Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase

Abstract

Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients.

Reprogramming of fatty acid metabolism in cancer

“…206 Importantly, several ACLY inhibitors including ETC-1002 (Phase 2/3 clinical trials) and hydroxycitrate (randomised control trials) have shown high efficacy in lowering low-density lipoprotein-cholesterol and good tolerability in patients with cardiovascular disease and type 2 diabetes (Table 1), thus indicating that ACLY inhibition could represent a well-tolerated therapeutic strategy. [207][208][209][210][211] There is considerable interest in ACLY as a target for anticancer drugs; however, clinical trial studies in this context are far more limited when compared with dyslipidaemia cases. Nevertheless, there is a plethora of preclinical evidence to support the integral role of ACLY in tumorigenesis and the potential clinical benefits for its selective inhibition.…”

Bempedoic acid for the treatment of dyslipidemia

“…17 The study of healthy volunteers demonstrated a mean decrease in LDL-C levels of 36% in the bempedoic acid group compared to a 4% increase in the placebo group (40% placebo-adjusted LDL-C reduction; p <0.0001). 18 , 19 The phase I trials demonstrated that there were no adverse effects related to bempedoic acid dosing and bempedoic acid was overall determined to be safe to proceed with phase II trials.…”

“…LDL-C levels were lowered by 22% in the bempedoic acid arm and no reduction was seen in the placebo arm ( p <0.0001). 19 , 25 In a study by Ballantyne et al, 26 134 patients with LDL-C levels between 115 and 220 mg/dL while taking atorvastatin ≤20 mg daily, pravastatin ≤40 mg daily, rosuvastatin ≤10 mg daily, or simvastatin ≤20 mg daily were randomized to receive bempedoic acid 120 mg, 180 mg, or placebo daily for 12 weeks. Patients who had bempedoic acid added onto concurrent statin therapy experienced an LDL-C reduction of 17% (120 mg daily) and 24% (180 mg daily) compared to 4% with placebo ( p =0.0055 and p <0.0001, respectively).…”

Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management

“…The ACL inhibitor ETC-1002 (bempedoic acid) has been found to lower cholesterol biosynthesis by depriving cells of the necessary substrates. To date, studies either as monotherapy or as combination therapy with statins have shown positive results, without significant side effects (Bilen and Ballantyne, 2016 ; Lammel Lindemann and Webb, 2016 ). The promising LDL-lowering effects of ETC-1002 from phase II trials remain to be confirmed by a phase III programme assessing its efficacy, safety and long-term outcomes (Bilen and Ballantyne, 2016 ).…”

“…To date, studies either as monotherapy or as combination therapy with statins have shown positive results, without significant side effects (Bilen and Ballantyne, 2016 ; Lammel Lindemann and Webb, 2016 ). The promising LDL-lowering effects of ETC-1002 from phase II trials remain to be confirmed by a phase III programme assessing its efficacy, safety and long-term outcomes (Bilen and Ballantyne, 2016 ). Since this agent has been also found to reduce C-reactive protein levels, better CVD outcomes may be possible through its implication in pro-inflammation processes (Penson et al, 2017 ).…”