Bempedoic Acid Study 1 Results Published in The New England Journal of Medicine Demonstrate Significant LDL-Cholesterol Lowering and Reduced Marker of Underlying Cardiovascular Inflammation, with a Similar Tolerability to Placebo

• 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 
[email protected]  

Investor Contact: 
Alex Schwartz 
Esperion 
734-249-3386 
[email protected]

^[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  

SOURCE Daiichi Sankyo Europe