Oral PCSK9 Inhibitor Enlicitide Sustains LDL-C Reductions

In an interview with Pharmacy Times, Christie Ballantyne, MD, chief of cardiology and cardiovascular research and director of cardiometabolic disease prevention at Baylor College of Medicine, discussed longer-term data for enlicitide (Lipfendra; Merck), an oral proprotein convertase subtilisin/kexin-type 9 (PCSK9) inhibitor, from the open-label CORALreef Extension (NCT06492291) study presented at the American Heart Association Scientific Sessions 2026.

Ballantyne explained that extension studies add safety exposure beyond the 52-week phase 3 trials. He said 87% of participants chose to enroll, low-density lipoprotein (LDL) cholesterol reductions were sustained, and those who had received a placebo saw a similar benefit, with no new safety signals. Some participants reduced background statin or ezetimibe (Zetia; Organon) therapy in the open-label setting. A large, blinded cardiovascular outcomes trial remains ongoing.

Pharmacy Times: Why do longer-term data matter so much for a new oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor like enlicitide?

Christie Ballantyne, MD: You want to look at both efficacy and safety for any new therapy, and long-term extensions are useful to basically get more safety exposure. For example, in the initial phase 3 program, there were 2 important trials in the CORALreef program: CORALreef Lipids (NCT05952856) and CORALreef HeFH [heterozygous familial hypercholesterolemia] (NCT05952869). Each of those were 52 weeks, and then you look at the on-drug treatment. There was a 2:1 randomization. You’d like to make sure that it’s still good exposure: a lot of patients for 1 year. Looking at the efficacy, it was approximately a 60% reduction in LDL cholesterol (LDL-C). Very good reductions in non-high-density lipoprotein (HDL) cholesterol and apolipoprotein B (apoB): around 52% to 53% for non-HDL cholesterol, apoB around 50%, and lipoprotein(a) [Lp(a)] down 25%. But you want to say, well, what happens if you keep going further?

Now, in the long-term extension, patients could roll over into the study if they were eligible. One of the things you want to look at is, do most people want to roll over? Eighty-seven percent of the people wanted to go into the long-term extension. They were happy with what they were getting in the baseline trials. Then you want to see if the LDL-C reduction is sustained. Remember, some of those patients were on placebo. Did they get the same benefit? That’s what we saw: they went down the same 60%. The LDL reductions were sustained, and now you have a longer exposure. You’ve got about 4200 patient-years of exposure to the drug, so that’s getting a lot more information. And there were no new safety side effects that showed up. Five hundred people were on the drug for over 2 years. So if this is part of any kind of a program, you’d like to see this data.

As a reminder, there’s a very large outcomes trial that’s in progress, and the patient exposure in that is even greater. But that is blinded; we’re not able to see that data. There is a data safety monitoring board that meets on a regular basis, and they basically [provide] the information to the investigators, to the FDA, to the European Medicines Agency (EMA) if there’s any kind of a new development, which there has not been.

Pharmacy Times: What do the extension results show about how durable LDL-C lowering with enlicitide is over time?

Ballantyne: If we look at the extension, basically, [LDL-C reduction] is preserved over the follow-up period. Now, there are some people, about 10% to 15% of people, who had some changes in their background therapy. This happens sometimes; we’d call it de-escalation. It’s open label. They see the results, and what we see is some people get a little worried when their LDLs are very low, and they may reduce the dose of statin or ezetimibe or something like that. But basically, the results were very reassuring that we’re seeing sustained reductions over a longer period of time with no new adverse events.