Conference Coverage

Evinacumab, novel lipid-lowerer, extends promise in phase 2 results


AHA 2020

Treatment with evinacumab, an investigational lipid-lowering drug with a novel mechanism of action, safely led to roughly a halving of LDL cholesterol levels in patients with treatment-refractory hypercholesterolemia in a multicenter, phase 2 study of 272 patients treated for 16 weeks.

The study enrolled patients with either heterozygous familial hypercholesterolemia (FH) (72% of patients), or patients with hypercholesterolemia and clinical evidence of atherosclerotic cardiovascular disease who had failed to reached their recommended level of LDL cholesterol by treatment (when tolerated) with a statin, ezetimibe, and a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

Notably, only 8 of the 272 randomized patients entered the study not on treatment with a PCSK9 inhibitor. Despite these background treatments, all enrolled patients were above their goal LDL-cholesterol level, with an average level of 148 mg/dL.

The study’s primary endpoint was the percent change from baseline in LDL cholesterol after 16 weeks compared with placebo among patients treated with subcutaneous drug delivery either weekly or every other week, and among patients treated with intravenous delivery every 4 weeks. Results of the dose-ranging study showed that the highest subcutaneous dosage tested produced a 56% cut in LDL cholesterol, while the highest IV dosage led to a 51% drop, Robert S. Rosenson, MD, said at the virtual scientific sessions of the American Heart Association. Concurrently with his report, the results were published online in the New England Journal of Medicine.

The drug’s safety among 194 patients who received evinacumab was “reassuring,” said Dr. Rosenson, professor of medicine and director of the cardiometabolic disorders unit at Icahn School of Medicine at Mount Sinai in New York. “I see no concerning signals in the safety profile,” he said in an interview, an assessment that other experts shared.

“Safety looks pretty good. I don’t see any major concerns,” said lipidologist and endocrinologist Anne C. Goldberg, MD , professor of medicine at Washington University in St. Louis. The LDL-cholesterol effect shown was “very, very impressive in these hard to treat patients,” added Dr. Goldberg, who was a coinvestigator on the study.

“Nothing stands out” as a safety concern in the new data, agreed Robert H. Eckel, MD , an endocrinologist and lipid specialist at the University of Colorado in Aurora.

Drug’s unique mechanism extends potential benefits

The phase 2 study included dose-ranging assessments of both subcutaneous and intravenous treatment with evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, an enzyme that inhibits two different lipases involved in metabolizing LDL cholesterol and other lipoproteins including triglycerides. When the drug inhibits angiopoietin-like 3, the lipases remain more active and further reduce levels of their target lipoproteins.

New lipid-lowering drug class slashes LDL in HoFH patients

“The powerful contribution of this drug is that it works by a pathway independent of the LDL receptor,” said Dr. Rosenson.

By this mechanism evinacumab cut not only LDL cholesterol, but also lowered triglycerides by 53%-62% at the highest dosages, an effect seen as a potential plus. “Prospects are favorable for a drug that not only lowers atherogenic lipoproteins but also lowers triglycerides [TGs]. That’s a distinguishing feature of this treatment,” compared with other agents that lower LDL cholesterol, Dr. Rosenson said. It could make evinacumab especially attractive for treating patients with diabetes, who often have elevated TG levels, he noted. But Dr. Eckel cautioned that a clinical benefit directly linked to TG lowering has not yet been proven.


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