Enlicitide, Oral PCSK9 Inhibitor, Cuts LDL 60% in CORALreef Trials

Enlicitide (Lipfendra; Merck), the first oral PCSK9 inhibitor, produced a low-density lipoprotein (LDL) cholesterol reduction of approximately 60% sustained through 52 weeks, alongside ApoB lowering of more than 50%, according to Ann Marie Navar, MD, PhD, a lead investigator on CORALreef Lipids (NCT05952856) and associate professor of medicine at UT Southwestern Medical Center.

In an interview with The American Journal of Managed Care^®, she framed ApoB as the more important biomarker, noting that several studies suggest the magnitude of ApoB lowering matters more than LDL cholesterol lowering. Because ApoB captures every atherogenic particle—LDL, very-low-density lipoprotein, and lipoprotein(a) (Lp[a])—the reduction reflects a drop not just in cholesterol content but in the number of circulating cholesterol-carrying lipoproteins. Enlicitide also lowers Lp(a), though Navar called that effect modest next to dedicated Lp(a) therapies: "icing on the cake" rather than the primary driver of benefit.

CORALreef Trial Data and Comparative Efficacy

The approval was informed by Merck’s 2 large phase 3 trials. CORALreef HeFH (NCT05952869) evaluated the macrocyclic peptide in patients with heterozygous familial hypercholesterolemia (HeFH), and CORALreef Lipids enrolled patients with or at risk for atherosclerotic cardiovascular disease who were not at lipid goals.

No head-to-head studies exist, Navar cautioned, but indirect PCSK9 inhibitor comparison suggests enlicitide and the monoclonal antibodies evolocumab and alirocumab lower LDL cholesterol more than inclisiran, the small interfering RNA, which lands closer to 50% to 55%, likely because inclisiran shuts off hepatic PCSK9 synthesis but leaves extrahepatic PCSK9 untouched. Because enlicitide binds PCSK9 in the bloodstream exactly as the monoclonals do, Navar finds it biologically hard to imagine it would not eventually show similar cardiovascular outcomes.

Enlicitide Dosing and Access Considerations

Patients should take enlicitide first thing in the morning on an empty stomach and wait 30 minutes before eating or drinking; black coffee or black tea is permitted. It can be co-administered with other fasting medications such as levothyroxine or oral semaglutide and with a statin or ezetimibe as add-on therapy. For a missed dose, patients should wait until the stomach has been empty for at least 4 hours, then take it and again wait 30 minutes.

For patients who refuse injections, an oral option removes a real barrier. Navar is optimistic that enlicitide's lower wholesale acquisition cost translates into lower copays, but payer coverage is still unsettled.