Esperion Announces Completion of Phase 3 LDL-C Lowering Development Program
Esperion recently announced completion of the Phase 3 LDL-C Lowering Development Program of bempedoic acid and positive cumulative results. The program consisted of four, pivotal, Phase 3, randomized, double-blind, placebo controlled studies to evaluate the LDL-C lowering efficacy and safety and tolerability of bempedoic acid 180 mg compared to placebo in high cardiovascular risk patients, including atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) patients.
The Phase 3 program included 3,621 high cardiovascular risk patients taking maximally tolerated statin (which could include no statin) who required additional LDL-C lowering. The Program achieved its efficacy endpoints and other key measures at 12 weeks for bempedoic acid, including:
-On-treatment LDL-C lowering of an additional 18 percent to 31 percent (vs. placebo, p<0.001), and in the intent to treat analysis, LDL-C lowering of an additional 17 percent to 28 percent (p<0.001).
-Reductions of 19 percent to 33 percent in high-sensitivity C-reactive protein (hsCRP), an important marker of the underlying inflammation associated with cardiovascular disease.
-Reductions in hemoglobin A1c (HbA1c) of 0.19% to 0.31% vs. placebo in the subset of 1002 patients with diabetes
In the Phase 3 LDL-C lowering development program, adjudicated major adverse cardiovascular events (MACE) in the bempedoic acid arm as compared to placebo were:
-3-component MACE: 1.9 percent for bempedoic acid compared to 2.3 percent for placebo
-4-component MACE: 3.8 percent for bempedoic acid compared to 4.2 percent for placebo
-5-component MACE: 4.0 percent for bempedoic acid compared to 4.6 percent for placebo
In the Phase 3 program, bempedoic acid was observed to be safe and well-tolerated. The vast majority (>80%) of patients were studied for 52 weeks. Across the program there were no clinically relevant differences between the bempedoic acid and placebo treatment groups in the occurrence of:
-Adverse events (AEs) with 73 percent in each group;
-Serious adverse events (SAEs) with 14 percent and 13 percent, respectively; SAE neoplasms were balanced at 1 percent in both arms.
-Discontinuations due to AEs with 11 percent and 8 percent, respectively;
-Fatal adverse events were very low overall at 0.8 percent and 0.3 percent, respectively (compared to a 1.8% fatality rate for people 65-74 year olds according to the CDC).
-No fatal adverse events were determined to be related to study medication.
-CV deaths were balanced between the study arms (0.4% vs. 0.3%) as was sepsis (0.1% in both arms).
-The bempedoic acid arm included a case of gas poisoning and a case of pancreatitis resulting from a pancreatic pseudocyst.
Esperion initiated its global, pivotal, Phase 3 clinical development program in January 2016 to evaluate the safety, tolerability and consistent, complementary LDL-C-lowering efficacy of bempedoic acid and the bempedoic acid / ezetimibe combination pill in patients with atherosclerotic cardiovascular disease (ASCVD), or who are at a high risk for ASCVD, with hypercholesterolemia who continue to have elevated levels of LDL-C despite the use of maximally-tolerated statins and ezetimibe, leaving them at high risk for cardiovascular events. The program includes five studies in approximately 4,000 patients, four for bempedoic acid and one for the bempedoic acid / ezetimibe combination pill.
-Two pivotal studies evaluating bempedoic acid (Studies 1 & 2) in 3,008 patients with ASCVD and/or HeFH on maximally-tolerated statins, with top-line results reported in May 2018 and October 2018, respectively;
-Two pivotal studies evaluating bempedoic acid (Studies 3 & 4) in 613 patients with ASCVD, or at a high risk for ASCVD, considered statin intolerant, with top-line results reported in May and March 2018, respectively;
-One pivotal study evaluating the bempedoic acid / ezetimibe combination pill (053 Study) in 382 patients with ASCVD, or at high risk for ASCVD, on maximally tolerated statins, with top-line results reported in August.
Esperion plans to submit New Drug Applications (NDAs) to the US FDA for bempedoic acid and the bempedoic acid/ezetimibe combination pill for LDL-C-lowering indications during the first quarter of 2019. Additionally, Esperion plans to submit Marketing Authorization Applications (MAAs) to the European Medicines Agency (EMA) during the second quarter of 2019.
Through the complementary mechanisms of action of inhibition of cholesterol synthesis (bempedoic acid) and inhibition of cholesterol absorption (ezetimibe), the bempedoic acid/ezetimibe combination pill 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% 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).
With a targeted mechanism of action, bempedoic acid is a first-in-class, complementary, orally available, once-daily ATP Citrate Lyase (ACL) 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, including 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 a monotherapy, 35% in combination with ezetimibe when used with maximally tolerated statins, and up to 48% LDL-C lowering in combination with ezetimibe as monotherapy.
The effect of bempedoic acid on cardiovascular morbidity and mortality has not yet been determined. The company has 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 Cholesterol Lowering via Bempedoic Acid, an ACL-inhibiting Regimen (CLEAR) Outcomes — is an event-driven, global, randomized, double-blind, placebo-controlled study expected to enroll approximately 12,600 patients with hypercholesterolemia and high CVD risk at more than 1,000 sites in approximately 30 countries.
High levels of LDL-C can lead to a build-up of cholesterol in artery walls (known as atherosclerosis), potentially leading to cardiovascular events, including heart attack or stroke. In the US, 78 million people, or more than 20% of the population, have elevated LDL-C; an additional 73 million people in Europe and 30 million people in Japan also live with elevated LDL-C. There are approximately 13 million people in the US 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 6 million patients with ASCVD and/or HeFH on maximally tolerated statins require less than 30% additional LDL-C lowering to achieve treatment goals.
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.
Esperion is the Lipid Management Company passionately committed to developing and commercializing 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 combination pill, 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, visit www.esperion.com and follow us on Twitter at https://twitter.com/EsperionInc.
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