52-week trial results of enlicitide in hypercholesterolemia

In CORALreef Lipids among patients with ASCVD or risk thereof and elevated LDL-c levels, the oral PCSK9i enlicitide lowered LDL-c at 24 and 52 weeks compared with placebo and also reduced non-HDL-c, apoB, and Lp(a) at 24 weeks. There were no significant safety concerns.

This summary is based on the publication of Navar AM, Mikhailova E, Catapano AL, et al. - A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide. N Engl J Med. 2026;394:529-539. doi: 10.1056/NEJMoa2511002

Introduction and methods

Background

Although PCSK9 inhibitors effectively reduce LDL-c levels [1-3], they have been underused in clinical practice [4]. A possible barrier is they are available only as an injectable. Recently, enlicitide decanoate, an oral macrocyclic peptide that inhibits PCSK9 binding to LDL receptors, was shown to lower LDL-c levels in short-term phase 1 and 2 trials (up to 8 weeks) [5,6].

Aim of the study

The authors investigated the efficacy and safety of enlicitide in patients with a history of a major ASCVD event or risk thereof over a 52-week period.

Methods

The CORALreef Lipids (A Study of Enlicitide Decanoate (Oral PCSK9 Inhibitor) in Adults with Hypercholesterolemia) trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 2909 adults with a history of a major ASCVD event (e.g., ACS, coronary revascularization, MI, ischemic stroke) and LDL-c ≥55 mg/dL (≥1.4 mmol/L) or who were at intermediate-to-high risk of a first ASCVD event and had LDL-c ≥70 mg/dL (≥1.8 mmol/L) were included. Participants were randomized in a 2:1 ratio to enlicitide 20 mg once daily or placebo for 52 weeks, in addition to stable lipid-lowering therapy. After the treatment, participants completed an 8-week follow-up period for safety assessment or could enroll in a separate open-label extension study.

Outcomes

The primary efficacy endpoint was the mean percent change in LDL-c level from baseline to 24 weeks. Key secondary multiplicity-controlled efficacy endpoints were the mean percent change in LDL-c level from baseline to 52 weeks, mean percent changes in non-HDL-c and apoB levels from baseline to 24 weeks, and percent change in Lp(a) level from baseline to 24 weeks.

Safety endpoints included the frequencies of adverse events and adverse events leading to discontinuation of the study drug. Prespecified safety topics of clinical interest were new or worsening diabetes mellitus and drug-induced liver injury.

Main results

Efficacy

• At baseline, the overall mean ± SD LDL-c level at baseline was 96.1 ± 38.9 mg/dL. After 24 weeks, the least-squares (LS) mean percent change in LDL-c level (i.e., primary endpoint) was −57.1% (95%CI: −61.8% to −52.5%) in patients treated with enlicitide (n=1935) and 3.0% (95%CI: 0.9%–5.1%) in those receiving placebo (n=969) (estimated between-group difference: −55.8 percentage points; 95%CI: −60.9 to −50.7; P<0.001).
• As for the first key secondary endpoint, the adjusted between-group difference in LS mean percent change in the LDL-c level from baseline to 52 weeks for enlicitide versus placebo was −47.6 percentage points (95%CI: −52.7 to −42.5; P<0.001).
• From baseline to 24 weeks, adjusted between-group differences in LS mean percent change for enlicitide versus placebo were −53.4 percentage points (95%CI: −55.5 to −51.2; P<0.001) for non-HDL-c and −50.3 percentage points (95%CI: −52.1 to −48.5; P<0.001) for apoB. After 52 weeks, there were still large differences between the treatment groups.
• Finally, the between-group difference in median percent change in Lp(a) level from baseline to 24 weeks was −28.2 percentage points (95%CI: −30.3 to −26.0; P<0.001).

Safety

• During the 52-week treatment period and subsequent 8-week follow-up, the incidence of adverse events was 64.3% in the enlicitide group and 62.1% in the placebo group (estimated difference: 2.2%; 95%CI: −1.5% to 5.9%).
• There were also no apparent differences in the frequencies of serious adverse events (9.9% vs. 12.0%; estimated difference: -2.1%; 95%CI: −4.6% to 0.3%), adverse events leading to discontinuation of the study drug (3.1% vs. 4.1%), and deaths (0.7% vs. 0.7%) between the enlicitide and placebo groups.

Conclusion

In the CORALreef Lipids trial among patients with ASCVD or risk thereof and elevated LDL-c levels, treatment with oral enlicitide resulted in a placebo-corrected reduction in LDL-c levels of 56 percentage points from baseline to 24 weeks and 48 percentage points from baseline to 52 weeks. In addition, enlicitide reduced the levels of non-HDL-c, apoB, and Lp(a) from baseline to 24 weeks compared with placebo. The safety profile of enlicitide did not indicate significant safety concerns.

Find this article online at N Engl J Med.

References

1. Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507-19.
2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.
4. Hwang J, Peterson ED, Gupta A, Decicco E, Sarnes E, Navar AM. Prescriber uptake and use of novel lipid-lowering therapies. J Am Heart Assoc 2025;14(9):e040768.
5. Johns DG, Campeau L-C, Banka P, et al. Orally bioavailable macrocyclic peptide that inhibits binding of PCSK9 to the low density lipoprotein receptor. Circulation 2023;148:144-58.
6. Ballantyne CM, Banka P, Mendez G, et al. Phase 2b randomized trial of the oral PCSK9 inhibitor MK-0616. J Am Coll Cardiol 2023;81:1553-64.