Building a pipeline with innovative medicines at the core
We work hard to lower LDL-C by discovering and developing innovative and combination medicines.
Cardiovascular Outcomes Trial
Our global cardiovascular outcomes trial (CVOT), called CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Outcomes, is a first-of-its-kind, landmark CVOT in patients with statin intolerance to determine the effect of bempedoic acid on cardiovascular morbidity and mortality.
CLEAR Outcomes is a Phase 3, event-driven, randomized, multicenter, double-blind, placebo-controlled trial designed to evaluate whether treatment with bempedoic acid reduces the risk of cardiovascular events. The primary endpoint of the study is the effect of bempedoic acid on four-component major adverse cardiovascular events (MACE). The study enrolled more than 14,000 patients at over 1,200 sites in 32 countries.1-3
The CLEAR Outcomes study has now accumulated the targeted 1,620 primary major adverse cardiovascular events (MACE-4) (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). With achievement of this milestone, we have begun closing out the study, including conducting several thousand in-person and virtual follow up visits and compiling all the data from this global trial. We anticipate reporting topline results from the study in the first quarter of 2023.
For a comprehensive overview of inclusion and exclusion criteria, and endpoint information, please see the study description on clinicaltrials.gov.
- Esperion completes patient enrollment in the global CLEAR cardiovascular outcomes trial for bempedoic acid [press release]. Ann Arbor, Michigan: Esperion Therapeutics, Inc.; September 5, 2019. Accessed January 16, 2020.
- Ruscica M, Banach M, Sahebkar A, Corsini A, Sirtori CR. ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials. Exp Opin Pharmacother. 2019. doi:10.1080/14656566.2019.1583209.
- Data on file. Esperion Therapeutics, Inc. 2020.
CLEAR Outcomes trial facts
- 14,000+ patients
- Completed enrollment in August 2019
- >1,200 sites in 32 countries
- Largest trial in Esperion’s history
- Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy
- 47.9% women, 52.1% men
- Mean age: 65.5±9.0 years
- LDL cholesterol: 140.7±34.1 mg/dL
- 42.6% <130 mg/dL
- 33.1% 130-<160 mg/dL
- 24.3% ≥160 mg/dL
- Time to four-component major adverse cardiovascular events (MACEs), including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization
Oral PCSK9 inhibitor - Investigational Stage
All currently approved PCSK9 treatment options are delivered by injection. A study in patients with chronic disease show that four out of five patients prefer a pill to an injectible.1 That’s why Esperion is in the investigational stage of developing a small molecule PCSK9 inhibitor that can be taken as a tablet.
PCSK9 (proprotein convertase subtilisin/kexin type 9) is an enzyme responsible for regulating low-density lipoprotein (LDL) receptors. PCSK9 inhibitors stop LDL receptors from being broken down, increasing the number of LDL receptors present to remove cholesterol from the blood. Current approved PCSK9 inhibitors are delivered as injections. A tablet, oral PCSK9 inhibitor would fill a key gap in non-statin treatment options for patients.
PCSK9 is a validated target for the treatment of dyslipidemia and reduction of cardiovascular risk.
- Multinational Internet-based survey of patient preference for newer oral or injectable Type 2 diabetes medication.
Dibonaventura, M. D., Wagner, J. S., Girman, C. J., et al. Patient preference and adherence, 4, 397–406. (2010).
Next Gen ACLYi - Investigational Stage
ATP-citrate lyase (ACLY) is an enzyme strategically positioned at the intersection of nutrient catabolism and cholesterol and fatty acid biosynthesis. Esperion Therapeutics is leading the investigation of ACLY biology having brought the first ACLY inhibitor to the market. While preclinical studies and Mendelian randomized trials support a causal role for ACLY in dyslipidemia and ASCVD, they also suggest potential additional effects on metabolism that may benefit other disease states such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD)/ non-alcoholic steatohepatitis (NASH)1,2. Furthermore, emerging evidence implicates ACLY as a key metabolic checkpoint utilized by multiple cell types to sense nutrient availability and coordinate metabolic adaptions with cell-specific functions3,4. This expanded understanding has provided key insight into novel connections between chronic positive energy balance and aberrant metabolism and the maladaptation of multiple inflammatory, immune, fibrotic, extra-cellular matrix remodeling, and proliferative processes5-8.
Esperion’s scientific team is exploring this novel insight into ACLY biology. Along with the implementation of leading-edge discovery technology and data science approaches, Esperion aims to reveal new therapeutic opportunities and develop next-generation inhibitors optimized to address multiple life-threatening diseases.
Key Publications and Referencecs:
- Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis.
Pinkosky, S., Newton, R., Day, E. et al. Nat Commun 7, 13457 (2016).
- Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia.
Morrow, M., Batchuluun, B., Wu, J., et al. Cell Metabolism 34, 919–936 (2022).
- Mendelian Randomization Study of ACLY and Cardiovascular Disease.
Ference BA, Ray KK, Catapano AL, Ference TB, et al. The New England journal of medicine, 380(11), 1033–1042 (2019).
- Targeting ATP-Citrate Lyase in Hyperlipidemia and Metabolic Disorders.
Pinkosky SL, Groot PHE, Lalwani ND, et al. Trends in molecular medicine, 23(11), 1047–1063 (2017).
- A non-canonical tricarboxylic acid cycle underlies cellular identity.
Arnold, P.K., Jackson, B.T., Paras, K.I. et al. Nature 603, 477–481 (2022).
- Lipogenesis inhibitors: therapeutic opportunities and challenges.
Batchuluun, B., Pinkosky, S.L. & Steinberg, G.R. Nat Rev Drug Discov 21, 283–305 (2022).
- Exploring the Role of ATP-Citrate Lyase in the Immune System.
Dominguez, M., Brüne, B., and Namgaladze, D. Front. Immunol. 12 (2021).
- The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.
Hochrein, S., Wu, H., Eckstein, M., et al. Cell Metabolism 34, 516–532 (2022).
- Sugar addiction: An Achilles’ heel of auto-immune diseases?
Zaiss, D.M.W., and Coffer, P.J. Cell Metabolism 34, 503-505 (2022).