▲ReadoutGlobal8 Nov 20251 min read
An oral PCSK9 peptide cuts LDL cholesterol by more than half in phase 3
Merck’s daily pill reaches the territory of injectable PCSK9 drugs in its first large phase 3 readout.
Holds at Phase 3 The molecule is closer to patients than before.
The readThis is the strongest evidence yet that a macrocyclic peptide can be taken by mouth and still hit a hard target at a useful level. The open question is whether people take a daily pill more reliably than a twice-monthly shot.
The result
In CORALreef Lipids, adults with high LDL cholesterol who were already on standard therapy took enlicitide or placebo once a day. At 24 weeks, LDL cholesterol fell by a little over half on average compared with placebo, and the effect held through later time points. Merck reported a safety profile similar to placebo in this trial. Exact figures should be checked against the published paper.
Why a pill matters here
PCSK9 is a protein in the blood that removes LDL receptors from liver cells. Blocking it lets the liver clear more cholesterol. Antibodies already do this well, but they are injections and uptake has been modest.
Enlicitide is a macrocycle: a ring-shaped peptide designed to bind PCSK9 tightly and to be absorbed from the gut, helped by an absorption enhancer. Most peptides are destroyed or not absorbed when swallowed, so a working oral version is an engineering result as much as a clinical one.
What stays the same
- The stage track does not move: this is a phase 3 result, not a filing.
- LDL is a surrogate. The larger CORALreef Outcomes trial is designed to show fewer cardiovascular events.
- Like oral semaglutide, the pill comes with rules on how it is taken, which can affect real-world use.
Outcome data (heart attacks and strokes, not just LDL) and the first regulatory filings.
Primary sourceCORALreef Lipids results presented at AHA Scientific Sessions 2025
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