Patients treated with bempedoic acid in addition to high-intensity statin therapy had a further reduction in LDL, according to results presented in a late-breaker session at the National Lipid Association Scientific Sessions.

“Bempedoic acid, or ETC-1002, is a pro-drug, and it needs to be converted into its active form by a very specific Acyl-CoA synthetase that is almost exclusively found in the liver and to a much lesser extent in the kidneys, but not in the muscle cell,” Mary McGowan, MD, chief medical officer at Esperion Therapeutics and co-director of the Lipid Clinic at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, said in the presentation. “By [converting] ETC-1002, you get ETC-1002 CoA, and this is an inhibitor of ATP citrate lyase. ATP citrate lyase is an enzyme upstream from the HMG-CoA reductase enzyme, and as such, inhibition here does exactly what statins do.”

McGowan added that the enzyme decreases intercellular cholesterol production, which upregulates LDL receptors which in turn increases the removal of LDL from the bloodstream, lowering serum LDL levels.

Mary McGowan

Previous studies

Other phase 2 studies were completed, in which a total of 1,045 patients were treated with bempedoic acid or placebo. When bempedoic acid was used as monotherapy, patients saw a 30% reduction in LDL. The combination of bempedoic acid and ezetimibe (Zetia, Merck) lowered LDL by 48%. The addition of bempedoic acid to low- and moderate-dose statins lowered LDL by an additional 20% to 24%.

In the present study, researchers assessed the LDL-lowering efficacy of 180 mg of bempedoic acid when added onto a background of 80 mg of atorvastatin. Also analyzed were “the pharmacokinetics of steady-state of atorvastatin and its active metabolite, ortho-hydroxy atorvastatin, alone and in combination with steady-state bempedoic acid,” McGowan said.

This study enrolled a total of 64 patients who were on either low- and moderate-intensity statins with LDL > 115 mg/dL or high-intensity statins with LDL > 100 mg/dL. All patients in the first treatment period received 80 mg of atorvastatin.

After 28 days of receiving daily atorvastatin, patients were randomly assigned to either receive bempedoic acid (n = 41; mean age, 58 years; 51% women) or placebo (n = 23; mean age, 58; 44% women) in addition to the atorvastatin 80 mg treatment.

LDL reduction

At 28 days after randomization, the least-squares mean percentage change on LDL from baseline was +9% in the placebo group and –13% in the bempedoic acid group (difference, –22%; 95% CI, –36.4 to –7.96; P = .0028), which “was consistent with what we saw in our previous studies,” McGowan said. Bempedoic acid also significantly lowered apolipoprotein B, non-HDL, total cholesterol and high-sensitivity C-reactive protein, she said.

Researchers also analyzed the pharmacokinetics, in which maximum concentration did not change.

“Atorvastatin [pharmacokinetics], the [area under the curve] increased by 29%, and the ortho-hydroxy atorvastatin, a primary metabolite of atorvastatin, increased by 22%,” McGowan said.

Patients did not experience serious adverse events. Four unique patients had myalgia (n = 2) or elevated creatine kinase (n = 2). Myalgia symptoms improved while patients remained on the study drug, and [creatine kinase] elevations were not confirmed on repeat measurement, McGowan said.

“In this study, utilizing 80 mg of atorvastatin in combination with bempedoic acid, we had no [alanine aminotransaminase] or [aspartate aminotransferase] greater than three times the upper limit of normal either in the placebo group or the bempedoic acid group, and we had no patients with repeated and confirmed [creatine kinase] elevations of greater than five times the upper limit of normal,” McGowan said.

“We presented these data to the FDA for review. Subsequently, the FDA concurred with our proposal to use high-intensity atorvastatin 40 [mg and] 80 mg in our phase 3 program, which is ongoing now,” McGowan said. “We have four large clinical trials ongoing now for LDL reduction. One is completely enrolled, 2,230 patients, and we have a large [CV] outcome trial ongoing in patients at high CV risk, including those with statin intolerance.” – by Darlene Dobkowski

Reference:

McGowan M, et al. Late Breakers. Presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.