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We work hard to lower LDL-C by discovering and developing innovative and combination medicines. 

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 metabolic associated fatty liver disease (NAFLD)/metabolic associated 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 References:

  1. 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).
  2. 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).
  3. 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).
  4. 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).
  5. 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).
  6. Lipogenesis inhibitors: therapeutic opportunities and challenges.
    Batchuluun, B., Pinkosky, S.L. & Steinberg, G.R. Nat Rev Drug Discov 21, 283–305 (2022).
  7. Exploring the Role of ATP-Citrate Lyase in the Immune System.
    Dominguez, M., Brüne, B., and Namgaladze, D. Front. Immunol. 12 (2021).
  8. 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).
  9. Sugar addiction: An Achilles’ heel of auto-immune diseases?
    Zaiss, D.M.W., and Coffer, P.J. Cell Metabolism 34, 503-505 (2022).

Pipeline Graphic

CLEAR Program/Cardiovascular Outcomes Trials

The CLEAR Program is a large, scientifically rigorous clinical research initiative that has enrolled >60,000 patients across more than 30 countries. For more information on the CLEAR Program and Esperion's completed clinical trials, please visit esperionscience.com.