CORALreef AddOn: Novel PCSK9 Inhibitor Reduces LDL‑C in Patients Not Meeting Goals

The novel oral PCSK9 inhibitor enlicitide produced substantial reductions in LDL‑cholesterol (LDL‑C) in statin‑treated adults who were not meeting LDL targets, according to the CORALreef AddOn trial, presented during an Investigative Horizons session at ACC.26 and published in JACC. 

In this phase 3 study across eight countries, 301 patients on background statin therapy were randomized to enlicitide 20 mg, bempedoic acid 180 mg, ezetimibe 10 mg, or bempedoic acid plus ezetimibe, all given for 56 days. 

The cohort had a mean age of 64 years, 37% women, and hypercholesterolemia with either established atherosclerotic cardiovascular disease (ASCVD) or intermediate‑ to high‑risk primary‑prevention profiles.

At day 56, enlicitide cut LDL‑C by 65%, far exceeding the reductions seen with bempedoic acid (6%), ezetimibe (28%), and bempedoic acid plus ezetimibe (37%). 

Enlicitide also drove larger declines in apolipoprotein B (ApoB) and non–HDL‑C, with consistent effects across subgroups. 

Safety events and discontinuations (2–4%) were similar across arms. 

The authors conclude that enlicitide is a potent, well‑tolerated add‑on option for patients who need more aggressive LDL‑C lowering beyond statins plus current oral nonstatin therapies.

Two on‑treatment post hoc analyses from the broader CORALreef program found that patients remaining on enlicitide for up to 52 weeks sustained mean LDL‑C reductions of about 60–65% compared with placebo, with adverse‑event rates similar to placebo. 

Taken together, these data support enlicitide as a promising new once‑daily oral PCSK9‑targeted agent for high‑risk and difficult‑to‑treat hypercholesterolemia, pending regulatory review and guideline incorporation.