Targeting ANGPTL3: CME Session Highlights

ANGPTL3 (angiopoietin-related protein 3) was the focus of another CME session covering basic biology, genetics and clinical trials. ANGPTL3 is an endogenous inhibitor of lipoprotein lipase, the main enzyme involved in hydrolysis of triglyceride-rich lipoproteins, as well as endothelial lipase (1). Consequently, it is a pivotal modulator of plasma triglycerides, as well as levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol. Broadly, ANGPTL3 regulates the partitioning of energy between skeletal muscle and adipose tissue during fasting and refeeding (1). Professor Stefano Romeo (University of Gothenburg, Sweden) commented that the mechanisms underlying these changes are complex and not yet fully elucidated.

Interest in ANGPTL3 as a therapeutic target for preventing atherosclerotic cardiovascular disease has been driven by evidence that carriage of loss-of-function ANGPTL3 variants not only associated with lower triglycerides but also reduced the risk for major coronary events (2,3). Novel treatments targeting ANGPTL3 therefore offer new therapeutic potential.

One of these therapies is evinacumab, a fully human monoclonal antibody against ANGPTL3. In addition to experimental studies (4), functional analyses of LDLR variants in patients with homozygous familial hypercholesterolaemia (HoFH) suggested LDL‑C lowering potential for evinacumab (5). Following on from a proof-of-concept study (6), evinacumab was investigated in the phase III ELIPSE trial in 65 HoFH patients with elevated LDL-C levels despite stable maximally tolerated lipid lowering therapy. At 24 weeks, treatment with evinacumab 15 mg/kg intravenously every 4 weeks reduced LDL-C levels by 49% and was similarly effective in patients with null/null or non-null/null mutations. Importantly, fewer patients on evinacumab than placebo required lipoprotein apheresis (7.0% vs. 22.7%, p=0.085) (7). Professor Frederick Raal (University of the Witwatersrand, Johannesburg, South Africa commented that evidence from the ELIPSE trial suggests that the major mechanism of LDL-C lowering with evinacumab involves increased clearance, as the effects of treatment with and without lomitapide were identical.

The same regimen of evinacumab was also effective for the management of patients with atherosclerotic cardiovascular disease and refractory hypercholesterolaemia, halving LDL-C levels against a background of maximally tolerated lipid lowering therapy (8). 

The management of these difficult-to-treat patients, particularly patients with HoFH, poses a significant challenge. While statin-ezetimibe treatment is foundational, few patients are adequately controlled, and PCSK9 monoclonal antibody therapy is less effective than in heterozygous FH, so that many require invasive apheresis (if it is available). The availability of evinacumab offers new opportunities for lowering LDL-C in HoFH patients, involving mechanisms beyond those targeting the LDL receptor.

Furthermore, clinical trials are also investigating the potential of evinacumab for managing severe hypertriglyceridaemia. Professor Robert S. Rosenson (Icahn School of Medicine at Mount Sinai, New York, USA) discussed the results of a phase II trial in this clinical setting, which were also reported as a poster at EAS Helsinki 2021.

Find more at the meeting 

References

  1. Kersten S. Angiopoietin-like 3 in lipoprotein metabolism. Nat Rev Endocrinol 2017;13:731-9.
  2. Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054–63.
  3. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017;377:211-221.
  4. Musunuru K, Porcello JP, Do R et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010;363:2220–7.
  5. Banerjee P, Chan KC, Tamagotchi M, et al. Functional analysis of LDLR (Low-Density Lipoprotein Receptor) variants in patient lymphocytes to assess the effect of evinacumab in homozygous familial hypercholesterolemia patients with a spectrum of LDLR activity. Arterioscler Thromb Vasc Biol 2019;39:2248-60.
  6. Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017;377:296-7.
  7. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020;383:711-20.
  8. Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med 2020;383:2307-19.
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