The novel PCSK9 oral inhibitor enlicitide effectively lowered LDL-C in adults already being treated with statins, demonstrating a potential role as an add-on option for patients not meeting LDL-C goals, according to results from the CORALreef AddOn trial presented during an Investigative Horizons session at ACC.26 in New Orleans and simultaneously published in JACC.

The phase 3 double-blind trial assessed the efficacy of enlicitide against other oral nonstatin therapies over 56 days. Conducted in eight countries, 301 statin-treated patients were randomized: 101 to a group taking 20 mg of enlicitide, 50 to a group receiving 180 mg of bempedoic acid, 50 to a group receiving 10 mg of ezetimibe and 100 to a group receiving 180 mg of bempedoic acid plus 10 mg of ezetimibe.

The mean age of patients was 64 years and 37% were women. All had hypercholesterolemia with either a history of a major atherosclerotic cardiovascular disease (ASCVD) event plus an LDL-C level ≥55 mg/dL (44% of patients) or were at intermediate to high risk for a first major ASCVD event plus an LDL-C level ≥70 mg/dL at screening (56% of patients). The mean LDL-C was 91.6 mg/dL.

The primary endpoint was the mean percentage change in LDL-C from baseline to day 56. Secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non–HDL-C.

Fasting lipids were obtained at screening and days 1, 21 and 56 and at treatment discontinuation, and ApoB and lipoprotein(a) were measured on days 1, 21 and 56.

Results showed there was a significant 65% reduction in LDL-C with enlicitide vs. 6% with bempedoic acid, 28% with ezetimibe and 37% with bempedoic acid plus ezetimibe. Results were similar across subgroups.

In addition, patients receiving enlicitide had a significantly greater reduction in ApoB and non–HDL-C than those in the other groups.

Regarding safety, adverse events and discontinuations (2-4%) were similar across groups.

“Enlicitide demonstrated superior efficacy in lowering LDL-C as well as ApoB, non–HDL-C , and [lipoprotein](a) compared with approved oral add-on agents for patients requiring lipid lowering beyond first-line statin therapy. These data support the potential of enlicitide as a new therapeutic option for patients who need lipid lowering beyond what can be provided with statins alone,” concluded Alberico L. Catapano, MDHc, PhD, et al.

Meanwhile, results from two separate post hoc on-treatment analyses conducted using data from CORALreef Lipids and CORALreef HeFH were also presented at ACC.26 by Ann Marie Navar, MD, FACC. In both cases, individuals who remained on treatment experienced significant and sustained reductions in LDL-C through week 52 with an adverse event profile similar to placebo.

Specifically, in CORALreef Lipids, 1,935 participants were treated with enlicitide and 969 treated with placebo. Of these, 88.4% and 88.9%, respectively, remained on treatment at week 52. On-treatment placebo-adjusted mean percent LDL-C reductions were -62.9% at week 24 and -58.0% at week 52. In CORALreef HeFH, approximately 94% of participants receiving enlicitide remained on treatment at week 52, compared with roughly 90% receiving placebo. On-treatment placebo-adjusted mean percent LDL-C reductions were -62.2% at week 24 and -65.3% at week 52. The overall incidence of adverse events was 157 (77.7%) in the enlicitide group and 77 (76.2%) in the placebo group.

Clinical Topics: Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins

Keywords: ACC Annual Scientific Session, ACC26, New Orleans, PCSK9, Cholesterol, LDL, Hypercholesterolemia