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WASHINGTON -- It's a green light for bempedoic acid (Nexletol): FDA approved the once-daily oral pill for low-density lipoprotein (LDL) cholesterol lowering as an adjunct to maximally tolerated statin therapy, .

With this approval, bempedoic acid is now indicated for people with heterozygous familial hypercholesterolemia (FH) or established atherosclerotic cardiovascular disease who require additional lowering with hypercholesterolemia. Bempedoic acid is an oral adenosine triphosphate (ATP) citrate lyase inhibitor from Esperion Therapeutics that reduces cholesterol and fatty acid synthesis in the liver.

The pill is to be taken at 180 mg orally once daily with or without food. The drug label warns against concomitant use with simvastatin greater than 20 mg or pravastatin greater than 40 mg.

Bempedoic acid marks the first oral non-statin drug for LDL reduction to be approved in nearly two decades. Reuters reported the drug would be sold at roughly .

FDA approval for the drug was based on LDL-lowering and safety data from several phase III pivotal trials. The last of these to be reported was 2018's CLEAR Wisdom, which showed a 17% reduction in LDL with 12 weeks of bempedoic acid compared with placebo among 779 patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous FH already on maximally tolerated statin treatment.

Separately, the CLEAR Harmony safety study of 2,230 people showed that the drug reduced mean LDL cholesterol level by 16.5% but was associated with more adverse events leading to discontinuation and a higher incidence of gout.

Given bempedoic acid's modest magnitude of efficacy, its main clinical application is likely to be in combination with ezetimibe in patients unwilling to take a statin, according to Jennifer Robinson, MD, MPH, of the University of Iowa in Iowa City.

Esperion had waited years for the FDA to give the go-ahead to market bempedoic acid in the U.S.

In 2016, FDA first accepted the Investigational New Drug application for the fixed dose combination of bempedoic acid 180 mg and ezetimibe 10 mg. There was concern back then that the agency would cease to favor LDL as a surrogate endpoint when there were no data on hard outcomes like death and myocardial infarction to support the drug's actual clinical benefits.

In March 2017, the FDA said it would in considering approval for an LDL-lowering indication for bempedoic acid. The agency stipulated, however, that it would still require a cardiovascular outcomes trial before approving the drug for a cardiovascular risk reduction indication.

In 2019, upon completion of the phase III studies, Esperion had New Drug Applications accepted for bempedoic acid alone and in combination with ezetimibe.

The CLEAR outcomes trial won't have data reported until 2022 at the earliest. It is expected to enroll 12,600 statin-intolerant patients with or at high risk for cardiovascular disease.

"As we have seen for many drugs in the past, such as torcetrapib, estrogen, and others, a drug could lower LDL and still be bad for patients. Without data of clinical benefits, I will not be using bempedoic acid," said Rita Redberg, MD, of the University of California San Francisco Health.

In the meantime, patients with high cholesterol continue to have options such as statins and PCSK9 inhibitors.

"Statins are still first line and that shouldn't change given the extensive data for CVD lowering," commented Amit Khera, MD, of UT Southwestern Medical Center in Dallas. "However, there is a niche here for the patients that truly can't tolerate a statin or an adequate dose of statin. PCSK9 inhibitors are a good option but can be a challenge to obtain and are not cost effective in those without ASCVD, FH, or very high-risk conditions."

Bempedoic acid is not yet approved in Europe, though the European Medicines Agency's Committee for Medicinal Products for Human Use .

The bempedoic acid/ezetimibe combination tablet has yet to be approved by the FDA; its PDUFA date is Feb. 26.

The fixed-dose combination pill cut LDL by 32% in the intention-to-treat analysis of a phase III study reported in 2018 involving 382 patients with ASCVD, or heterozygous FH putting them at high risk for ASCVD, on maximally tolerated statins.

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