Daiichi Sankyo Europe and Esperion Announce Validation of the Marketing Authorisation Application (MAA) for Bempedoic Acid and the Bempedoic Acid / Ezetimibe Fixed Dose Combination Tablet

- Daiichi Sankyo Europe (hereafter, Daiichi Sankyo) and Esperion Therapeutics Inc. (hereafter, Esperion) announced today the validation of the Marketing Authorisation Application (MAA) for bempedoic acid and the bempedoic acid / ezetimibe fixed dose combination tablet by the European Medicines Agency (EMA). Validation confirms that the application is complete and commences the scientific review process by the EMA's Committee for Medicinal Products for Human Use (CHMP).  Bempedoic acid is an oral, once-daily ATP Citrate Lyase (ACL) inhibitor that reduces cholesterol and fatty acid synthesis in the liver.1 Bempedoic acid and the bempedoic acid / ezetimibe fixed dose combination tablet could become an important treatment option for patients with hypercholesterolemia who are not yet at their target LDL-C goals with existing therapies or who have statin intolerance.  This MAA validation for the LDL-C lowering indication is based on the successful completion of the global pivotal Phase 3 programme, which demonstrated bempedoic acid was well tolerated and efficacious for chronic use in almost 4,800 patients. Patients treated with bempedoic acid produced 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. In the Phase 3 trials, rates of treatment-emergent adverse events, muscle-related adverse events and discontinuations were similar in the bempedoic acid and placebo treatment group.2 There is a significant unmet need for patients with elevated LDL-C who are not reaching their treatment goals with existing therapies. This is particularly true for patients taking statins only at the maximum tolerated dose or are statin intolerant and need additional LDL-C lowering.3 Bempedoic acid has a liver specific mode of action and therefore has the potential to avoid the muscle related adverse drug reactions (ADRs) associated with statin therapy. Bempedoic acid can be used in combination with other lipid lowering drugs and will offer a once-daily, convienent, oral option for patients not at target goals.4 Bempedoic acid expands Daiichi Sankyo Europe's commitment to cardiovascular care and the development of innovative and convenient treatments. "Unlike some of the historical cardiovascular players who have decided to focus their effort on other therapeutic areas, we remain committed to the cardiovascular field. With bempedoic acid, our first-in-class treatment, we build on our dedication to address critical unmet needs for patients in Europe who have limited options and who are not reaching their target LDL-C level," said Benoit Creveau, Head of Marketing Cardiovascular at Daiichi Sankyo Europe. "We are very pleased to partner with Daiichi Sankyo Europe to establish bempedoic acid as the most preferred LDL-C lowering treatment option after statins for patients and physicians in Europe. We expect Daiichi Sankyo Europe's significant cardiovascular reach and expertise will help establish bempedoic acid and the bempedoic acid / ezetimibe fixed dose combination tablet as important tools in physicians' and patients' fight against elevated LDL-C levels," said Tim Mayleben, President and Chief Executive Officer of Esperion. "The results from the pivotal Phase 3 LDL-C development programme of bempedoic acid and bempedoic acid / ezetimibe fixed dose combination tablet provide compelling evidence that bempedoic acid is an efficacious and well tolerated therapeutic option and we hope to make it available as soon as possible to European patients," adds Rodney Smith, MD, Head of Medical Affairs at Daiichi Sankyo Europe. Esperion completed its Phase 3 LDL-C development programme of bempedoic acid and the bempedoic acid / ezetimibe fixed dose combination tablet in October 2018. This robust development programme forms the bases for FDA and EMA approval decisions that are expected during the first half of 2020. The global cardiovascular outcomes trial of bempedoic acid, CLEAR Outcomes, is ongoing, and cardiovascular risk reduction data are expected during 2022. 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 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 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.5 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.2 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.1 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 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.2 Rates of treatment-emergent adverse events, muscle-related adverse events and discontinuations were similar in the bempedoic acid and placebo treatment groups.5 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. About Esperion Esperion is the Lipid Management Company passionately committed to developing and commercialising convenient, complementary, cost-effective, 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 fixed dose 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. Product Communications Contact:Lydia Worms Daiichi Sankyo Europe GmbH+49(89)[email protected] Investor Contact:Alex [email protected] References: 1 Pinkosky L. et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nature. 2016: 10.1038. 2 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 December 12, 2018. 3 Rosei EA et al. Management of Hypercholesterolemia, Appropriateness of Therapeutic Approaches and New Drugs in Patients with High Cardiovascular Risk. High Blood Press Cardiovasc Prev. 2016; 23(3): 217–230. 4 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; 10:5560567. 5 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 December 12, 2018. 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. February 2019, BEM/19/0001