Breakthrough Clinical Results
Merck announced positive topline results from the Phase 3 CORALreef Lipids trial evaluating enlicitide decanoate, an investigational oral PCSK9 inhibitor for adults with hypercholesterolemia. The trial met all primary and key secondary endpoints, demonstrating statistically significant and clinically meaningful reductions in LDL-C compared to placebo at Week 24. Reductions were also observed in non-HDL-C, ApoB, and Lp(a). Enlicitide showed a favorable safety profile with comparable discontinuation rates between treatment groups. Merck plans to submit these results to regulatory authorities and present the data at a future scientific congress. This is the third Phase 3 trial showing positive results for enlicitide, potentially offering a new oral treatment option for managing LDL cholesterol levels.
Key Highlights
- Enlicitide decanoate met all primary and key secondary endpoints in the Phase 3 CORALreef Lipids trial.
- Statistically significant and clinically meaningful reductions in LDL-C were observed compared to placebo.
- Favorable safety profile with comparable discontinuation rates between treatment groups.
- Merck plans to submit data to regulatory authorities and present findings at a future scientific congress.
Enlicitide Decanoate Clinical Trials Beyond Hypercholesterolemia
Based on a thorough review of the available information, there is no data regarding clinical trials of Enlicitide decanoate for indications other than hypercholesterolemia. The medication appears to be primarily studied for:
- Atherosclerotic cardiovascular disease (ASCVD) and ASCVD risk equivalents
- Heterozygous familial hypercholesterolaemia as demonstrated in the ORION-9, -10 and -11 trials
- Hypercholesterolemia with glucose intolerance in the PIAT study (a 52-week open-label, investigator-led, randomised, parallel-group study)
- Combined hyperlipidemia (mentioned in European Commission approval contexts)
It should be noted that all these conditions are directly related to lipid disorders and cholesterol management, rather than representing entirely different therapeutic areas.
The available information indicates that inclisiran (which may be related to the compound in question) has been evaluated in clinical trials focusing on patients with various forms of hypercholesterolemia and related cardiovascular risk factors, but does not mention trials for non-hypercholesterolemia indications.
Without specific information about intervention models for trials in other therapeutic areas, no details can be provided about dosing regimens, administration protocols, or methodological approaches for non-hypercholesterolemia indications.
Incidence and Prevalence
Latest Estimates of Hypercholesterolemia Prevalence Globally
Recent studies provide significant insights into the global prevalence of hypercholesterolemia across different populations and regions:
In Kazakhstan, a 2024 study revealed a hypercholesterolemia prevalence of 43.5% based on a nationally representative survey of 6,720 participants aged 18-69. The prevalence increased with age, with the 60-69 age group showing the highest rate at 71.14%. Women had slightly higher rates than men, particularly those over 50.
Contrastingly, in the United States, a 2024 projection study estimated that hypercholesterolemia will decline from 45.8% in 2020 to 24.0% by 2050, bucking the trend of other cardiovascular risk factors that are expected to increase.
A 2023 meta-analysis found that the pooled prevalence of hypercholesterolemia in Indigenous populations was 28.9% (95% CI: 22.4%-36.4%), affecting approximately 1 in 3 to 1 in 4 individuals. Regional variations were notable: 24.3% in North America compared to 40.0% in Australia.
For familial hypercholesterolemia (FH), a 2021 systematic review and meta-analysis estimated the prevalence in the general population at 0.32% (95% CI: 0.26% to 0.39%), corresponding to 1 in 313 individuals. This analysis included 44 studies covering 10,921,310 subjects. The prevalence was significantly higher in specific populations: 3.2% (1 in 31) among subjects with ischemic heart disease, 6.7% (1 in 15) among those with premature IHD, and 7.2% (1 in 14) among those with severe hypercholesterolemia. Notably, only 17 of 195 countries (9%) worldwide have reported FH prevalence, leaving 91% of countries with unknown prevalence.
In Zhejiang Province, China, a 2024 study reported a dyslipidemia prevalence of 72.39%, significantly higher in women than men. Hypercholesterolemia was more common in individuals with lower socioeconomic status.
A 2020 study of adults with type 1 diabetes in Saudi Arabia found various lipid abnormalities, including hypercholesterolemia in 23% of participants, with 27.8% having more than one abnormal lipid condition.
A 2020 comparison between Mexican-American and Mexican populations found hypercholesterolemia was higher in Mexican MHAS females at 53.3% (95% CI = 50.3-56.2).
In Malaysia, a 2025 study reported that respondents with hypercholesterolemia had a 29.2% prevalence of impaired fasting glucose.
Among Lithuanian children and adolescents with type 1 diabetes mellitus, a 2013 study found hypercholesterolemia in 22.3% of subjects.
A 2013 US study of adolescents aged 12-19 years found that females exhibited a lower prevalence of ideal total cholesterol (65% versus 72%) compared with males.
These findings highlight significant regional variations in hypercholesterolemia prevalence, with rates influenced by factors including age, gender, socioeconomic status, and comorbid conditions.
Study Design Parameters
Study Design Parameters and Endpoints in Key Hypercholesterolemia Trials
Trial Designs
Key hypercholesterolemia trials feature diverse methodologies, including well-designed trials lasting 6 to 52 weeks comparing rosuvastatin to other statins. Notable designs include 1-year dose-titration studies comparing rosuvastatin with atorvastatin, pravastatin, and simvastatin. The ODYSSEY APPRISE study was a multicentric, prospective, single-arm, Phase 3b open-label trial investigating alirocumab. Other designs include post hoc analyses of 8-week, randomized, double-blind, Phase III trials comparing ezetimibe with statin therapy, and the BUDCA study - a double-blind, randomized, placebo-controlled, dose-ranging study.
Patient Populations
Trials typically enrolled patients with hypercholesterolemia requiring lipid-lowering treatment, high-risk patients with cardiovascular disease, and those with heterozygous or homozygous familial hypercholesterolemia. Other populations included patients with hypertriglyceridaemia or mixed dyslipidaemias and those with severe hypertriglyceridemia (fasting TGs ≥ 500 mg/dL).
Primary Endpoints
Most trials focused on LDL-C reduction as the primary endpoint, including: - Achievement of NCEP target LDL-cholesterol levels - Percentage of patients achieving LDL-C levels <70 mg/dL - Percentage of patients achieving LDL-C levels <50% of baseline - Reduction in total cholesterol, apolipoprotein B, apolipoprotein B/A1 ratio, and non-HDL-C - Reduction in triglyceride-rich lipoproteins (TRLs)
In the ODYSSEY COMBO I study, the primary endpoint was percent change in LDL-C from baseline to week 24, with results showing -48.2% for alirocumab versus -2.3% for placebo.
Secondary Endpoints
Secondary endpoints commonly included changes in: - Total cholesterol: ezetimibe/simvastatin produced greater reductions (-17.5%) compared to rosuvastatin (-10.3%) - Non-HDL-C: ezetimibe/simvastatin showed greater reductions (-23.4%) than rosuvastatin (-14.0%) - Apolipoprotein B: ezetimibe/simvastatin demonstrated greater reductions (-17.9%) than rosuvastatin (-9.8%) - HDL-C: both treatments showed similar effects - Triglycerides: ezetimibe/simvastatin showed borderline significantly greater reduction
Goal Attainment
Trials frequently measured the percentage of patients achieving target LDL-C levels. In ODYSSEY COMBO I, 75% of alirocumab patients versus 9% of placebo patients achieved LDL-C <70 mg/dL. In a pitavastatin study, 94.2% of pitavastatin/ezetimibe patients versus 69.1% of pitavastatin-only patients achieved their LDL-C goal.
Safety Outcomes
Safety endpoints included treatment-emergent adverse events (TEAEs), with the ODYSSEY APPRISE trial reporting an overall incidence of 75.0%. Other safety parameters included monitoring of liver function (ALT, AST), muscle effects (creatine kinase elevations), and cardiovascular outcomes including blood pressure response and markers of oxidative stress and endothelial dysfunction.
Results Highlights
Rosuvastatin allowed more patients to achieve NCEP target LDL-cholesterol levels than atorvastatin (98% vs 87%), with the difference most marked in high-risk patients (97% vs 61%). Ezetimibe combined with low-intensity rosuvastatin showed efficacy comparable to high-intensity rosuvastatin monotherapy, and evinacumab showed >50% reduction in TRLs at the highest doses.