The bempedoic acid / ezetimibe fixed dose combination tablet is a non-statin, orally available, once-daily, therapy characterised by complementary mechanisms of action of its individual component, namely, local (hepatocyte) inhibition of cholesterol synthesis (bempedoic acid) and suppression of cholesterol absorption (ezetimibe). Inhibition of ATP citrate lyase by bempedoic acid ultimately lowers circulating LDL-C following the up-regulation of hepatocyte LDL receptors. In addition, suppression 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 and, in turn, upregulating the LDL receptors. The Phase 3 data demonstrated that this well tolerated fixed dose combination results in a 38% (placebo-corrected) lowering of LDL-C when used with maximally tolerated statins.[i]
With a targeted mechanism of action, bempedoic acid is a first-in-class, complementary, oral, once-daily ATP citrate lyase inhibitor that reduces cholesterol 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. 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.[ii]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% LDL-C lowering (placebo corrected) when used with maximally tolerated statins and 28 % LDL-C lowering (placebo corrected) in statin intolerant patients or patients on low dose statin and up to 38% (placebo corrected) LDL-C lowering in fixed dose combination with ezetimibe. Rates of treatment-emergent adverse events, muscle-related adverse events and discontinuations were similar in the bempedoic acid and placebo treatment groups.[iii],[iv],[v]
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, 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.[vi]
[i] Ballantyne CM. et al. Bempedoic Acid Plus Ezetimibe Fixed-Dose Combination in Patients With Hypercholesterolemia and High CVD Risk Treated With Maximally Tolerated Statin Therapy. Eur J Prev Cardiol. 2019;
[ii] Pinkosky L et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016: 7:13457.
[iii] Ray K, et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. New Eng J Med. 2019; 380:1022-1032.
[iv] Ballantyne CM. et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis. 2018; 277:195-203.
[v] Laufs U. et al. Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance. J Am Heart Assoc. 2019; 8:e011662.
[vi] 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 May 2019.