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Bempedoic acid shows promise for LDL lowering in high-risk patients
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NEW ORLEANS — Treatment with bempedoic acid, an investigational oral, once-daily therapy that is designed to work in the liver to inhibit cholesterol biosynthesis, resulted in significant LDL reduction after 12 weeks compared with a placebo in patients at high risk for CV events who were receiving maximally tolerated statin and other lipid-lowering therapy enrolled in the CLEAR Wisdom trial.
These findings, presented at the American College of Cardiology Scientific Session, come on the heels of the CLEAR Harmony trial, just published in The New England Journal of Medicine, showing significant decreases in LDL after 12 weeks of treatment with bempedoic acid (Esperion Therapeutics) with maximally tolerated statin therapy in patients with either atherosclerotic CVD, heterozygous familial hypercholesterolemia or both.
“CLEAR Wisdom provides additional evidence that bempedoic acid is efficacious in patients at high CV risk with hypercholesterolemia despite receiving maximally tolerated statin therapy,” Anne C. Goldberg, MD, FACP, FAHA, FNLA, professor of medicine at Washington University School of Medicine in St. Louis, said during a presentation here.
Improvements observed
The phase 3 trial enrolled 779 patients with pre-existing atherosclerotic CVD and/or heterozygous familial hypercholesterolemia who were currently receiving maximally tolerated statin therapy with or without another lipid-lowering therapy.
Treatment with bempedoic acid 180 mg once daily reduced LDL at week 12 — the primary endpoint — by 17.4% compared with placebo (P < .001).
Patients continued to take the study medications for 1 year so the researchers could monitor the safety of bempedoic acid and the durability of treatment effects. The effect on LDL observed at 12 weeks was maintained through 1 year, according to data presented.
Further, LDL lowering with bempedoic acid was observed across statin-intensity subgroups. The researchers reported more robust lowering with bempedoic acid (–24.6%) compared with placebo (–2.6%) in patients taking no statins (n = 77; 22% change; P < .001).
At 12 weeks, treatment with bempedoic acid was associated with greater decreases in total cholesterol (–9.9% vs. 1.3% increase; P < .001), apolipoprotein B (–9.3% vs. 3.7% increase; P < .001), non-HDL (–10.8% vs. 2.3% increase; P < .001) and high-sensitivity C-reactive protein (–18.7% vs. –9.4%; P = .039) compared with placebo.
There were no significant differences between both groups for any adverse events, serious adverse events, study drug discontinuation due to adverse events and fatal adverse events. Major adjudicated CV events — 5-point MACE including CV death, nonfatal MI, nonfatal stroke, coronary revascularization and hospitalization for unstable angina — were reported for 6.1% of patients assigned bempedoic acid vs. 8.2% assigned placebo. There was a similar incidence of fatal treatment-emergent adverse events positively adjudicated as CV death in the bempedoic acid (n = 4; 0.8%) and placebo (n = 2; 0.8%) groups, Goldberg said. Two additional fatal treatment-emergent adverse events in the bempedoic acid group were due to gas poisoning and septic shock, she said.
“All fatal adverse events and serious adverse events were assessed as unrelated to the study medication,” Goldberg said.
The most common adverse events in this study were nasopharyngitis and urinary tract infection.
The researchers also evaluated the impact of treatment in patients with a history of diabetes and found no worsening of 12-week glycemic measurements in patients with a history of diabetes compared with placebo. The percent of patients experiencing on-treatment blood glucose of 126 mg/dL or greater was 69.7% with bempedoic acid vs. 75.3% with placebo. At 12 weeks, HbA1c was reduced by 0.08% in the bempedoic acid group vs. an increase of 0.13% in the placebo group.
“Bempedoic acid may provide an additional therapeutic option to safely lower LDL cholesterol in high CV risk patients with elevated cholesterol levels treated with maximally tolerated statins and other lipid-modifying therapies,” Goldberg said during the presentation.
Patients enrolled in CLEAR Wisdom had a mean age of 64 years and more than 60% were men. At baseline, all patients had LDL greater than 100 mg/dL and were already taking the highest tolerated dose of a statin. In addition to ASCVD, 80% of the patients had high BP and 30% had diabetes. Six percent had familial hypercholesterolemia. Two-thirds of the patients were randomly assigned to bempedoic acid and one third to placebo once daily as an add-on to the statin they were already taking, according to a press release.
‘An additional therapeutic option’
Bempedoic acid is a small-molecule drug being developed for the treatment of hyperlipidemia. Bempedoic acid is a pro-drug activated in the liver by very-long-chain acyl-CoA synthetase-1. It inhibits ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase and upregulates LDL receptors and lowers LDL, Goldberg explained during the presentation.
“Activated bempedoic acid acts in the same cholesterol synthesis pathway as statins,” Goldberg said.
According to Esperion, new drug applications for bempedoic acid and a bempedoic acid/ezetimibe combination have been submitted to the FDA and are under regulatory review for marketing authorization by the European Medicines Agency. – by Darlene Dobkowski
References:
Goldberg AC, et al. Late-Breaking Clinical Trials IV. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
Ray KK, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1803917.
Disclosures: The CLEAR Wisdom trial was sponsored and funded by Esperion Therapeutics. Goldberg reports she received grants/research support from Amgen, Amarin, Ionis, Pfizer, Regeneron and Sanofi and honoraria from Akcea, Esperion, Merck, the National Lipid Association, Novartis, Regeneron/Sanofi and 23andMe.
Perspective
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Robert S. Rosenson, MD
The CLEAR Wisdom study evaluated the effects of bempedoic acid, an ATP-citrate lyase inhibitor, on LDL and CRP in a study of patients treated with moderate-to-high-intensity statins and a few people on low-intensity statins or no statins at all.
This trial showed that bempedoic acid lowers LDL by an average of about 15%. In people with low-intensity statins or no statins at all, there was a greater reduction in LDL.
As a safety endpoint, the researchers also showed that there were fewer CV events. The question is, is this explained by the LDL lowering or is it explained by the reduction in systemic inflammation, as shown by CRP?
One of the exciting aspects of bempedoic acid is that the receptor for ATP-citrate lyase is not in the skeletal muscle; therefore, one would expect there would not be any adverse muscle events in patients treated with this agent. There are many of our patients who are at risk for CVD or have CVD who cannot tolerate the dosage of statin based on guidelines because they have adverse muscle events. This treatment, bempedoic acid, provides an opportunity for those individuals. There is a large outcomes study that is investigating the effects of bempedoic acid on CV events in people that have statin muscle intolerance.
For early data, it was compelling, it was interesting and it seems directionally appropriate for that population intolerant to statins for muscle-related reasons.
Perspective
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Russell Luepker, MD, MS
The message is that bempedoic acid has potential to be useful. Researchers have been trying to find treatments beyond statins because some people have trouble with statins or some people do not get to target LDL. We keep lowering the target all the time. Bempedoic acid works in the same pathway as statins, but in a different place. To have an additive drug like ezetimibe, having a different pathway is helpful.
They have now shown that it has an effect, it is reasonably safe and it may be a good alternative to statins. I suspect that the FDA wants to see if there are health effects beyond lipid lowering (ie, reduction in disease endpoint) from doing this. For example, everybody believed in estrogen replacement because it improved lipid patterns remarkedly in women. It was great therapy and it should prevent disease until they actually tested it in a clinical trial to see if it did. It made your cholesterol and HDL look better, but it did not protect women.
This was an interesting study and I am pleased that companies are looking for new approaches to lower LDL.
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