Enlicitide Superior to Oral Non-Statin Therapies for LDL-C Lowering, With Alberico Catapano, PhD

Enlicitide achieved substantially greater reductions in LDL-C, ApoB, and non-HDL-C than other oral non-statin therapies in the recently reported results from CORALreef AddOn.1,2

These data were presented at the American College of Cardiology (ACC) Scientific Sessions 2026 in New Orleans, Louisiana, by Alberico Catapano, PhD, research director and head of the laboratory of lipoproteins and atherosclerosis and of the lipid clinic at MultiMedica IRCCS.1

“The development of oral PCSK9 inhibitors has been discussed for a long time,” Catapano told HCPLive in an exclusive interview. “Physicians always want to have multiple different ways of administering a drug – some patients prefer the oral approach, so having both tools on hand is good for both parties.”

CORALreef AddOn was a phase 3, randomized, double-blind, active-comparator trial comparing the investigational novel oral PCSK9 inhibitor enlicitide and oral non-statin therapies ezetimibe and bempedoic acid. Eligible patients had to have either a history of a major atherosclerotic cardiovascular disease (ASCVD) event or intermediate to high risk for development of a first major ASCVD event and had to be currently treated with a low, moderate, or high intensity statin, among other criteria.3

After enrollment, patients were randomly assigned in a 2:1:1:2 ratio to receive either enlicitide 20 mg, bempedoic acid 180 mg, ezetimibe 10 mg, or bempedoic acid 180 mg plus ezetimibe 10 mg, all of which were administered once daily for 56 days. The primary endpoint was mean percentage change in LDL-C from baseline to day 56, while secondary endpoints included mean percent changes in ApoB and non-HDL-C over the same period.2

Catapano and colleagues enrolled 301 patients, of whom 298 completed the trial. A total of 101 patients were assigned to enlicitide, 50 to bempedoic acid, 50 to ezetimibe, and 100 to ezetimibe plus bempedoic acid. The mean percentage change in baseline in LDL-C was -64.6% (95% CI, -68.3 to -60.9) with enlicitide, -6.3% (95% CI, -13.5 to 0.8) with bempedoic acid, -27.8% (95% CI, -32.3 to -23.4) with ezetimibe, and -36.5% (95% CI, -40.8 to -32.2) with bempedoic acid and ezetimibe. Enlicitide was superior to each comparator (all P <.001).2

The team also recorded greater reductions in ApoB and non-HDL-C with enlicitide, while the proportion of patients with adverse events and discontinuations due to adverse events was similar across all treatment arms. Ultimately, investigators determined that enlicitide demonstrated its potential role as a potent and important add-on to lower LDL-C when goals are not met by statins alone.2

Catapano also addressed the future of enlicitide’s path through the approval pipeline. He cited the ongoing extension study, as well as predicting a rough timeline of when enlicitide would apply for regulatory approval.

“There are other studies ongoing, and other analyses ongoing,” Catapano said. “I’m pretty sure there will be data on ApoB and other biomarkers. The outcome study is also ongoing – enlicitide will likely be approved before this study is complete, but it will still be needed to study the events.”

Editors’ Note: Catapano reports disclosures with Regeneron, Amgen, Sanofi, Merck, AstraZeneca, and Novartis.

References

1. Catapano A, Mikhailova E, Navar A, et al. Efficacy and Safety of Enlicitide Decanoate, an Oral Macrocyclic Peptide Inhibitor of PCSK9, Compared With Bempedoic Acid, Ezetimibe, or Bempedoic Acid Co-administered With Ezetimibe in Statin-Treated Adults With Hypercholesterolemia: Phase 3 CORALreef AddOn Trial. Abstract presented at the American College of Cardiology Scientific Sessions 2026, New Orleans, LA. March 28-30, 2026.

2. Catapano A, Mikhailova E, Navar A. et al. Oral PCSK9 Inhibitor Enlicitide versus Oral Non-statin Therapies: A Phase 3 Randomized Clinical Trial. JACC. null2026, 0 (0). https://doi.org/10.1016/j.jacc.2026.03.036

3. Merck Sharp & Dohme LLC. A Study to Evaluate the Efficacy of Enlicitide (MK-0616, Oral PCSK9 Inhibitor) Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia (MK-0616-018/CORALreef AddOn). ClinicalTrials.gov Identifier: NCT06450366. Updated March 27, 2026. Accessed April 9, 2026. https://clinicaltrials.gov/study/NCT06450366