Oral PCSK9 inhibitor lowers LDL by up to 60%

Key takeaways:

• An oral PCSK9 inhibitor lowered LDL cholesterol by up to 60% and improved other lipid parameters at 24 weeks.
• The results were similar to those seen with injectable PCSK9 inhibitors.

NEW ORLEANS — A novel once-daily oral PCSK9 inhibitor lowered LDL by up to 60% at 24 weeks in patients with heart disease or at high risk for it, according to a trial presented at the American Heart Association Scientific Sessions.

The CORALreef LIPIDS trial of enlicitide (Merck) vs. placebo included patients with atherosclerotic cardiovascular disease and LDL 55 mg/dL or greater and patients at risk for a first major ASCVD event with LDL 70 mg/dL or greater. All patients were on optimized and stable background lipid-lowering therapy before enrollment, Ann Marie Navar, MD, PhD, associate professor of medicine (cardiology) at UT Southwestern Medical School, said during a press conference.

“Although we have a number of lipid-lowering therapies that effectively lower LDL cholesterol, the majority of patients, even our highest-risk patients with ASCVD, fail to reach LDL goals,” Navar said during the press conference. “Some of the most powerful agents we have after statins are PCSK9 inhibitors. But unfortunately, the injectable PCSK9 inhibitors that are currently available, including monoclonal antibodies and [small interfering] RNA therapies, remain remarkably underutilized. Enlicitide decanoate is an oral PCSK9 inhibitor, and it works similar to the monoclonal antibodies by binding to PCSK9 protein and preventing it from binding to the LDL receptor, leading to upregulation of the LDL receptor and enhanced ability to clear LDL cholesterol from the blood.”

The trial’s 2,912 patients (mean age, 63 years; 39% women) were randomly assigned 2:1 to enlicitide 20 mg or placebo once daily for 52 weeks and were followed for 8 weeks beyond that.

“It’s hard to summarize in one snippet why people aren’t making their LDL cholesterol goals, but there are several things that I think explain it in part,” Navar told Healio. “Although we have a bunch of options for additional LDL cholesterol lowering, they are just not being prescribed. Up to 40% of cardiologists and well over 90% of primary care doctors have never prescribed an injectable PCSK9 inhibitor. There are a lot of reasons for that, but one may be that it takes some time to explain how to use an injectable. The hope for enlicitide as an oral therapy is that it is not only easy to take for the patients, and it’s easy to prescribe for the doctors, who will be able to say ‘Here’s a pill, take it first thing in the morning,’ and not have to go through all the steps of explaining an injection.”

In the initial analysis of the primary outcome of change in LDL at 24 weeks, LDL was reduced by 57.1% in the enlicitide group and increased by 3% in the placebo group (least-squares mean between-group difference, 55.8%; 95% CI, 60.9% to 50.7%; P < .001), Navar said during the press conference. She said in a reanalysis conducted to revise rules on handling of missing data due to biologically impossible baseline values in five patients included in the first analysis, LDL was reduced by 59.6% in the enlicitide group and increased by 4% in the placebo group (least-squares mean between-group difference, 59.7%; 95% CI, 62.3% to 57.1%; P < .001).

At 52 weeks, in the initial analysis, LDL was reduced by 50.4% in the enlicitide group and increased by 3% in the placebo group (least-squares mean between-group difference, 47.6%; 95% CI, 52.7% to 42.5%; P < .001), and in the reanalysis, LDL was reduced by 52.7% in the enlicitide group and increased by 4% in the placebo group (least-squares mean between-group difference, 52.4%; 95% CI, 55.1% to 49.7%; P < .001), she said.

The results are similar to those seen with the injectable PCKS9 inhibitor monoclonal antibodies alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen), she said.

At week 24, compared with placebo, enlicitide lowered non-HDL (between-group difference, 53.4%; 95% CI, 55.5% to 51.2%; P < .001), apolipoprotein B (between-group difference, 50.3%; 95% CI, 52.1% to 48.5%; P < .001) and lipoprotein(a) (between-group difference, 28.2%; 95% CI, 30.3% to 26%; P < .001), she said.

In addition, Navar said, at 24 weeks, the goal of LDL 55 mg/dL or lower and at least a 50% reduction was achieved by 70.3% of the enlicitide group and 1.5% of the placebo group (between-group difference, 68.8%; 95% CI, 66.5%-70.9%), and the goal of LDL 70 mg/dL or lower and at least a 50% reduction was achieved by 67.5% of the enlicitide group and 1.2% of the placebo group (between-group difference, 66.3%; 95% CI, 64.1%-68.5%).

Adverse events occurred in 64.3% of the enlicitide group and 62.1% of the placebo group, serious adverse events occurred in 9.9% of the enlicitide group and 12% of the placebo group and moderate or severe adverse events occurred in 33.5% of the enlicitide group and 32.4% of the placebo group, she said.

Discontinuation of the study drug due to an adverse event occurred in 3.1% of the enlicitide group and 4.1% of the placebo group, whereas discontinuation due to a drug-related adverse event occurred in 1.6% of the enlicitide group and 2% of the placebo group, and one patient in the enlicitide group discontinued the drug due to a serious drug-related adverse event, Navar said. The rate of death during the study period was 0.7% in both groups, she said.

The adherence rate to the study drug was 97% and the adherence rate to fasting instructions was more than 97%, and 85% of patients opted to continue to an open-label extension of the trial, she said.

“The key take-home message is that enlicitide lowered LDL cholesterol, non-HDL, Apo B and lipoprotein(a) remarkably and almost identically to the injectable monoclonal antibody PCSK9s,” Navar told Healio. “We now have a highly effective oral nonstatin therapy that lowers LDL cholesterol by up to 60%, helping to get a lot more patients to cholesterol goals.”

A cardiovascular outcomes trial of enlicitide is ongoing, according to a press release from the AHA. Navar said that based in part on data from CORALreef Lipids and a trial of enlicitide in patients with familial hypercholesterolemia, Merck expects to file for FDA approval of enlicitide in early 2026.

For more information:

Ann Marie Navar MD, PhD, can be reached at cardiology@healio.com.

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