General Information

Nexletol (bempedoic acid) is an adenosine triphosphate-citrate lyase (ACL) inhibitor.

Nexletol is specifically indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.

Nexletol is supplied as a tablet for oral administration. The recommended dosage of Nexletol, in combination with maximally tolerated statin therapy, is 180 mg administered orally once daily. Nexletol can be taken with or without food. After initiation of Nexletol, analyze lipid levels within 8 to 12 weeks.

Mechanism of Action

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Bempedoic acid and its active metabolite, ESP15228, require coenzyme A (CoA) activation by very long-chain acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA and ESP15228-CoA, respectively. ACSVL1 is expressed primarily in the liver. Inhibition of ACL by ETC-1002-CoA results in decreased cholesterol synthesis in the liver and lowers LDL-C in blood via upregulation of low-density lipoprotein receptors.

Clinical Trial Results

The FDA approval of Nexletol was based on two multi-center, randomized, double-blind, placebo-controlled trials that enrolled 3009 adult patients with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who were on maximally tolerated statin therapy.

Study 1 was a multi-center, randomized, double-blind, placebo-controlled 52-week trial that evaluated safety and efficacy of bempedoic acid in patients with HeFH and/or ASCVD. Efficacy of Nexletol was evaluated at Week 12. The trial included 2,230 patients randomized 2:1 to receive either Nexletol (n = 1488) or placebo (n = 742) as add-on to a maximally tolerated lipid lowering therapy. The primary efficacy outcome measure of the study was the percent change from baseline to Week 12 in LDL-C. The difference between Nexletol and placebo in mean percent change in LDL-C from baseline to Week 12 was -18%.

Study 2 was a multi-center, randomized, double-blind, placebo-controlled, 52-week trial in patients with HeFH and/or ASCVD. Efficacy of Nexletol was evaluated at Week 12. The trial included 779 patients randomized 2:1 to receive either Nexletol (n = 522) or placebo (n = 257) as add-on to a maximally tolerated lipid lowering therapy. The primary efficacy outcome measure of the study was the percent change from baseline to Week 12 in LDL-C. The difference between Nexletol and placebo in mean percent change in LDL-C from baseline to Week 12 was -17 %.