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EAS 2017 April 25: Plenary focuses on future prospects for management of triglycerides

26 April 2017   (0 Comments)
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Attention has refocused on plasma triglycerides, a biomarker of circulating triglyceride-rich lipoproteins and their metabolic remnants, with accumulating evidence from epidemiologic, mechanistic and genetic studies showing causality in atherosclerotic cardiovascular disease (ASCVD). This in turn has prompted a re-evaluation of the definition of hypertriglyceridaemia by the EAS Consensus Panel, as well as recommendations for management.1

This renaissance in triglycerides has been largely driven by improved understanding of the biology and genetics of triglyceride heritability, which in turn have paved the way for new targets and pharmacotherapeutic approaches, commented Professor Anne Tybjaerg-Hansen (Rigshospitalet, Copenhagen, Denmark) in the Tuesday Plenary session. Among those under consideration are APOC3, and angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4), either as antisense agents or as monoclonal antibodies. The rationale for each of these was discussed.

APOC3

APOC3 is expressed in the liver and intestine, and is controlled by positive and negative regulatory elements that are spread throughout the gene cluster inhibitor of lipoprotein lipase (LPL). There is extensive evidence to support this genetic locus to plasma levels of apolipoprotein (apo)CIII, triglycerides and very low-density lipoprotein (VLDL)-triglycerides. Mendelian randomization studies have also shown an association between loss-of-function (LOF) mutations in APOC3 with low levels of triglycerides and decreased incidence of cardiovascular disease, leading some to suggest that this may be the next PCSK9.2-4

Volanesorsen, a second generation antisense drug, is one such novel agent that has been developed to specifically target APOC3. Studies in patients with hypertriglyceridaemia, as well as familial chylomicronaemia syndrome (reported in the clinical latebreaker session on Tuesday) provide evidence of benefit in lowering plasma triglycerides.5,6 However, as with all novel agents, it is important to balance the efficacy and side effects of treatment, most commonly injection site reactions, flu-like symptoms, and reduction in platelet count. Indeed, the potential for thrombocytopenia was an initial concern of this mode of therapy, although a recent review indicated that there were no class generic effects on platelet numbers.7

ANGPTL4

ANGPTL4, a secreted protein that increases plasma triglycerides levels by inhibiting LPL, is another target that has raised much interest. Once again, genetic studies have been instrumental in providing a rationale for development, showing that loss-of-function or inactivating variants in ANGPTL4 were associated with favourable lipid profiles, specifically lowering of triglycerides, as well as protection from coronary heart disease.8,9  

Therapeutic modulation via targeting of ANGPTL4, possibly as a monoclonal antibody therapy, may offer potential.  Although at an earlier stage of development, the issue of balancing efficacy and safety is highly relevant, especially given reports of lymphadenopathy in an experimental knockout mouse model, and in mice and non-human primates treated with an ANGPTL4 antibody.

ANGPTL3

In concluding the session, Professor Tybjaerg-Hansen considered the evidence for ANGPTL3, a circulating protein synthesized exclusively in the liver that inhibits LPL and endothelial lipase (EL), enzymes that hydrolyze triglycerides and phospholipids in plasma lipoproteins. Once again, genetic studies have provided a basis for development, with a study in heterozygous carriers of ANGPTL3 loss of function mutations showing reduction in circulating triglycerides, as well as 34% reduction in the risk of coronary artery disease.10

A monoclonal antibody therapy to ANGPTL3 (REGN1500) has shown beneficial effects on plasma triglycerides in experimental animal models without any changes in liver, adipose, or myocardial triglycerides, suggesting therapeutic potential.11 In a proof of concept study this ANGPTL3 monoclonal antibody has had encouraging results, albeit in patients with homozygous familial hypercholesterolaemia (as reported in the clinical latebreaker session on Tuesday).12  So far, however, there is little information on the side effect profile of this treatment.

And the list of novel agents currently being investigated for the management of triglycerides continues. Among the new possibilities, a first in class selective peroxisome proliferator alpha modulator (SPPARM-α) has had encouraging results, with a cardiovascular outcomes study planned (PROMINENT:  Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN patiENTs with diabetes).

After lagging behind for so long, the future for improved management of hypertriglyceridaemia with agents specifically targeting novel targets looks bright.

References

1. Hegele RA, Ginsberg HN, Chapman MJ et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014;2:655-66.

2. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.

3. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute., Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.

4. Bernelot Moens SJ, van Capelleveen JC, Stroes ES. Inhibition of ApoCIII: the next PCSK9? Curr Opin Lipidol 2014;25:418-22.

5. Yang X, Lee SR, Choi YS et al. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. J Lipid Res 2016;57:706-13.

6. Gaudet D, Digenio A, Alexander V et al. The APPROACH Study: A randomized, double-blind, placebo-controlled, Phase 3 study of volvanesorsen administered subcutaneously to patients with familial chylomicronaemia syndrome (FCS). Reported at EAS Congress Prague 23-26 April, 2017.

7. Crooke ST, Baker BF, Witztum JL et al. The Effects of 2'-O-Methoxyethyl Containing Antisense Oligonucleotides on Platelets in Human Clinical Trials. Nucleic Acid Ther 2017 Feb 1. doi: 10.1089/nat.2016.0650. [Epub ahead of print]

8. Dewey FE, Gusarova V, O’Dushlaine C et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med 2016;374:1123-33.

9. Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med 2016;374:1134-44.

10. Stitziel NO, Khera AV, Wang X et al. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol 2017;69:2054-63.

11. Gusarova V, Alexa C1, Wang 2 et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res 2015;56:1308-17.

12.  Gaudet D, Gipe D, Hovingh GK et al. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolaemia; a single arm, open-label, proof of concept study.

 


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