👤 Robert Pordy

Patients with severe hypertriglyceridemia (sHTG) have variable lipoprotein lipase (LPL) activity levels that may influence therapeutic response. This exploratory analysis investigated post-heparin triglyceride lipase and phospholipase activities in three cohorts of patients with sHTG who received evinacumab (angiopoietin-like 3 inhibitor) for 12 or 24 weeks during a phase 2 trial: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function (LOF) LPL pathway mutations; cohort 2, multifactorial chylomicronemia syndrome (MCS) with heterozygous LOF LPL pathway mutations; and cohort 3, MCS without LPL pathway mutations. Post-heparin plasma samples were obtained at baseline and at week 24 (end of the treatment period). Triglyceride lipase activities (LPL and hepatic lipase [HL]) were measured using both a colorimetric and a scintillation assays. Phospholipase activities (HL and endothelial lipase [EL]) were measured using a colorimetric assay. Baseline post-heparin LPL triglyceride lipase activity was lowest in cohort 1; treatment with evinacumab for 12 or 24 weeks did not alter activity at week 24 versus baseline across cohorts using the colorimetric assay. Non-HL triglyceride lipase activity (mostly LPL) assessed using the scintillation assay showed a significant increase in cohort 1 at 24 weeks versus baseline (P = 0.04). Neither HL nor EL phospholipase activities differed among cohorts or changed with evinacumab treatment. High intra- and inter-patient variability in lipase activity was observed with all methods. Post-heparin LPL triglyceride lipase activity was lower in patients with sHTG with bi-allelic LPL pathway mutations and increased in that group with evinacumab. The high variability in lipase activities observed via differing methods supports the need for more robust assays. Show less

Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability. To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab. A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients. After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L). The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype). Show less

Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated low-density lipoprotein cholesterol (LDL-C). HoFH primarily results from loss-of-function (LOF) mutations in the LDL receptor (LDLR), reducing LDL-C clearance such that patients experience severe hypercholesterolemia, exacerbating the risk of developing cardiovascular events. Treatment options such as statins, lomitapide, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and apheresis help lower LDL-C; however, many patients with HoFH still fail to reach their target LDL-C levels and many of these lipid-lowering therapies are not indicated for pediatric use. Angiopoietin-like protein 3 (ANGPTL3) has been identified as a target to treat elevated LDL-C by acting as a natural inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), enzymes involved in the hydrolysis of the triglyceride and phospholipid content of very low-density lipoproteins. Persons heterozygous for LOF mutations in ANGPTL3 were reported to have lower LDL-C than non-carriers and lower risk of coronary artery disease. Evinacumab is a first-in-class human monoclonal antibody that specifically binds to ANGPTL3 to prevent its inhibition of LPL and EL. In clinical trials, a 15 mg/kg intravenous dose every 4 weeks has shown a mean percent change from baseline in LDL-C of ~50% in adult, adolescent, and pediatric patients with HoFH. This mini review article describes the mechanism of action of evinacumab, evinacumab population PK and PD modeling, and clinical development history of evinacumab for the treatment of HoFH. Show less