Novel Lipid Therapies: 5 Things to Know

Alan P. Jacobsen, MB, BCh, BAO; Eamon Y. Duffy, MD, MBA; Seth S. Martin, MD, MHS


June 23, 2020

Editorial Collaboration

Medscape &

4. Bempedoic acid may prove a viable oral option in patients intolerant to statin therapy or as an adjunct to statin therapy.

Approved by the FDA and EMA in February 2020, bempedoic acid is another nonstatin agent shown to lower LDL. An inhibitor of adenosine triphosphate citrate lyase, bempedoic acid reduces cholesterol synthesis and upregulates LDL receptors in the liver, promoting cholesterol clearance from the blood.

Two phase 3 studies, CLEAR Harmony and CLEAR Wisdom, evaluated the safety and efficacy of bempedoic acid as an adjunct to maximally tolerated statin therapy in patients with ASCVD and/or HeFH versus placebo. The CLEAR Harmony trial assessed patients for 1 year, and the CLEAR Wisdom trial assessed participants for 12 weeks. Both studies showed significant reductions in LDL levels in patients receiving add-on bempedoic acid compared with those given placebo. A notable safety finding in the Clear Harmony trial was an increased risk of gout flare in the treatment arm.

The enzyme required to activate bempedoic acid is liver specific and not present in muscle tissue, so bempedoic acid is a potential option for patients intolerant to statin therapy due to muscle-related side effects. A 12-week study, CLEAR Tranquility, assessed the safety and efficacy of bempedoic acid plus ezetimibe versus ezetimibe plus placebo in patients with a history of statin intolerance and elevated LDL levels. Results from the trial showed that bempedoic acid plus ezetimibe reduced LDL levels 28% more than placebo plus ezetimibe. Pending cost considerations, this oral combination therapy may represent an effective alternative for patients intolerant to statin therapy.

The ongoing CLEAR Outcomes trial, comprising an estimated 12,600 patients at high CV risk with elevated LDL levels who are intolerant to statin therapy, is assessing the effectiveness of bempedoic acid as monotherapy versus placebo. This trial is expected to conclude in 2022.

5. Gene-silencing therapies that target lipoprotein a and TG levels are showing promise as lipid-lowering therapies.

Several novel antisense oligonucleotide agents capable of silencing key regulatory proteins in the lipoprotein a and apolipoprotein CIII (apo CIII) pathways are currently under investigation, most notably TQJ230 (AKCEA-APO(a)-LRx) and ISIS 678354 (AKCEA-APOCIII-LRx). In a similar manner as inclisiran, these agents are hepatocyte-specific due to the presence of a GalNAc modification.

A randomized, placebo-controlled dose-ranging trial of 286 participants with ASCVD and elevated lipoprotein a levels demonstrated an 80% reduction in lipoprotein a among patients who received the highest dosing schedule of TQJ230 (AKCEA-APO(a)-LRx) (20 mg weekly) compared with a 6% reduction among patients who received placebo. There were no significant adverse effects, the most common of which was injection-site reaction. Moreover, there were no significant differences in platelet count or liver and renal function between the TQJ230 (AKCEA-APO(a)-LRx) and placebo groups. Similar dramatic reductions were seen in apo CIII and TG levels in another randomized controlled trial that evaluated ISIS 678354 (AKCEA-APOCIII-LRx). These promising early data have led to much anticipation of the findings from ongoing phase 3 clinical trials for both therapies.  

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