Homozygous familial hypercholesterolemia is a rare genetic disorder of lipid metabolism affecting approximately 1 in 300,000 persons. The condition is most often caused by the presence of loss-of-function variants in the low-density lipoprotein (LDL) receptor, which leads to low or absent hepatic clearance of LDL cholesterol from the circulation. Genetic alterations that cause a virtually complete absence of LDL-receptor expression (null homozygotes) result in higher LDL cholesterol levels than alterations that partially reduce LDL-receptor activity with either two non-null alleles or one null and one non-null allele (non-null homozygotes).This disorder is characterized by a markedly elevated plasma LDL cholesterol level from birth, which results in an increased risk of premature atherosclerotic cardiovascular disease. Attempts to lower cholesterol levels often require multiple lipid-lowering drugs and LDL apheresis. Despite these therapies, a majority of patients with this disorder do not reach guideline-recommended LDL cholesterol levels. Because traditional lipid-lowering therapies such as statins and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors act by up-regulating LDL-receptor ex-pression, they have little efficacy in these patients and virtually no activity in those with two null alleles. Angiopoietin like 3 (ANGPTL3) is an inhibitor of lipoprotein and endothelial lipase and plays a key role in lipid metabolism by increasing the levels of triglycerides and other lipids. Loss of function variants in ANGPTL3 have been associated with low levels of both LDL cholesterol and triglycerides and with a 41% lower risk of coronary artery disease, despite the presence of low levels of high-density lipoprotein (HDL) cholesterol. Both ANGPLT3 loss-of-function variants and ANGPTL3 pharmacologic inhibition reduce LDL cholesterol levels independently of the LDL receptor. Evinacumab is a fully human monoclonal antibody that is an inhibitor of ANGPTL3. In a phase 2, open-label, proof-of-concept study involving nine patients with homozygous familial hypercholesterolemia, evinacumab treatment resulted in a mean reduction from baseline of 49% in the LDL cholesterol level. Here, we describe the results of a phase 3, randomized, placebo-controlled, parallel group trial, the Evinacumab Lipid Studies in Patients with Homozygous Familial Hypercholesterolemia (ELIPSE HoFH) trial, which we con-ducted to further evaluate the efficacy and safety of evinacumab in patients with null null variants and in those with non-null variants.

In this double blind, placebo controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24.

The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deci liter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from base-line in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of –49.0 percentage points (95% confidence interval [CI], –65.0 to –33.1; P<0.001); the be-tween-group least-squares mean absolute difference in the LDL cholesterol level was –132.1 mg per deciliter (95% CI, –175.3 to –88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null–null variants (–43.4% vs. +16.2%) and in those with non-null variants (–49.1% vs. –3.8%). Adverse events were similar in the two groups.

In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks.

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Pancreatic disorders and Therapy