Times of New Technology: Therapies

The causal relationship between blood cholesterol and atherosclerotic cardiovascular disease (ASCVD) required many decades of research to establish and validate, and initial treatments focused on diet. However, in the last 50 years, and particularly the last 10, we have made great strides in lipid-lowering therapies that have been accelerated by the use of genomics for target identification and biotechnology for drug development. A brief timeline of therapies as approved by the United States Food & Drug Administration highlights the progression:

•    1973: First bile acid sequestrant, cholestyramine.
•    1987: First statin, lovastatin.
•    2002: First cholesterol absorption inhibitor, ezetimibe.
•    2004: First combination lipid-lowering tablet, simvastatin plus ezetimibe; first prescription-strength omega-3 fatty acids, omega-3-acid ethyl esters of eicosapentaenoioic acid (EPA) and docosahexaenoic acid.
•    2012: First ethyl ester of EPA, icosapent ethyl.
•    2015: First proprotein convertase subtilisin/kexin type
9 (PCSK9) monoclonal antibodies, alicocumab and evolocumab.
•    2020: First ATP-citrate lyase inhibitor, bempedoic
acid; first nonstatin combination lipid-lowering tablet, bempedoic acid plus ezetimibe.
•    2021: First angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, evinacumab; first small interfering RNA (siRNA) PCSK9 inhibitor, inclisiran.

The identification of genes, such as PCSK9, in which a loss-of-function mutation leads to improved lipids and less ASCVD has led to the biotech development of fully human monoclonal antibodies and RNA-silencing approaches, which provide unprecedented LDL-lowering efficacy on top of statin therapy and reduced dosing frequency. Instead of daily tablets and/or capsules, injections are administered monthly or bimonthly for the monoclonal antibodies and twice yearly for the siRNA PCSK9 inhibitors.

Although lipid therapy has advanced and is now used routinely, many patients still cannot achieve optimal levels. How can we better help our patients? What’s next?

Promising new therapies are already in the pipeline, with treatment targets identified by genetics and therapeutic approaches that use genetic strategies. Another ANGPTL3 inhibitor is in development (ARO-ANG3) that uses siRNA to block ANGPTL3, for both cholesterol and triglyceride reduction. Apo C-III, which inhibits lipolysis of triglyceride-rich lipoproteins, is also a target to reduce triglyceride, with both antisense (olezarsen [AKCEA-APOCIII-LRx]) and siRNA (ARO-APO3) inhibitors in development. To lower elevated lipoprotein(a), antisense (pelacarsen [AKCEA-APO(a)-LRX]) and siRNA (AMG890 and SLN360) targeting its unique apolipoprotein, apo(a), may provide the first specific treatment for this underrecognized dyslipidemia. In addition to expanding treatment targets, genetic advances have led to great progress in gene therapy and genomic editing, including the discovery and application of clustered regularly interspaced short palindromic repeats (CRISPR). Because the liver is a particularly attractive target for therapeutic CRISPR editing and the key organ for regulating lipid metabolism, lipid disorders are prime candidates for gene therapy and genomic editing. Even the most efficacious therapy is effective only if used. Strategies to improve treatment adherence are also emerging. Besides the increasing availability of combination tablets (for ezetimibe plus rosuvastatin, simvastatin, or bempedoic acid), oral PCSK9 inhibitors are in early development that may provide substantial LDL reduction without requiring injections, including MK-0616 and NNC0385-0434.