Low-density lipoprotein cholesterol (LDL-C) is also known as "bad cholesterol." Elevated LDL-C levels can lead to hypercholesterolemia, a condition that often further contributes to the formation of arterial plaques. Data from the New England Journal of Medicine (NEJM) shows that excessively high LDL-C levels increase the global risk of death from chronic diseases by 6.4 times, making it arguably the "most insidious threat to life."
On April 8, 2026, Merck officially announced that it had presented detailed Phase III data for its oral PCSK9 inhibitor Enlicitide (MK-0616) CORALreef AddOn at the 2026 American College of Cardiology (ACC) Annual Meeting. The results were simultaneously published in the *Journal of the American College of Cardiology* ( JACC ) . As the world's first oral PCSK9 inhibitor to enter Phase III clinical trials, this drug demonstrated overwhelming superiority in head-to-head trials, potentially ending the "injection era" for this target .
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According to a Merck press release, enlicitide is an investigational, once-daily oral proprotein convertase subtilisin/ subtilisin 9 (PCSK9) inhibitor . The CORALreef AddOn (NCT06450366) study is a multicenter, randomized, double-blind clinical trial designed to evaluate the efficacy and safety of enlicitide (20 mg once daily) versus ezetimibe monotherapy (10 mg once daily), bepadocanol monotherapy (180 mg once daily), and ezetimibe in combination with bepadocanol in patients with hypercholesterolemia who have a history of major ASCVD events or are at risk of major ASCVD events and are receiving statin therapy. The primary endpoint was the mean percentage change in LDL-C levels from baseline at week 8. Key secondary endpoints included the mean percentage change in non-HDL-C and apolipoprotein B (ApoB) levels from baseline.
Regarding the primary endpoint, the trial results showed that, after 8 weeks of treatment with Enlicitide in addition to statin therapy, patients' LDL-C levels decreased by 64.6% from baseline. Compared with the control drugs, Enlicitide demonstrated significant lipid-lowering advantages : an additional 56.7% reduction in LDL-C compared to the bepadocanine group; an additional 36.0% reduction in LDL-C compared to the ezetimibe group; and an additional 28.1% reduction in LDL-C compared to the bepadocanine plus ezetimibe group. All comparisons were statistically significant.
Enlicitide also performed exceptionally well on key secondary endpoints , reducing apolipoprotein B by 54.6%, non-HDL cholesterol by 58.0% , and lipoprotein(a) by 26.2%; 78.2% of patients achieved an LDL-C reduction of ≥50% and a level <55mg/dL, far exceeding the target achievement rate of 2%-20% in the control group.
In terms of safety, the drug was well tolerated with no serious adverse events, and adherence in all treatment groups exceeded 96%, consistent with previous studies. In December 2025, the drug received priority review from the FDA and is expected to be approved in the second half of 2026. Enlicitide is expected to become the world's first marketed oral PCSK9 inhibitor. Furthermore, Phase III clinical trials for this drug are progressing simultaneously in China.
Despite existing lipid-lowering therapies such as statins and injectable PCSK9 inhibitors, most patients with atherosclerotic cardiovascular disease still fail to reach their LDL-C target values. Enlicitide aims to block the interaction between the PCSK9 protein and the low-density lipoprotein (LDL) receptor, targeting the same site as existing PCSK9 inhibitors. However, Enlicitide's core value lies in achieving a dual breakthrough of "high efficacy + convenient oral administration," addressing a long-standing clinical challenge in lipid-lowering therapy . Its 64.6% LDL-C reduction even surpasses that of injectable PCSK9 inhibitors, while also outperforming traditional oral medications such as ezetimibe and bepadiasic acid, demonstrating superior efficacy as a monotherapy compared to a combination of two drugs.

The PCSK9 target was once considered "untreatable for oral use," but Merck overcame the bioavailability challenge through macrocyclic peptide technology, setting a benchmark for the industry. AstraZeneca is another pharmaceutical giant currently developing similar therapies . AstraZeneca, Pfizer, and other giants are currently developing oral PCSK9 inhibitors.

According to data from a Phase II clinical trial released by AstraZeneca in 2025 , an oral PCSK9 cholesterol-lowering drug that the company is developing can reduce "bad cholesterol" levels by nearly 51%. AstraZeneca also stated that this investigational drug can help 84% of patients reach the recommended cholesterol level, compared to only 13% of patients taking statins alone.

In recent years, the demand for PCSK9 inhibitors has been strong, and new formulations using various technological approaches have been launched, including a PCSK9 injection developed by Novartis that requires injection once every six months. However, globally, currently available PCSK9 lipid-lowering drugs are only injectable solutions; oral medications are not yet available. Undeniably, the success of Enlicitide marks the official entry of lipid-lowering therapy into the "era of potent oral medication." With Merck's progress in clinical trials and registration applications for Enlicitide, another "blockbuster" lipid-lowering drug is on the horizon.

https://mp.weixin.qq.com/s/KikcHzkPOhsh_FM16iGRtQ