We are harnessing innovative science in order to explore investigational therapies that address both cardiovascular and cardiometabolic risk. As we look to the future, we are working to build a pipeline of treatments that are not only focused on lowering cholesterol.
Growing our pipeline with a cardiovascular outcomes trial (CVOT) and an investigational early-stage Next Gen ACLY Inhibitor program.
We are focused on building a pipeline with innovative medicines at the core.
Our goal is to discover and develop innovative and combination medicines to lower LDL-C.
Next Gen ACLY Inhibitor
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. 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, kidney disease 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 adaptations with cell-specific functions 3,4. 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, extracellular matrix remodeling, and proliferative processes 5-8.
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 investigate new therapeutic opportunities and develop next-generation inhibitors optimized to address multiple life-threatening diseases.
References
- Pinkosky, S., Newton, R., Day, E. et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis.. Nat Commun 7, 13457 (2016).
- Morrow, M., Batchuluun, B., Wu, J., et al. Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia. Cell Metabolism 34, 919–936 (2022).
- Ference BA, Ray KK, Catapano AL, Ference TB, et al. Mendelian Randomization Study of ACLY and Cardiovascular Disease. N Engl J Med. 380(11), 1033–1042 (2019).
- Pinkosky SL, Groot PHE, Lalwani ND, et al.Targeting ATP-Citrate Lyase in Hyperlipidemia and Metabolic Disorders. Trends in molecular medicine 23(11), 1047–1063 (2017).
- Arnold, P.K., Jackson, B.T., Paras, K.I. et al. A non-canonical tricarboxylic acid cycle underlies cellular identity. Nature 603, 477–481 (2022).
- Batchuluun, B., Pinkosky, S.L. & Steinberg, G.R. Lipogenesis inhibitors: therapeutic opportunities and challenges. Nat Rev Drug Discov 21, 283–305 (2022).
- Dominguez, M., Brüne, B., and Namgaladze, D. Front. Exploring the Role of ATP-Citrate Lyase in the Immune System. Immunol. 12 (2021).
- Hochrein, S., Wu, H., Eckstein, M., et al. The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming. Cell Metabolism 34, 516–532 (2022).
- Zaiss, D.M.W., and Coffer, P.J. Sugar addiction: An Achilles’ heel of auto-immune diseases? Cell Metabolism 34, 503-505 (2022).