Session on Lipids Offers New Data for Bempedoic Acid, Olpasiran

A Saturday session at the European Society of Cardiology 2023 Congress in Amsterdam, titled “Clinical Trial Updates on Prevention and Lipid Lowering,” offered additional data from 2 trials presented in the past year: the first involving the nonstatin bempedoic acid, which is already approved to treat low-density lipoprotein (LDL) cholesterol, and the second for olpasiran, a small interfering RNA (siRNA) being developed to reduce lipoprotein (a), or Lp(a).

New Data for CLEAR Outcomes

Nicholls

In March, this trial of 13,970 patients reported that bempedoic acid (Nexletol, Esperion) demonstrated a risk reduction of 13% for major adverse cardiovascular events (MACE) over 3.4 years while reducing LDL cholesterol by 22%. Two prespecified analyses were presented: Stephen Nicholls, MBBS, PhD, of Victorian Heart Institute, Monash University, Melbourne, Australia, offered the first set of data, which was an analysis of total cardiovascular (CV) events.¹ Nicholls showed that compared with placebo, patients taking bempedoic acid experienced:

• a 20% risk reduction in 4-part MACE, a composite of composite of nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, and CV death,
• a 17% risk reduction in 3-part MACE, which was a composite of nonfatal MI, nonfatal stroke, and CV death,
• a 31% risk reduction in total MIs, and
• a 22% risk reduction in total coronary revascularizations.

Nicholls focused most of presentation on the benefits of bempedoic acid for high-risk patients, not only upon an initial CV event, but also for those who may experience a subsequent event.

“Patients who experienced multiple events during the course of the CLEAR Outcomes study were older, they were more likely to be male, they were more likely be [receiving] secondary prevention, and are more likely to have a prevalent history of documented coronary artery disease,” he said.

As he explained, more than 2600 clinical events in the study occurred in 1734 patients; 1134, or about two-thirds, had 1 event, while 612, or roughly one-third, had multiple events. “We have coronary revascularization representing essentially one-third of the first events, but representing two-thirds of the subsequent events,” Nicholls said.

He then broke down the HR for total and first events by primary and secondary end points, and all favored bempedoic acid over placebo:

• For the primary outcome (4-part MACE), total events, HR 0.80 (95% CI, 0.72-0.89), P = .0001.
• For the primary outcome, first event, HR 0.87 (95% CI, 0.70-0.96), P = .004.
• For the secondary outcome (3-part MACE), total events, HR 0.83 (95% CI, 0.73-0.93), P = .002.
• For the secondary outcome, first event, HR 0.85 (95% CI, 0.76-0.96), P = .006.

Analyses that individual examined first and total nonfatal MI, all MI, revascularization, and stroke also favored bempedoic acid. HRs that examined the numbers of patients who experienced their first, second, third, and fourth events all favored bempedoic acid. “These data reinforce the importance of cholesterol lowering in high-risk patients with the potential to prevent multiple events moving forward,” Nicholls said.

Ray

A second prespecified analysis of CLEAR Outcomes, by Kausik K. Ray, MD, FMedSci, of Imperial College, London, focused on the value of bempedoic acid in avoiding new-onset diabetes, a result that can occur with statin use.² Patients taking bempedoic acid were comparable to those taking placebo in experiencing new-onset diabetes (11.1% vs 11.5%). Ray also presented data showing that among patients who had diabetes, their condition did not worsen while taking bempedoic acid.

Among the patients in the study, 45.6% had type 2 diabetes, defined as hemoglobin A_1c of 6.5% or higher; 41.5% had prediabetes, defined as A_1c of 5.7% to 6.4%; and 12.9% had normal glycemic status. To no surprise, the likelihood of a CV event increased as glucose levels rose, both for the 4-part MACE and 3-part MACE. Ray emphasized that while the HRs in both 4-part MACE and 3-part MACE for patients with diabetes were in the same range as those for the overall study population, the absolute reductions were much larger for the patients with diabetes. For the diabetes population, the HR for 4-part MACE was 0.83 (95% CI, 0.72-0.95); for 3-part MACE, the HR was 0.80 (95% CI, 0.68-0.93).

Both Nicholls and Ray emphasized the importance of these findings for patients who cannot tolerate statins or will not take them.

“Firstly, these analyses show that when statins cannot be tolerated, bempedoic acid used as monotherapy can provide clinically meaningful reductions in cardiovascular disease in people with diabetes,” Ray said in a statement. “Secondly, we know statins can increase the risk of diabetes. Although bempedoic acid works in the same pathway as statins, no signal for increased risk of diabetes was noted, providing assurance for the use of bempedoic acid in people without diabetes that cardiovascular benefits come at the cost of worsening glucose control.”

Effects of Olpasiran Last Beyond Final Dose

Updated phase 2 data from the OCEAN(a)-DOSE study, presented at the same ESC session, show that patients who took at least a 75-mg dose of olpasiran every 12 weeks continued to experience lowering of lipoprotein(a), or Lp(a), for nearly a year after their last dose.

The initial presentation of OCEAN(a)-DOSE in November showed that olparisan demonstrated the ability to reduce more than 95% of Lp(a) at 36 weeks. The end of the treatment period was 48 weeks. An analysis from the off-

O'Donoghue

treatment extension period, presented Saturday by Michelle L. O’Donoghue, MD, MPH, associate professor of Cardiovascular Medicine, Harvard Medical School and lead investigator, showed that patients retained 40% to 50% of that Lp(a) reduction after follow-up of at least 72 weeks and as long as 96 weeks after randomization.

Higher concentrations of Lp(a), which are genetically driven, have been associated with increased inflammation and higher risk of atherosclerotic CV disease, especially coronary heart disease, in which fatty material builds up in the artery walls. Genome-wide association studies now support the role of Lp(a) in heart valve thickening that restricts blood flow. Olparisan works by disrupting the messenger RNA that sets the assembly of Lp(a) particles in motion.

In an interview, O’Donoghue said no new safety concerns were identified in the extension period. Previously, the chief concerns about safety and tolerability were injection site reactions and localized hypersensitivity reactions. No new reactions were reported, she said. A phase 3 study is now enrolling patients, she said. The therapy works on a different pathway from statins, so it is being studied with statins as background therapy—although there is some evidence that statins may increase Lp(a) levels.

How common is elevated Lp(a)?

“It depends on what you define as an abnormal threshold,” O’Donoghue said during the interview. “The most commonly quoted number is that 20% of [the population] has elevated Lp(a),” although O’Donoghue explained that figure is a somewhat arbitrary cutoff. “We don’t know exactly what constitutes an abnormal threshold. That being said, most people would say 1 in 5 people have high Lp(a).”

Certain groups are more likely to have elevated Lp(a), including Black and Asian populations, she said, so efforts are under way to enroll a diverse group of participants in the phase 3 clinical trial.

Interest in Lp(a) seems to be increasing—both in Amsterdam and at the March meeting of the American College of Cardiology in New Orleans, long lines formed to get free Lp(a) testing. In July, the American Society of Preventive Cardiology held an extended symposium on the topic, featuring both the OCEAN study and the HORIZON study for a competing therapy being developed by Novartis.

Still, a few skeptics quizzed O’Donoghue during her presentation. How sure is she about the mechanism? And will removing Lp(a) have unintended effects on LDL cholesterol? O’Donoghue said these were interesting questions to study.

One thing is settled, she said. Amgen had studied a 6-month dose in phase 2, but it will pursue 12-week dosing in phase 3. “Certainly, one could make an argument for [dosing] every 24 weeks,” she said. “There was just more variability when it came to 24-week dosing.”

References

1. Nicholls SJ, Nelson AJ, Lincoff AM, et al. Impact of bempedoic acid on total cardiovascular events: a prespecific analysis of the CLEAR Outcomes study. Presented at: the European Society of Cardiology 2023 Congress, August 25-28, 2023; Amsterdam, the Netherlands. Late-breaking science.
2. Ray KK. Cardiovascular benefits and risk of new onset diabetes by glycaemic status with bempedoic acid: prespecified analyses of the CLEAR OUTCOMES trial. Presented at: the European Society of Cardiology 2023 Congress, August 25-28, 2023; Amsterdam, the Netherlands. Late-breaking science.
3. O’Donoghue M. OCEAN(a)-DOSE extension. Presented at: the European Society of Cardiology 2023 Congress, August 25-28, 2023; Amsterdam, the Netherlands. Late-breaking science.