Experimental drug halves cholesterol levels in phase 2 clinical trials
Scientists are reporting promising results from a phase 2 clinical trial of a cholesterol-reducing drug called evinacumab. The study reports that in patients with extremely high cholesterol, the drug was able to reduce levels by about half, compared to a placebo.
While cholesterol is an essential component of cells, a type called low-density lipoprotein (LDL) cholesterol is often referred to as “bad” cholesterol due to the health problems it can induce in high concentrations in the bloodstream. That condition, called hypercholesterolemia, can lead to increased risk of heart attacks, stroke and other cardiovascular issues.
The current best treatment is a triple therapy of high-intensity statins, an inhibitor that targets a liver protein called PCSK9, and a drug that reduces how much cholesterol is absorbed through the small intestine. And yet, even this regime isn’t enough for many patients with an inherited form of the condition, known as heterozygous familial hypercholesterolemia (HeFH).
While existing drugs target an LDL receptor gene, evinacumab uses a different mechanism to bring cholesterol levels under control.
"Evinacumab is a fully human monoclonal antibody that inhibits angiopoietin like protein 3 (ANGPLT3) and lowers LDL cholesterol through an LDL receptor independent pathway,” says Robert Rosenson, principal investigator of the trial. “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 phase 2 clinical trial of evinacumab was double-blinded and placebo-controlled, and involved 272 patients with hypercholesterolemia. The drug (and placebo) was administered either subcutaneously (just under the skin) or intravenously (into the bloodstream), at different doses and intervals.
After 16 weeks, participants who received weekly subcutaneous doses of 450 mg of evinacumab had LDL cholesterol levels that were 56 percentage points lower than the placebo group. A group who received 300 mg per week saw a drop of 52.9 percentage points, while those who received 300 mg every two weeks saw a drop of 38.5 percentage points.
The intravenous groups fared reasonably well too. A group that received 15 mg of evinacumab per kilogram (2.2 lb) of body weight had cholesterol levels some 50.5 percentage points lower than the placebo group, while those that received 5 mg per kg saw a drop of 24.2 percentage points.
"Our study demonstrates that a regimen of either subcutaneous or intravenous evinacumab can have a significant impact on LDL cholesterol," says Rosenson. "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.”
The team says that evinacumab seems to be well tolerated by most patients. One had difficulty breathing and another had a mild anaphylactic reaction, which improved when they stopped taking the medication. There were two deaths during the trial, but they were linked to pre-existing conditions.
Evinacumab is currently being reviewed by the FDA in the US and similar bodies in the European Union. The results of the trial were published in the New England Journal of Medicine.