From the Journals

Bempedoic acid safely dropped LDL, now seeks FDA approval

Publish date: March 13, 2019

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Safety signals raise concerns

The primary endpoint of bempedoic acid’s safety, assessed by means of the incidence of adverse events and changes in safety laboratory variables during the CLEAR Harmony trial, did not differ meaningfully between the bempedoic acid group and the placebo group. However, patients in the bempedoic acid group had an excess risk of adverse events leading to discontinuation of the blinded trial regimen, an excess risk of gout, and higher blood concentrations of uric acid than those in the placebo group.

In further analyses of nonprimary and secondary endpoints, there were additional potentially troubling signals, although the 95% confidence intervals were wide: 0.9% of the patients treated with bempedoic acid died, compared with 0.3% of those in the placebo group; 0.4% and 0.1%, respectively, died from adjudicated cardiovascular disease; and 0.6% and 0.1%, respectively, were hospitalized for heart failure. Although the findings are potentially alarming, the imprecision that is reflected in the 95% confidence intervals renders the relative risk values virtually meaningless, but can these effect estimates be unseen?

The cumulative data from randomized treatment trials and from studies of human genetics say that, for a given reduction in the LDL cholesterol level, drugs that inhibit ATP citrate lyase and do not have off-target effects ought to yield reductions in the risk of cardiovascular disease that are similar to those achieved with statins. However, analysis of endpoints in treatment trials for which there is marginal statistical power is best avoided. Fortunately for bempedoic acid, an ongoing phase 3, cardiovascular outcome trial will provide additional information.

More broadly, the genetic characterization of drug targets is set to revolutionize how we develop medicines.

Michael V. Holmes, MD, is an epidemiologist at the University of Oxford, England. He made these comments in a published editorial (N Engl J Med. 2019 Mar 14;380[11]:1076-9). He had no disclosures.

A novel, oral drug, bempedoic acid, safely cut LDL cholesterol levels by almost 20% in patients who had maxed out their statin treatment, in a pivotal trial with more than 2,000 patients. These findings were the centerpiece of a 4,000-patient-experience labeling application submitted to the Food and Drug Administration in late February 2019 for this first member of the ATP citrate lyase inhibitor class. Based on its performance, bempedoic acid seems on track for agency approval.

Aside from demonstrating safety, the efficacy goal of the CLEAR Harmony (Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk) trial was to cut LDL cholesterol as an add-on to maximally tolerated statin treatment, as well as discretionary use of other lipid-lowering agents in patients with atherosclerotic cardiovascular disease.

That goal appeared to be met by the CLEAR Harmony results, as well as the results from four other studies that contributed data to the approval application filed for bempedoic acid. A clinical outcomes study is underway with more than 12,000 patients aimed at showing incremental clinical benefit from bempedoic acid on top of approved treatments for lowering LDL cholesterol, but those results are not expected until 2022. Until then, the application’s data focus on the evidence that the new drug safely lowers LDL cholesterol when used on top of existing treatments.

“Bempedoic acid provides an additional therapeutic option to safely lower LDL cholesterol in patients with high risk for atherosclerotic cardiovascular disease already treated with a statin,” Kausik K. Ray, MD, said when he first reported these findings during the annual meeting of the European Society of Cardiology last August in Munich. The same results appeared in a newly released article (N Engl J Med. 2019 Mar 14;380[11]:1022-32).

^{Mitchel L. Zoler/MDedge News}

Dr. Kausik K. Ray

Maximum recommended statin dosages exist because, for every doubling of the statin dosage, LDL cholesterol levels drop by about another 6%, but adverse events grow more common. Because bempedoic acid and other ATP citrate lyase inhibitors work via the same metabolic pathway as that of statins – HMG CoA reductase inhibitors – “we did not know whether squeezing another 20% of LDL cholesterol lowering would be tolerated. What we have clearly and reassuringly shown is it is well tolerated,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

The CLEAR Harmony results showed in 2,230 randomized patients that treatment with bempedoic acid cut LDL cholesterol levels by an average of 18% more compared with placebo in the intention-to-treat analysis, and by 20% in an on-treatment analysis.

By seeking U.S. marketing approval for bempedoic acid based on LDL-lowering and safety only, but without data on clinical endpoints, the company developing the drug is following a path already established by several other lipid-lowering drug classes.

Dr. Christie M. Ballantyne

“Statins, ezetimibe and the PCSK9 inhibitors were all approved based on clinical trial results that showed LDL-cholesterol reductions with what the FDA judged to be acceptable safety, but without results from completed outcomes trials,” Christie M. Ballantyne, MD, a coauthor of the CLEAR Harmony study and professor and chief of cardiology at Baylor College of Medicine in Houston, said in an interview.

Bempedoic acid safely dropped LDL, now seeks FDA approval

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