Merck reported a new engineered-enzyme manufacturing approach for enlicitide decanoate, positioning the drug as a potential first oral PCSK9 inhibitor. The work, published in Science, targets the core chemistry challenge of making the macrocyclic peptide—described by Merck and external experts as a “monster of a molecule.” The company says the biocatalysis route cut synthesis steps by more than half and achieved a 39% yield on multi-kilogram scale. Merck’s approach replaces traditional protecting-group strategies with engineered enzymes that drive successive reaction steps. PCSK9 inhibitors are already established in cardiovascular risk reduction, but all approved therapies are injectables. An oral option could change access and adherence for a large patient population if the program advances clinically. Key actors include Merck biocatalysis leadership (David Thaisrivongs) and external academic chemist commentary from the University of Michigan (Alison Narayan).