pleased to reiterate the findings from our topline results, which showed that bempedoic acid had an adverse event profile similar to placebo, as well as significantly lowered LDL-C and hsCRP over the course of the study," said Wolfgang Zierhut, MD, Head of Antithrombotic and Cardiovascular Medical Affairs Department at Daiichi Sankyo Europe. "We continue to be encouraged by these results and believe that bempedoic acid and the bempedoic acid / ezetimibe combination tablet will serve an important unmet need for patients who require additional LDL-C lowering and are not reaching their goals with existing treatment options."
Design of Global Pivotal Phase 3 CLEAR Wisdom (1002-047, also known as Study 2)
The 52-week, global pivotal Phase 3 randomised, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of bempedoic acid 180 mg/day versus placebo. The study was conducted at 93 sites in North America and Europe. A total of 779 patients were randomised 2:1 to receive bempedoic acid or placebo. The primary efficacy objective was to assess the 12-week LDL-C lowering efficacy of bempedoic acid versus placebo. Secondary objectives included evaluating the safety and tolerability of bempedoic acid versus placebo, the 24-week and 52-week LDL-C lowering efficacy of bempedoic acid versus placebo, and its effects on other risk markers after 12 weeks of treatment, including hsCRP.
Bempedoic Acid / Ezetimibe 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 combination tablet is our lead, 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 safe and well-tolerated combination results in a 35 percent lowering of LDL-C when used with maximally tolerated statins, a 43 percent lowering of LDL-C when used as a monotherapy, and a 34 percent reduction in hsCRP. 
With a targeted mechanism of action, bempedoic acid is a first-in-class, complementary, orally available, once-daily ATP Citrate Lyase inhibitor that, reduces cholesterol biosynthesis and lowers LDL-C by up-regulating the LDL receptor. Similar to statins, bempedoic acid also reduces hsCRP, a key marker of inflammation associated with cardiovascular disease.(()) Completed Phase 2 and Phase 3 studies conducted in almost 4,800 patients, and approximately 3,100 patients treated with bempedoic acid, have demonstrated an additional 20 percent LDL-C lowering when used with maximally tolerated statins, up to 30 percent LDL-C lowering as monotherapy, 35 percent LDL-C lowering in combination with ezetimibe when used with maximally tolerated statins and up to 48 percent LDL-C lowering in combination with ezetimibe as monotherapy.4
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, global, 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.(())
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 [http://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 percent 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 percent of ASCVD patients who are not able to reach their LDL-C goals with statins alone, need less than a 40 percent 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 commercialising 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.
This press release contains forward-looking statements and information about future developments in the sector, and the legal and business conditions of DAIICHI SANKYO Co., Ltd. Such forward-looking statements are uncertain and are subject at all times to the risks of change, particularly to the usual risks faced by a global pharmaceutical company, including the impact of the prices for products and raw materials, medication safety, changes in exchange rates, government regulations, employee relations, taxes, political instability and terrorism as well as the results of independent demands and governmental inquiries that affect the affairs of the company. All forward-looking statements contained in this release hold true as of the date of publication. They do not represent any guarantee of future performance. Actual events and developments could differ materially from the forward-looking statements that are explicitly expressed or implied in these statements. DAIICHI SANKYO Co., Ltd. assume no responsibility for the updating of such forward-looking statements about future developments of the sector, legal and business conditions and the company.
 Goldberg AC. et al. Efficacy and Safety of Bempedoic Acid Added to Maximally Tolerated Statins in Patients with Hypercholesterolemia and High Cardiovascular Risk: The CLEAR Wisdom Trial. Presented at ACC 2019.
 De Backer G. et al. Lipid Management of Patients with Coronary Heart Disease in 27 Countries in Europe: Results of EUROASPIRE V Survey of the European Society of Cardiology. Presented at EAS 2018. Available at: https://www.eas-society.org/news/399857/EAS2018-Late-Breaking-Clinical-Trial-EUROASPIRE-V.htm [https://www.eas-society.org/news/399857/EAS2018-Late-Breaking-Clinical-Trial-EUROASPIRE-V.htm] Last accessed March 2019
 Pinkosky L. et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nature, 2016; 10:1038.
 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. Journal of Clinical Lipidology 2016; 10:556-567
 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 [https://investor.esperion.com/static-files/1639de53-9494-4299-98a5-0b6f1317678a]. Last accessed March 8, 2019.
 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 [https://investor.esperion.com/static-files/32936da0-96f9-40e5-a12b-bd00ece6698d]. Last accessed March 8, 2019.
 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 [https://clinicaltrials.gov/ct2/show/NCT02993406?term=bempedoic+acid&rank=4]. Last accessed December 12, 2018.
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March 2019 BEM/19/0003
Web site: http://www.daiichisankyo.com/