CORALreef Lipids
A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide
Clinical Question
Does the oral PCSK9 inhibitor enlicitide effectively lower LDL cholesterol levels compared to placebo in adults with established atherosclerotic cardiovascular disease or at high risk for a first ASCVD event?
Bottom Line
Once-daily oral enlicitide 20 mg reduced LDL cholesterol by approximately 56–60 percentage points compared to placebo at 24 weeks, with 67.5% of patients achieving LDL-C <55 mg/dL with ≥50% reduction. The drug also significantly lowered non-HDL cholesterol, apolipoprotein B, and lipoprotein(a), with no apparent increase in adverse events. This oral PCSK9 inhibitor offers efficacy comparable to injectable anti-PCSK9 monoclonal antibodies.
Major Points
- First phase 3 trial of an oral PCSK9 inhibitor (enlicitide decanoate) for LDL-C lowering
- Enlicitide reduced LDL-C by 57.1% vs +3.0% increase with placebo at 24 weeks (adjusted difference −55.8 pp, p<0.001)
- Effect sustained at 52 weeks with adjusted difference of −47.6 percentage points
- LDL-C reduction (adjusted -55.8 pp primary / -59.7 pp post-hoc) is comparable to injectable PCSK9 inhibitors from phase 3 trials: alirocumab -62 pp at week 24, evolocumab -59 pp at week 48, inclisiran -47 pp (ORION-10) and -43 pp (ORION-11) at day 510. Greater than oral bempedoic acid (-18 pp) and ezetimibe (-19 pp), and obicetrapib (-33 pp).
- Non-HDL-C reduced by 53.4 pp, ApoB by 50.3 pp, and Lp(a) by 28.2 pp vs placebo
- 67.5% achieved LDL-C <55 mg/dL with ≥50% reduction (vs 1.2% placebo)
- No significant differences in adverse events, serious adverse events, or deaths
- No increase in new-onset or worsening diabetes mellitus
- High adherence (97.2%) to daily oral dosing with fasting requirements
- Cardiovascular outcomes trial (CORALreef Outcomes) ongoing with projected completion December 2029
- Post-hoc reanalysis with revised handling of biologically impossible beta-quantification values: true between-group LDL-C reduction was -59.7 pp at week 24 (95% CI -62.3 to -57.1) and -52.4 pp at week 52 — larger than the primary analysis due to protocol-prespecified data-handling rule that converted biologically impossible values to 1 mg/dL rather than treating them as missing.
- Open-label extension study ongoing (NCT06492291) to assess long-term durability and adherence beyond 52 weeks.
Design
Study Type: Phase 3, multinational, double-blind, randomized, placebo-controlled trial
Randomization: 1
Blinding: Double-blind; participants and investigators blinded to treatment assignment; matching placebo (note: placebo did not contain sodium caprate excipient)
Enrollment Period: August 2023 to July 2025
Follow-up Duration: 52 weeks treatment + 8 weeks safety follow-up
Centers: 168
Countries: USA, Japan, UK, Spain, Colombia, South Africa, Argentina, China, Italy, and 5 other countries (14 countries total, per paper)
Sample Size: 2904
Analysis: Intention-to-treat; ANCOVA model with baseline value as covariate, treatment and stratification factors (renal function, geographic region) as fixed effects; washout imputation for missing data; nonparametric bootstrap (1000 samples) for CIs; aligned-rank Wilcoxon test for Lp(a); hierarchical testing for multiplicity control
Registration: NCT05952856
Inclusion Criteria
- Age ≥18 years
- History of major ASCVD event (ACS, MI, coronary revascularization, ischemic stroke, cerebrovascular revascularization, or PAD with acute limb ischemia/revascularization/major amputation) with LDL-C ≥55 mg/dL
- OR intermediate-to-high risk for first ASCVD event (heterozygous FH, diabetes, stable angina, prior TIA, symptomatic PAD, age ≥40 with 10-year ASCVD risk ≥7.5%, or CAC score ≥100) with LDL-C ≥70 mg/dL
- Stable dose of appropriate lipid-lowering therapy for ≥30 days (including at least moderate- or high-intensity statin unless documented statin intolerance)
Exclusion Criteria
- Active or recent treatment with a PCSK9 inhibitor
- Uncontrolled hypertension
- Uncontrolled diabetes
- Active liver disease
- Triglyceride level ≥400 mg/dL at screening
Arms
| Field | Enlicitide | Control |
|---|---|---|
| Intervention | Enlicitide decanoate 20 mg oral tablet once daily, taken in the morning on an empty stomach with food/beverages (other than water) withheld for 30 minutes after dosing; formulation contains sodium caprate as permeation enhancer | Matching placebo tablet once daily with same administration instructions; formulation did not contain sodium caprate |
| Duration | 52 weeks | 52 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Mean percent change in LDL cholesterol level from baseline to week 24 | Primary | +3.0% (95% CI 0.9 to 5.1) | −57.1% (95% CI −61.8 to −52.5) | <0.001 | |
| Mean percent change in LDL-C from baseline to week 52 | Adjusted Difference: −47.6 percentage points; 95% CI: −52.7 to −42.5 | Secondary | +4.0% (95% CI 1.7 to 6.3) | −50.4% (95% CI −54.2 to −46.6) | <0.001 | |
| Mean percent change in non-HDL-C from baseline to week 24 | Adjusted Difference: −53.4 percentage points; 95% CI: −55.5 to −51.2 | Secondary | +2.6% (95% CI 0.8 to 4.5) | −53.7% (95% CI −55.0 to −52.5) | <0.001 | |
| Mean percent change in ApoB from baseline to week 24 | Adjusted Difference: −50.3 percentage points; 95% CI: −52.1 to −48.5 | Secondary | +2.9% (95% CI 1.3 to 4.4) | −49.6% (95% CI −50.8 to −48.5) | <0.001 | |
| Median percent change in Lp(a) from baseline to week 24 | Median Difference: −28.2 percentage points; 95% CI: −30.3 to −26.0 | Secondary | 0.0% (IQR −14.9 to 13.3) | −29.0% (IQR −50.4 to −7.0) | <0.001 | |
| LDL-C <70 mg/dL with ≥50% reduction at week 24 | Secondary | 1.5% | 70.3% | Not reported | |
| LDL-C <55 mg/dL with ≥50% reduction at week 24 | Secondary | 1.2% | 67.5% | Not reported | |
| Post-hoc reanalysis — LDL-C % change from baseline to week 24 (treating biologically impossible beta-quantification values as missing instead of converting to 1 mg/dL) | Secondary | N/A (reanalysis of primary analysis) | -59.7 percentage points (95% CI -62.3 to -57.1) | <0.001 | |
| Post-hoc reanalysis — LDL-C % change from baseline to week 52 | Secondary | N/A (reanalysis) | -52.4 percentage points (95% CI -55.1 to -49.7) | <0.001 | |
| Any adverse event | Adverse | 602/969 (62.1%) | 1244/1935 (64.3%) | ||
| Serious adverse event | Adverse | 116/969 (12.0%) | 191/1935 (9.9%) | ||
| Moderate or severe adverse event | Adverse | 314/969 (32.4%) | 649/1935 (33.5%) | ||
| Discontinuation due to AE | Adverse | 40/969 (4.1%) | 60/1935 (3.1%) | ||
| Death | Adverse | 7/969 (0.7%) | 13/1935 (0.7%) | ||
| New-onset or worsening diabetes mellitus | Adverse | 56/969 (5.8%) | 119/1935 (6.1%) | ||
| Drug-induced liver injury | Adverse | 0 (0%) | 0 (0%) | ||
| Diabetes mellitus (AE) | Adverse | 42/969 (4.3%) | 79/1935 (4.1%) | ||
| Nasopharyngitis | Adverse | 40/969 (4.1%) | 74/1935 (3.8%) | ||
| COVID-19 | Adverse | 22/969 (2.3%) | 66/1935 (3.4%) |
Subgroup Analysis
Subgroup analyses for primary endpoint showed consistent LDL-C reduction across prespecified subgroups (Figure S3 in supplement). Results not detailed in main publication.
Criticisms
- Efficacy results reflect clinical trial setting rather than real-world adherence
- Protocol-prespecified data-handling rule for beta-quantification led to transformation of biologically impossible LDL-C values (≤0) to 1 mg/dL, underestimating treatment effect in primary analysis
- 52-week follow-up is short relative to lifetime lipid-lowering therapy; long-term durability unknown
- Missing data from deceased participants were imputed
- Trial not powered to detect rare adverse events
- Placebo formulation did not contain sodium caprate (permeation enhancer present in active drug), potentially affecting blinding
- Cardiovascular outcomes not assessed — awaiting CORALreef Outcomes trial (projected completion 2029)
- Requires fasting administration (30 min before food) which may affect real-world adherence
Funding
MSD (Rahway, NJ); Sponsor designed trial in collaboration with scientific advisory committee, performed data analysis, and participated in manuscript preparation
Based on: CORALreef Lipids (New England Journal of Medicine, 2026)
Authors: Ann Marie Navar, Elina Mikhailova, Alberico L. Catapano, ..., Christie M. Ballantyne; for the CORALreef Lipids Investigators
Citation: N Engl J Med 2026;394:529-39. DOI: 10.1056/NEJMoa2511002
Content summarized and formatted by NeuroTrials.ai.