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28 July 2017
Novel therapeutics for managing elevated triglycerides by targeting angiopoietin-like 3 (ANGPTL3)

Genetic insights have provided new direction for novel targets for managing triglycerides, a marker for triglyceride-rich lipoproteins and their remnants. This focus article covers two recent reports of first-in-man data for two therapeutic approaches to antagonism of ANGPTL3.

Dewey FE, Gusarova V, Dunbar RL et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; DOI: 10.1056/NEJMoa1612790
Summary
Comments & References
STUDY SUMMARY: ANGPTL3 monoclonal antibody, evinacumab
Dewey FE, Gusarova V, Dunbar RL et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; DOI: 10.1056/NEJMoa1612790
Objective: To investigate whether a) genetic deficiency or b) therapeutic antagonism of ANGPTL3 is associated with a reduced risk of atherosclerotic cardiovascular disease.
Study design:

a) Human genetics studies using data from five cohorts were used for identification of ANGPTL3 loss-of-function (LOF) variants.

b) The effects of pharmacologic antagonism of ANGPTL3 with a human monoclonal antibody (evinacumab) on lipid metabolism and atherosclerosis were studied in a mouse model of atherosclerosis. Subsequently, the effects of evinacumab on lipid levels were investigated in a phase I, first-in-man, randomised, placebo-controlled, double-blind, ascending single-dose clinical trial.

Study population:

a) Data from 58,335 subjects in the DiscovEHR human genetics study were used in identification of ANGPTL3 LOF variants.

b) 83 healthy subjects with mild to moderately elevated triglycerides (150 to 450 mg/dl) or low-density lipoprotein (LDL) cholesterol ≥100 mg/dl were included in the phase I study.

Efficacy variables:

a) Impact of ANGPTL3 LOF variants on lipid levels (triglycerides, LDL cholesterol and high-density lipoprotein [HDL] cholesterol) and coronary artery disease

b) Impact of evinacumab on atherosclerosis in a mouse model, and lipid levels (triglyerides, LDL cholesterol and HDL cholesterol) and safety in healthy human volunteers

Methods:

a) LOF variants in ANGPTL3 (p.Ser17Ter, p.Asn121fs, p.Asn147fs and c.495+6T→C variants) were identified by whole-exome sequencing, direct genotyping or the use of an allele-specific polymerase chain-reaction system. Tests of association for LOF variants in ANGPTL3 with lipid levels and with coronary artery disease were performed in 13,102 case patients and 40,430 controls in the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies.

b) APOE*3Leiden.CETP mice were used as an established model for hyperlipidemia with all features of mixed or familial dysbetalipoproteinaemia and atherosclerosis.  The design of the phase I trial is described above. Analysis of covariance was used to compare treatment effects in the phase I trial, with a two-sided p-value <0.05 indicative of statistical significance.

Results:

·       Subjects heterozygous for LOF ANGPTL3 variants had significantly lower serum levels of triglycerides (by 27%), HDL cholesterol (by 4%), and LDL cholesterol (by 9%) than those without these variants. Carriage of these variants was associated with 41% lower risk of coronary artery disease (adjusted odds ratio for any loss-of-function variant, 0.59; 95% confidence interval [CI], 0.41 to 0.85; p = 0.004).

·       In a mouse model of atherosclerosis, treatment with evinacumab was associated with a significantly greater decrease in atherosclerotic lesion size than controls (p<0.001).

·       In the phase I trial, evinacumab treatment resulted in reductions by up to 76% in triglycerides, by up to 23% in LDL cholesterol and by up to 18% in HDL cholesterol. The most frequent adverse event was headache (seven patients; 11%).

Conclusion: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease.
STUDY SUMMARY: ANGPTL3 antisense oligonucleotide
Graham MJ, Lee RG, Brandt TA et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017;DOI: 10.1056/NEJMoa1701329
Objective: To investigate whether a) genetic deficiency or b) therapeutic antagonism of ANGPTL3 is associated with a reduced risk of atherosclerotic cardiovascular disease.
Study design:

a) Human genetics studies using data from five cohorts were used for identification of ANGPTL3 loss-of-function (LOF) variants.

b) The effects of pharmacologic antagonism of ANGPTL3 with a human monoclonal antibody (evinacumab) on lipid metabolism and atherosclerosis were studied in a mouse model of atherosclerosis. Subsequently, the effects of evinacumab on lipid levels were investigated in a phase I, first-in-man, randomised, placebo-controlled, double-blind, ascending single-dose clinical trial.

Study population:

a) Data from 58,335 subjects in the DiscovEHR human genetics study were used in identification of ANGPTL3 LOF variants.

b) 83 healthy subjects with mild to moderately elevated triglycerides (150 to 450 mg/dl) or low-density lipoprotein (LDL) cholesterol ≥100 mg/dl were included in the phase I study.

Efficacy variables:

a) Impact of ANGPTL3 LOF variants on lipid levels (triglycerides, LDL cholesterol and high-density lipoprotein [HDL] cholesterol) and coronary artery disease

b) Impact of evinacumab on atherosclerosis in a mouse model, and lipid levels (triglyerides, LDL cholesterol and HDL cholesterol) and safety in healthy human volunteers

Methods:

a) LOF variants in ANGPTL3 (p.Ser17Ter, p.Asn121fs, p.Asn147fs and c.495+6T→C variants) were identified by whole-exome sequencing, direct genotyping or the use of an allele-specific polymerase chain-reaction system. Tests of association for LOF variants in ANGPTL3 with lipid levels and with coronary artery disease were performed in 13,102 case patients and 40,430 controls in the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies.

b) APOE*3Leiden.CETP mice were used as an established model for hyperlipidemia with all features of mixed or familial dysbetalipoproteinaemia and atherosclerosis.  The design of the phase I trial is described above. Analysis of covariance was used to compare treatment effects in the phase I trial, with a two-sided p-value <0.05 indicative of statistical significance.

Results:

·       Subjects heterozygous for LOF ANGPTL3 variants had significantly lower serum levels of triglycerides (by 27%), HDL cholesterol (by 4%), and LDL cholesterol (by 9%) than those without these variants. Carriage of these variants was associated with 41% lower risk of coronary artery disease (adjusted odds ratio for any loss-of-function variant, 0.59; 95% confidence interval [CI], 0.41 to 0.85; p = 0.004).

·       In a mouse model of atherosclerosis, treatment with evinacumab was associated with a significantly greater decrease in atherosclerotic lesion size than controls (p<0.001).

·       In the phase I trial, evinacumab treatment resulted in reductions by up to 76% in triglycerides, by up to 23% in LDL cholesterol and by up to 18% in HDL cholesterol. The most frequent adverse event was headache (seven patients; 11%).

Conclusion: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease.

 

COMMENT

In June, the R3i website discussed a proof-of-concept study showing that ANGPTL3 deficiency is associated with lower triglycerides and LDL cholesterol, as well as protection from coronary artery disease (1). Following on from this, these two reports have provided additional evidence of the benefit of inhibition of ANGPTL3 on coronary risk, as well as providing the first-in-man data for two novel therapeutic approaches targeting ANGPTL3.

In the first report discussed here, treatment with an ANGPTL3 moncolonal antibody, evinacumab, resulted in dose-dependent reductions in levels of triglycerides and LDL cholesterol, which were consistent with the lipid phenotype observed in subjects with ANGPTL3 LOF variants. The second report evaluated an antisense approach to ANGPTL3 inhibition. In this study, inhibition of ANGPTL3 led to lowering of triglycerides, LDL and VLDL cholesterol, as well as apolipoprotein C-III levels.  In addition, there was evidence from preclinical studies that treatment with this agent was also associated with reduction of hepatic triglycerides, which would be consistent with the ability of an antisense oligonucleotide to inhibit ANGPTL3 synthesis within the hepatocyte. Added to evidence of improvement in hepatic insulin sensitivity, these findings suggest future potential not only for management of elevated triglycerides, but also the possibility of treatment of patients with non-alcoholic steatohepatitis (NASH).

Taken together, these studies add to accumulating evidence that inhibition of ANGPTL3, either from genetic mutations or therapeutic approaches, will be beneficial. These findings support further development of both of these novel ANGPTL3 inhibitors for the management of individuals with elevated levels of atherogenic triglyceride-rich lipoproteins, with the ultimate aim of reducing the residual cardiovascular risk in these patients (2). Further data with each of these novel agents are awaited with interest.

References

1. Stitziel NO, Khera AV, Wang X et al; PROMIS and Myocardial Infarction Genetics Consortium Investigators. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054-63.

2. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.

Key words triglyceride-rich lipoproteins; angiopoietin-like 3; ANGPTL3; coronary artery disease; triglycerides; genetic studies; phase I clinical trial; monoclonal antibody; antisense oligonucleotide