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 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 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.
"The powerful contribution of this drug is that it works by a pathway independent of the LDL receptor," said 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, Rosenson said. It could make evinacumab especially attractive for treating patients with diabetes, who often have elevated TG levels, he noted. But Eckel cautioned that a clinical benefit directly linked to TG lowering has not yet been proven.
The drug also cut HDL cholesterol by an average of as much as 31% from baseline, though the consequence of this effect isn't clear. "I'm not worried about the HDL levels," said Goldberg, who noted that changes in HDL cholesterol produced by drug treatment have often not shown discernible effects.
Reaching Goals by IV or Subcutaneous Delivery
Another measure of evinacumab's efficacy was the percentage of patients who fell below the LDL-cholesterol threshold of 70 mg/dL set by recommendations of the American Heart Association and American College of Cardiology for the highest risk patients, and the less than 55 mg/dL goal set for similar patients by the European Society of Cardiology. Among the subcutaneously-treated patients, 64% achieved the goal of less than 70 mg/dL, and 49% hit the goal of less than 55 mg/dL. Among those who received IV treatment, 71% fell below the 70 mg/dL threshold, and 50% dropped below 55 mg/dL.
The good efficacy shown with subcutaneous dosing is critical, noted Eckel, as this represents a new dimension for evinacumab that had previously been tested only as an IV agent in patients with homozygous FH (N Engl J Med. 2020 Aug 20;383:711-20).
"Subcutaneous delivery is needed for wide real world use," Eckel noted in an interview.
Evinacumab's Role Hangs on Further Studies
The path that evinacumab takes from here into U.S. practice is not yet clear, said Rosenson. He cited the approval earlier in 2020 of another LDL-lowering drug, bempedoic acid (Nexletol) that received U.S. regulatory approval for a similar patient population after studies that proved only lipid-lowering safety and efficacy, without any clinical-endpoint data. He wondered: "Will the [Food and Drug Administration] require a cardiovascular outcomes trial" for evinacumab?
The growing experience using the PCSK9 inhibitor antibodies to treat hyperlipidemia has made clinicians comfortable with this general approach to lipid management, but if evinacumab never accumulates similar efficacy evidence that may relegate it to the backseat compared with the PCSK9 inhibitors for quite some time, suggested Goldberg, though she said she'd be willing to prescribe evinacumab to selected patients based on lipid-lowering evidence alone.
By providing an alternative mechanism for lipid lowering, evinacumab can serve as a useful add-on for patients not reaching their LDL-cholesterol goal with more established agents, thereby providing an alternative to LDL apheresis, which now serves as the lipid-lowering therapy of last resort, said both Rosenson and Goldberg.
The study was sponsored by Regeneron, the company developing evinacumab. Rosenson has been a consultant to Regeneron, and has also been a consultant to or received research funding from Amgen, 89Bio, Corvidia, CVS Caremark, Kowa, Novartis, and The Medicines Company. Goldberg has received research grants, personal fees, and nonfinancial support from Regeneron and Sanofi, research grants from Amarin, Amgen, Ionis/AKCEA, Novartis, and Pfizer, and personal fees from AKCEA, Esperion, Merck and Novartis. Eckel has been a consultant to KOWA and Novo Nordisk.
American Heart Association (AHA) Scientific Sessions 2020.
This article originally appeared on MDEdge.com.
Medscape Medical News © 2020
Cite this: Evinacumab, Novel Lipid-Lowerer, Extends Promise in Phase 2 Results - Medscape - Nov 16, 2020.