New Studies Give Bempedoic Acid a Bump as Lipid-Lowering Agent

Patrice Wendling

March 29, 2019

NEW ORLEANS — Bempedoic acid significantly lowers low-density lipoprotein (LDL) cholesterol when added to maximally tolerated statins in high-cardiovascular-risk patients, new research suggests.

Patients treated with the investigational oral agent had a 15.1% reduction in the primary end point of LDL cholesterol at 12 weeks compared with a 2.4% increase for placebo (17.4% placebo-corrected difference; P < .001) in the CLEAR Wisdom study.

Oral bempedoic acid also significantly reduced non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein levels.

Although not an outcomes trial, 1-year results showed a 2% reduction in adjudicated cardiovascular death, nonfatal MI, and nonfatal stroke events with bempedoic acid vs placebo (2.7% vs 4.7%). The 2% difference persisted when the composite end point further included coronary revascularization (5.7% vs 7.8%) and hospitalization for unstable angina (6.1% vs 8.2%).

"I think that the additional [LDL] lowering probably contributed but this is an exploratory finding at this point," Anne Goldberg, MD, Washington University School of Medicine, St. Louis, said during a late-breaking clinical trial session at the American College of Cardiology 68th Annual Scientific Session (ACC.19).

The results support those published just days earlier in the New England Journal of Medicine in a similar group of 2230 patients in the CLEAR Harmony study, in which bempedoic acid reduced LDL cholesterol at 12 weeks by an additional 19.2 mg/dL, representing an 18.1% difference vs placebo (P < .001).

Speaking with theheart.org | Medscape Cardiology, Valentine Fuster, MD, Mount Sinai Icahn School of Medicine, New York City, said "it's an opening door to a new pharmacological strategy," but added that he was surprised by the modest LDL lowering because bempedoic acid works by blocking the ATP citrate lyase enzyme upstream of statins in the same cholesterol synthesis pathway.

Still, "when ezetimibe came into the market, it had the same decrease in LDL cholesterol. It wasn't very striking," he said. "But when the analysis was made, the number of [subsequent cardiovascular] events that are actually being decreased, then the results become more much significant."

During the session, discussant Donald Lloyd-Jones, MD, Northwestern University Feinberg School of Medicine, Chicago, said: "We're all watching the development of this drug with interest because it will be useful to have more safe and effective drugs in our armamentarium if this makes it to the goal line."

CLEAR Wisdom randomly assigned 779 patients with atherosclerotic cardiovascular disease (about 95%) and/or heterozygous familial hypercholesterolemia to once-daily bempedoic acid 180 mg or placebo for 52 weeks. A little more than half the patients were receiving high-intensity statins; one-third, moderate-intensity statins; and the remainder, either a low-intensity regimen or no statin. Two-thirds of te patients were men, nearly all were white (94%), 84% had hypertension, and one-third had diabetes.

Mean LDL-C levels declined in the bempedoic acid group from 119.4 mg/dL to 97.6 mg/dL at week 12, and the reduction was maintained at 1 year (99.6 mg/dL), Goldberg said. LDL-C levels in the placebo group remained constant, at 122.4 mg/dL, 122.8 mg/dL, and 116.9 mg/dL, respectively.

Of special note, LDL-C levels declined at 12 weeks to a greater extent with bempedoic acid in patients not taking statins than in those taking low/moderate- or high-intensity statins (–24.6% vs –14.9% vs –14.4%).

During a press conference here, Goldberg stressed that the intention is for bempedoic acid to be an add-on therapy in patients who continue to have elevated LDL-C on lipid-lowering agents and not to replace statins as first-line therapy.

"Not everybody who doesn't get an LDL low enough with a statin or ezetimibe is actually going to be a candidate for adding PCSK9 [proprotein convertase subtilisin/kexin type 9 inhibitors], so having other therapies would be advantageous," she said.

Both Jones and Fuster remarked that it is critical to determine whether there is a similar relative reduction in LDL based on baseline LDL cholesterol status, or whether there is a fixed absolute change when adding bempedoic acid to statins. Goldberg agreed that such a stratified analysis is needed but said it has not been performed.

As to the safety of the drug, there were no significant differences between the bempedoic acid and placebo groups in the incidence of any adverse event (70.1% vs 70.8%), serious adverse events (20.3% vs 18.7%), or drug discontinuations due to adverse events (10.9% vs 8.6%)

The team did look at the subset of patients with diabetes and found no worsening of glycemic measurements, including 12-week change in fasting blood glucose (–0.5 mg/dL) or hemoglobin A1C (–0.08%), nor in the percentage of patients experiencing a blood glucose of at least 126 mg/dL (69.7% vs 75.3% for placebo).

CLEAR Harmony also found no evidence of new-onset or worsening diabetes between the bempedoic acid and placebo groups (3.3% vs 5.4%).

It did, however, show a significantly higher incidence of gout (1.2% vs 0.3%) and elevations in uric acid (0.73 mg/dL vs –0.6 mg/dL). The authors, led by Kausik K. Ray, MD, MPhil, Imperial College London, suggest the latter may be related to renal-transporter competition between the bempedoic acid glucuronide metabolite and uric acid.

Importantly, bempedoic acid, when compared with placebo, did not increase rates of myalgia (6.0% vs 6.1%), muscle spasms (4.2% vs 2.7%), or muscle weakness (9 vs 4 events), according to Ray and colleagues. Goldberg did not report these outcomes but noted that activated bempedoic acid is not present in skeletal muscle.

Asked during the press briefing where bempedoic acid may fit into clinical practice, William White, MD, University of Connecticut School of Medicine, Farmingham, replied that there are some patients who can't take statins or ezetimibe because of adverse effects, others who won't take a high enough dose of statins to achieve LDL lowering, and finally, a costly, injectable PCSK9 inhibitor might not appeal to others.

"It's a big wide world of people out there with hypercholesterolemia and it's not necessarily a one size fits all," White said.

Deepak Bhatt, MD, Brigham and Women's Hospital, Boston, said he'd be nervous substituting bempedoic acid for ezetimibe or the PCSK9 inhibitors, given the outcome and safety data available for these drugs, and added that's it's unlikely bempedoic acid will be cheaper than generic ezetimibe.

"I believe in the LDL hypothesis and I think the outcomes trial [for bempedoic acid] will likely be positive but I would be a bit cautious," Bhatt said.

Enrollment in the ongoing cardiovascular outcomes study, CLEAR Outcomes, is expected to be complete in the third quarter of 2019, with results available in 2022. In late February, Esperion Therapeutics submitted New Drug Applications to the US Food and Drug Administration for bempedoic acid and a bempedoic acid/ezetimibe combination tablet. The European Medicines Agency is currently reviewing applications for both drugs.

The trials were funded by Esperion Therapeutics. Goldberg reports g rants/research support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, and IONIS, and honoraria from the National Lipid Association, Esperion, Novartis, AKCEA, Regeneron/Sanofi, 23andMe, and Merck.

American College of Cardiology (ACC) 68th Annual Scientific Session: Abstract 409-08. Presented March 18, 2019.

N Engl J Med. 2019;380:1022-1032. Abstract

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