NEW ORLEANS — The final pivotal trial for bempedoic acid affirmed its modest LDL lowering effect and safety profile.
The small-molecule oral drug lowered LDL by 17.4 percentage points compared with placebo (P<0.001) in high cardiovascular risk patients atop maximally-tolerated statin medication at the 12-week primary endpoint to an achieved LDL 97.6 vs 122.8 mg/dL in the CLEAR Wisdom trial.
Bempedoic acid was not associated with more adverse events (overall, serious, leading to discontinuation, or fatal) than placebo or any worsening of glycemia in diabetes patients, Anne Carol Goldberg, MD, of Washington University in St. Louis, reported here at the American College of Cardiology meeting.
While the trial was not powered for clinical endpoints, there were about 2 percentage points fewer adjudicated major adverse cardiovascular events by various definitions, driven by fewer nonfatal MIs and coronary revascularizations.
The findings paralleled those from the similarly designed CLEAR Harmony trial, reported last week in the New England Journal of Medicine, showing an 18.1 percentage-point reduction in LDL relative to placebo at 12 weeks.
CLEAR Wisdom, the last of the randomized phase III trials on bempedoic acid to report out, included 779 patients with pre-existing atherosclerotic cardiovascular disease (94%), heterozygous familial hypercholesterolemia (5%), or both and a baseline LDL of at least 100 mg/dL that remained at least 70 mg/dL after a placebo run-in on maximally-tolerated statins.
The effect was greater in the small number of patients unable to tolerate any statin (24.6% LDL reduction) and similar between those on a low- or moderate-intensity versus high-intensity statin (14.9% and 14.4%).
Bempedoic acid also was associated with significant 9% to 10% reductions at week 12 in total cholesterol, apolipoprotein B, and non-HDL cholesterol as well as in high sensitivity C-reactive protein.
The most common adverse events were nasopharyngitis and urinary tract infection.
Comparison of gout adverse events between treatment groups was not available yet for CLEAR Wisdom, Goldberg noted.
In CLEAR Harmony, bempedoic acid had more adverse events leading to discontinuation (10.9% vs 7.1%) and a higher incidence of gout (1.2% vs 0.3%), which its investigators noted was tied to significantly greater change in uric acid and creatinine levels. Those effects are apparently due to “competition between the bempedoic acid glucuronide metabolite and uric acid for the same renal transporters that are involved in the excretion of these compounds.”
Gout flare risk could be important in the clinic, commented Donald Lloyd-Jones, MD, of Northwestern University in Chicago. “I think it would not be disqualifying for a new drug but would certainly be a consideration if prescribing it. You’d have to know the history of the patient before deciding.”
“Big picture is what we said in there [the panel discussion after presentation]: if this drug makes it all the way through to FDA approval, it will be nice to have further safe, effective, even if modestly effective drugs for both patients who may be less tolerant of statins or, maybe even someday, patients who can’t take any statin.”
Drugmaker Esperion has submitted marketing applications for bempedoic acid in the U.S. and Europe, both for the drug alone and as a fixed-dose combination pill with ezetimibe.
The CLEAR Outcomes cardiovascular endpoint trial of bempedoic acid in statin-intolerant individuals is underway, with results expected in 2022.
The trial was funded by Esperion Therapeutics.
Goldberg disclosed relationships with Esperion, Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, the National Lipid Association, Novartis, AKCEA, Regeneron/Sanofi, 23andMe, and Merck.