Merck Presents Phase 3 CORALreef AddOn Data for Enlicitide, Highlighting Strong LDL-C Reductions and Potential as First Oral PCSK9 Inhibitor
Merck has unveiled compelling late-breaking results from its Phase 3 CORALreef AddOn study, demonstrating the potential of enlicitide decanoate, an investigational oral PCSK9 inhibitor, to significantly reduce low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia who are at risk for or have established atherosclerotic cardiovascular disease (ASCVD). The findings were presented at the American College of Cardiology Annual Scientific Session and Expo 2026 and simultaneously published in the Journal of the American College of Cardiology (JACC).
These results mark the third positive Phase 3 study in the CORALreef clinical program, reinforcing the consistency of enlicitide’s efficacy and safety profile. Importantly, the therapy demonstrated statistically significant and clinically meaningful LDL-C reductions compared to widely used non-statin oral therapies, positioning it as a potentially transformative option in lipid management.
Addressing a Critical Gap in Cardiovascular Risk Management
Cardiovascular disease remains a leading cause of death worldwide, with elevated LDL cholesterol recognized as one of the most important modifiable risk factors. Despite the availability of statins and other lipid-lowering therapies, a substantial proportion of patients fail to achieve recommended LDL-C targets.
In particular, patients with ASCVD often require more aggressive lipid lowering to reduce the risk of heart attack, stroke, and other cardiovascular events. However, treatment gaps persist, driven by factors such as suboptimal adherence, tolerability issues, and limitations of existing therapies.
Enlicitide decanoate is designed to address these challenges by combining the potent LDL-C–lowering effects typically associated with injectable PCSK9 inhibitors with the convenience of once-daily oral administration. This approach has the potential to improve both efficacy and patient adherence, thereby enhancing overall cardiovascular outcomes.
CORALreef AddOn Study Design and Objectives
The CORALreef AddOn trial evaluated enlicitide in patients already receiving background statin therapy, reflecting real-world clinical practice where combination treatment is often necessary to achieve lipid goals. The study compared enlicitide to established oral non-statin therapies, including bempedoic acid, ezetimibe, and a combination of both agents.
The primary endpoint was the percentage reduction in LDL-C at eight weeks (day 56), while secondary endpoints included additional lipid parameters and the proportion of patients achieving predefined LDL-C targets.
Robust LDL-C Reductions Demonstrated
Results from the study showed that enlicitide delivered substantial LDL-C reductions when added to statin therapy. At eight weeks, patients receiving enlicitide experienced a 64.6% reduction in LDL-C from baseline, representing a magnitude of effect comparable to injectable PCSK9 inhibitors.
When compared directly to other oral therapies, enlicitide demonstrated clear superiority. LDL-C reductions were 56.7% greater than those achieved with bempedoic acid, 36.0% greater than ezetimibe, and 28.1% greater than the combination of bempedoic acid and ezetimibe. All comparisons were statistically significant, with p-values below 0.001.
These findings highlight the potential of enlicitide to deliver best-in-class lipid lowering among oral therapies, addressing a key unmet need for patients who require additional LDL-C reduction beyond statins.
Significant Improvements Across Secondary Lipid Endpoints
In addition to LDL-C, enlicitide demonstrated strong efficacy across multiple secondary lipid parameters, further supporting its comprehensive impact on cardiovascular risk factors.
The therapy reduced apolipoprotein B (ApoB), a key marker of atherogenic lipoproteins, by 54.6% from baseline. In comparison, reductions with bempedoic acid, ezetimibe, and their combination were substantially lower, at 5.4%, 20.2%, and 27.7%, respectively.
Similarly, enlicitide achieved a 58.0% reduction in non-high-density lipoprotein cholesterol (non-HDL-C), another important indicator of cardiovascular risk. This contrasted with reductions of 5.2% for bempedoic acid, 25.1% for ezetimibe, and 31.8% for the combination therapy.
These results demonstrate that enlicitide not only lowers LDL-C but also provides broad improvements across lipid parameters associated with atherosclerosis.
Favorable Impact on Lipoprotein(a)
The study also evaluated changes in lipoprotein(a), or Lp(a), an emerging cardiovascular risk factor that is not significantly affected by many traditional lipid-lowering therapies.
Treatment with enlicitide resulted in a 26.2% reduction in Lp(a) levels from baseline. In contrast, Lp(a) levels increased with bempedoic acid and its combination with ezetimibe and remained unchanged with ezetimibe alone.
This additional benefit may further enhance the cardiovascular risk reduction potential of enlicitide, particularly in patients with elevated Lp(a), a population with limited therapeutic options.
High Rates of LDL-C Goal Attainment
One of the most clinically meaningful findings from the CORALreef AddOn study was the high rate of LDL-C goal attainment achieved with enlicitide.
At eight weeks, 78.2% of patients treated with enlicitide reached the predefined target of at least a 50% reduction in LDL-C along with an absolute LDL-C level below 55 mg/dL. This represents a stringent goal aligned with current guidelines for high-risk patients.
In comparison, only 2.0% of patients receiving bempedoic acid, 8.0% of those receiving ezetimibe, and 20.0% of those receiving the combination therapy achieved the same target.
These findings underscore the potential of enlicitide to help a significantly greater proportion of patients reach recommended lipid goals, addressing a major gap in current treatment strategies.
Strong Adherence and Consistent Safety Profile
The study also reported high levels of adherence, with 98% of patients adhering to the study intervention and at least 96% following dosing instructions across all treatment groups. This level of adherence is particularly notable given the challenges often associated with long-term lipid-lowering therapy.
The safety profile of enlicitide was consistent with previous findings from the Phase 3 CORALreef Lipids and CORALreef HeFH trials. There were no clinically meaningful differences in adverse event rates between treatment groups.
Importantly, no serious adverse events (SAEs), treatment discontinuations due to drug-related adverse events, or discontinuations due to drug-related SAEs were reported among patients receiving enlicitide. This favorable safety profile supports its potential use as a long-term therapy for chronic lipid management.
Expert Perspectives on Clinical Impact
Clinical experts highlighted the significance of these findings in the context of ongoing challenges in cardiovascular risk reduction. The ability of enlicitide to deliver robust LDL-C lowering compared to existing oral therapies suggests that it could play a key role in improving outcomes for patients who remain above target despite current treatment options.
Given that a large proportion of patients with ASCVD do not achieve recommended LDL-C levels, the availability of an effective oral PCSK9 inhibitor could represent a major advancement in clinical practice.
Regulatory Progress and Future Outlook
Enlicitide has also gained regulatory momentum, with the U.S. Food and Drug Administration granting it a Commissioner’s National Priority Voucher (CNPV) in December 2025. This designation reflects the potential importance of the therapy in addressing unmet medical needs and may facilitate an accelerated review process.
Merck is continuing to advance the development and regulatory strategy for enlicitide, with the goal of bringing the therapy to patients as quickly as possible. If approved, it could become the first oral PCSK9 inhibitor available, offering a novel and convenient alternative to injectable therapies.
Transforming the Landscape of Lipid Management
The development of enlicitide represents a significant step forward in the evolution of lipid-lowering therapies. By combining potent efficacy with oral administration, the therapy has the potential to overcome many of the limitations associated with existing treatment options.
For patients, this could mean improved adherence, greater convenience, and better overall outcomes. For clinicians, it offers a powerful new tool to help patients achieve guideline-recommended lipid targets and reduce cardiovascular risk.
The Phase 3 CORALreef AddOn results provide strong evidence supporting the efficacy and safety of enlicitide decanoate as a next-generation lipid-lowering therapy. With substantial reductions in LDL-C and other key lipid parameters, high rates of goal attainment, and a favorable safety profile, enlicitide is emerging as a promising candidate in the fight against cardiovascular disease.
As Merck continues to advance this innovative therapy toward potential approval, enlicitide could redefine the standard of care for patients with hypercholesterolemia, particularly those at high risk of ASCVD who require more effective and accessible treatment options.
About CORALreef AddOn
CORALreef AddOn ( NCT06450366 ) is a Phase 3, randomized, double-blind, multicenter study designed to evaluate the efficacy and safety of enlicitide versus bempedoic acid, ezetimibe and bempedoic acid with ezetimibe, in adults with hypercholesterolemia and a history of a major ASCVD event or at risk for a first major ASCVD event who are treated with a statin. The primary endpoint is the mean percent change from baseline in LDL-C at week eight. Key secondary endpoints include mean percent change from baseline in non-HDL-C and ApoB. Non-multiplicity-controlled secondary endpoints included mean percent change in Lp(a) and the proportion of patients with at least a 50% reduction in LDL-C and an LDL-C <55 mg/dL (1.42 mmol/L).
About enlicity and PCSK9
Enlicitide has the potential to be the first approved oral PCSK9 inhibitor. It is designed to lower LDL-C via the same biological mechanism as currently approved monoclonal antibody, injectable PCSK9 inhibitors but in a daily pill form. Enlicitide is an investigational novel macrocyclic peptide that binds to PCSK9 and inhibits the interaction of PCSK9 with LDL receptors.
PCSK9 plays a key role in cholesterol homeostasis by regulating levels of the LDL receptor, which is responsible for the uptake of cholesterol into cells. Inhibition of PCSK9 is designed to prevent the interaction of PCSK9 with LDL receptors. This results in greater numbers of LDL receptors available on the cell surface to remove LDL cholesterol from the blood.
About CORALreef Clinical Trial Program
The efficacy and safety profile of enlicitide is being evaluated through the comprehensive CORALreef Clinical Trial program evaluating over 19,000 participants who have hypercholesterolemia. As previously announced, enlicitide demonstrated statistically significant and clinically meaningful reductions in LDL-C in three pivotal Phase 3 studies: CORALreef Lipids ( NCT05952856 ), CORALreef HeFH ( NCT05952869 ) and CORALreef AddOn ( NCT06450366 ). Enlicitide is continuing to be evaluated in the large cardiovascular outcomes trial, CORALreef Outcomes ( NCT06008756 ), which has completed enrollment with over 14,500 participants. Additional CORALreef clinical trials include CORALreef Extension ( NCT06492291 ), CORALreef Pediatric ( NCT07058077 ) and CORALreef Combination ( NCT07216482 ).
About hypercholesterolemia
Hypercholesterolemia, a type of hyperlipidemia, is a disorder in which there are elevated LDL-C levels in the blood. It affects approximately 86 million adults in the US and is a major risk factor for ASCVD. Nearly 70% of people with ASCVD who are treated with lipid-lowering therapies do not reach target LDL cholesterol levels. High LDL-C, if left untreated, can lead to ASCVD events such as heart attacks and strokes.
About the CV epidemic and atherosclerotic cardiovascular disease
The silent CV epidemic is the leading cause of deaths globally, contributing to the majority of heart attacks and strokes, and deaths related to CV continue to rise. ASCVD accounts for 85% of CV deaths. It is caused by the buildup of plaque within the arteries, leading to narrowed or blocked blood vessels that can result in serious CV events such as heart attacks and strokes as well as coronary artery disease, peripheral artery disease and cerebrovascular disease.
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