Oral PCSK9 Inhibition and the CORALreef AddOn Trial

Despite the widespread use of statins, the majority of high-risk patients still fail to reach their LDL targets, and the search for effective, accessible oral alternatives has never been more urgent. At ACC 2026, Pharmacy Times spoke with Alberico Catapano, PhD, professor of pharmacology and director of the Center for the Study of Atherosclerosis at the University of Milan and Multimedica, about the CORALreef AddOn trial (NCT06450366), the performance of an oral PCSK9 inhibitor head-to-head against existing non-statin therapies, and what it could mean for the future of cholesterol management.

Pharmacy Times: Many statin-treated patients still can't reach their LDL targets. How big is this unmet need, and who are the patients most affected?’

Alberico Catapano, PhD: It's true. A large proportion of patients at high or very high cardiovascular risk fail to reach their LDL goals. The goals are demanding, and rightly so, because we want to reduce LDL, which is genuinely causative in atherosclerotic disease, as low as possible. But statins alone won't get many patients there. The estimate is that only about 1 in 5 patients will reach their goal on statins alone. That means 80% of the people who need to go lower on LDL are not getting there. The unmet medical need is very real.

Pharmacy Times: Can you walk us through the CORALreef AddOn trial—who was enrolled, what were the key end points, and why was it designed as a head-to-head against other oral non-statin therapies?

Catapano: The reason this study was designed the way it was is straightforward—to establish how effective current oral non-statin treatments actually are at reducing LDL on top of statins. The trial tested bempedoic acid, ezetimibe, and the combination of the two against enlicitide (Merck) across 4 arms, enrolling patients at high or very high cardiovascular risk. The primary end point was the percentage reduction in LDL. The results showed a very large reduction with enlicitide—in the range of 64% to 65%—while the next best option, the combination of bempedoic acid and ezetimibe, achieved approximately 36.5%. That is a substantial difference, and far more patients reached their LDL goal with enlicitide compared to the combination therapy.

Pharmacy Times: What were the headline efficacy findings, and how meaningful are those numbers in terms of real cardiovascular risk reduction?

Catapano: The headline is a 65% LDL reduction with an oral therapy that appears to be safe. And I have no doubt it will continue to demonstrate a favorable safety profile. Importantly, only 1 in 5 patients failed to reach their LDL goal with enlicitide compared with 4 out of 5 when relying on the other oral options. That sets the stage for meaningfully better treatment and, ultimately, better cardiovascular outcomes.

Pharmacy Times: How did the safety and tolerability profile compare to other oral non-statin options currently available?

Catapano: So far, so good. We do have to acknowledge that the current data are limited to one year of follow-up, and longer-term data will be important. But there is nothing in the current data that raises concern, and I don't expect any surprises. All agents targeting PCSK9 have demonstrated a very strong safety record to date.

Pharmacy Times: Could this data reshape how we think about cholesterol management more broadly—particularly for patients who are needle-averse or have limited access to specialty care?

Catapano: Absolutely. As with any therapy, uptake depends on multiple factors. Having another effective option on the market gives physicians the ability to tailor treatment to patient preference and many patients do still prefer oral therapies over injectable ones. At the same time, cost will inevitably be part of the equation. How enlicitide is priced relative to existing options will play a significant role in how broadly it is adopted in practice. That is part of the real-world picture we will need to watch closely.