Merck’s oral, macrocyclic PCSK9 inhibitors are among the 12 candidates for 2021’s “Molecule of the Year” and have already gotten quite a few votes for 2021’s “Molecule of the Year.” They’ve been called “gamechangers” by readers, with impressive human proof-of-concept.
MK-0616 is a macrocyclic PCSK9 inhibitor with demonstrated once-daily PCSK9-lowering and LDL-cholesterol-lowering activities in a human clinical trial (<300 mg QD).
Currently, PCSK9-targeting therapies are only available by injection, and the cost-benefit of using large molecules to lower cholesterol has been hotly debated. Identification of oral PCSK9 inhibitors has been something of a “holy grail” for the field, but difficult to achieve due to the poor ligandability of the target, which acts through a protein-protein interaction with LDL-R.
While MK-0616 has not been formally published, related macrocycles have been disclosed that illustrate the concept. The discovery of such molecules is an interesting proof of concept for this emerging area of drug space (rationally designed oral macrocyclic peptides), with hits generated by a relatively new technology (mRNA display screen) and advanced with structure-based design (potency increased by 100,000x).
You can read more about all 12 “Molecules of the Year” in our newly released Premium slide deck.