Phase 2 Trial Suggests Evinacumab Cuts LDL-C by 50% in Refractory Hypercholesterolemia

Robert Rosenson, MD

A new therapy that shows promise for treating refractory hypercholesterolemia could be coming to the lipidologist’s armamentarium, according to the results of a phase 2 study presented at the American Heart Association (AHA) Scientific Sessions 2020.

Results from the double-blind trial suggest patients with refractory hypercholesterolemia receiving evinacumab, in both intravenous and subcutaneous doses, significantly reduced low density lipoprotein (LDL) cholesterol by more than 50% versus placebo therapy and that evinacumab generally well-tolerated among study participants.

“Our study assessing the safety and efficacy of evinacumab shows that it can lower LDL cholesterol by half in patients unable to attain target guidelines despite maximally tolerated lipid lowering therapy,” said lead investigator Robert Rosenson, MD, professor of medicine and director of Cardiometabolic Disorders at the Icahn School of Medicine at Mount Sinai, in a statement. “Evinacumab is a fully human monoclonal antibody that inhibits angiopoietin like protein 3 (ANGPLT3) and lowers LDL cholesterol through an LDL receptor independent pathway. Genetic studies have shown that people who are missing or have low levels of ANGPTL3 are known to have very low lifelong levels of LDL cholesterol and rarely suffer from atherosclerotic cardiovascular disease.”

The trial was designed with the aim of evaluating the safety and efficacy of evinacumab in patients with refractory hypercholesterolemia despite use of a PCSK9 inhibitor and maximally tolerated statin and ezetimibe. For inclusion in the study, patients needed to be 18-80 years at screening, have a primary diagnosis of hypercholesterolemia, either HeFH or non-HeFH with clinical ASCVD,and an LDL-C of 70 mg/dL or greater or 100 mg/dL or greater for those with and without clinical ASCVD, respectively.

In total, 272 patients were selected for inclusion and underwent randomization in the trial. For those in the subcutaneous portion of the trial, patients were randomized to receive either subcutaneous evinacumab at a dose of 450 mg weekly (n=40), 300 mg weekly (n=43), or 300 mg every 2 weeks (n=39) or placebo therapy (41 patients).In the intravenous portion of the trial, patients were randomized to intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (n=39) or 5 mg per kilogram every 4 weeks (n=36) or placebo (n=34). The primary end point of the trial was the percent change in LDL-C levels from baseline to week 16 with evinacumab compared to placebo.

Results at week 16 indicated the differences in least-squares mean change from baseline in LDL-C level between groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, or 300 mg every 2 weeks and placebo therapy were -56.0, -52.9, and -38.5 percentage points, respectively (P <.001 for all comparisons). In the intravenous evinacumab groups, investigators noted differences of -50.5 (P <.001) and -24.2 percentage points among patients receiving doses of 15 mg per kilogram and 5 mg per kg, respectively, versus the placebo group.

Additionally, investigators pointed out the responses to treatment could be observed as early as the first post-baseline lipid assessment and these were maintained through week 16. The safety analysis of trial data indicated the incidence of serious adverse events during the treatment period ranged from 3-16% among the trial groups.

“Our study demonstrates that a regimen of either subcutaneous or intravenous evinacumab can have a significant impact on LDL cholesterol,” Rosenson added. “If approved for use in this setting, evinacumab could potentially arm cardiologists with a major new add-on therapy to bring patients with HeFH to or closer to their cholesterol-lowering goal.”

This study, “Evinacumab in Patients with Refractory Hypercholesterolemia,” was presented at AHA 2020 and simultaneously published in the New England Journal of Medicine.