Merck's Once-Daily Cholesterol Pill Matches Injectable Efficacy in Phase 3 Trial, Opening Path to First Oral PCSK9 Inhibitor
Enlicitide decanoate cut LDL cholesterol by 57% in 2,900+ patients in the CORALreef Lipids Phase 3 trial — matching injectable PCSK9 inhibitors in pill form, with no meaningful safety signals over 52 weeks.
Overview
Merck’s experimental cholesterol drug enlicitide decanoate reduced low-density lipoprotein (LDL) — commonly called “bad” cholesterol — by approximately 57% compared to placebo in a Phase 3 clinical trial, matching the performance of existing injectable therapies in a once-daily oral pill. The results, published in February 2026 in The New England Journal of Medicine, represent the most successful Phase 3 result yet achieved with an oral cholesterol drug and put Merck at the front of an emerging race to bring oral PCSK9 inhibitors to market.
Trial Results
The CORALreef Lipids trial enrolled 2,912 patients with established atherosclerotic cardiovascular disease or risk factors, all of whom were already taking statin therapy. Participants were randomized 2:1 to 20 mg enlicitide once daily or placebo for 52 weeks. According to Medscape’s analysis, those receiving the drug achieved a 57.1% LDL reduction at 24 weeks — the primary endpoint — and a 50.4% reduction at 52 weeks, compared to roughly a 4% increase in the placebo arm.
Beyond LDL, enlicitide also reduced apolipoprotein B and lipoprotein(a), two additional cardiovascular risk markers. Crucially, when the trial’s lipid-lowering results were compared against standard doses of approved injectable PCSK9 inhibitors (evolocumab and alirocumab), the differences for LDL-C, ApoB, and Lp(a) did not exceed 3% — effectively demonstrating equivalent efficacy in an oral form.
No significant safety signals emerged over 52 weeks. Adverse event rates were similar between the enlicitide and placebo arms, including rates of new-onset diabetes, serious adverse events, and mortality.
Why This Matters
Injectable PCSK9 inhibitors — evolocumab (Repatha) and alirocumab (Praluent) — have been approved for years and produce dramatic LDL reductions, yet their real-world adoption has remained limited. As STAT News reported, the drugs achieve “the most we have ever achieved with an oral drug by far since the development of statins,” but fewer than half of high-cardiovascular-risk patients currently reach their LDL targets — even with statin therapy. Barriers include injection aversion, cost, and the logistical complexity of monthly self-injection or clinical administration.
An oral pill that matches injectable performance addresses the primary adoption obstacle. Enlicitide, taken once daily, would give cardiologists an option to prescribe to patients unwilling or unable to tolerate injections, potentially expanding the treatable population substantially.
Mechanism
Enlicitide is a macrocyclic peptide that binds to the PCSK9 protein in the bloodstream, preventing it from degrading LDL receptors on liver cells. With more LDL receptors available, the liver clears more LDL from the blood. The mechanism is identical to approved injectable monoclonal antibodies, but the drug’s oral bioavailability has historically been the challenge for small-molecule developers — PCSK9 proteins were long considered too large to target effectively with an oral drug.
What Comes Next
Enlicitide still faces a significant hurdle before FDA approval: the agency is expected to want evidence that lower LDL levels translate into fewer heart attacks and strokes — not just improved lab values. Merck has enrolled more than 14,500 patients in CORALreef Outcomes, a dedicated cardiovascular outcomes trial, with a projected completion date of December 2029. Regulatory submission and approval, if successful, would come after that readout.
The FDA has granted enlicitide a National Priority Voucher, a designation that accelerates certain regulatory processes and signals the agency’s recognition of the drug’s potential public health value.
Merck has also completed a third Phase 3 trial, CORALreef HeFH, in patients with heterozygous familial hypercholesterolemia — a genetic condition causing severely elevated LDL from birth — where the drug produced a 59.4% LDL reduction at 24 weeks.
Competition
AstraZeneca is also developing an oral PCSK9 inhibitor (AZD0780), but that program is several years behind enlicitide in development. If Merck successfully navigates the outcomes trial and regulatory process, it would hold a substantial first-mover advantage in what could become a major market segment — particularly if pricing undercuts existing injectables, which currently list at several hundred dollars per injection.
For patients at high cardiovascular risk who are already maximally statin-treated but not reaching LDL targets, an effective, affordable oral option would represent a meaningful clinical advance.