Proprotein convertase subtilisin/ kexin type 9 (PCSK9) is a secreted serine protease implicated in the progression of hypercholesterolemia.  Inhibitors of the PCSK9 : LDL (low-density lipoprotein) receptor (protein : protein interaction (PPI)) have demonstrated clinical benefit in the reduction of LDL cholesterol and are currently used in the treatment of dyslipidemia.  However, the current approved therapies which include two monoclonal antibodies and one siRNA, are limited due to administration by injection.  Our goal has been to elevate the medical benefit of PCSK9 inhibition through an efficacious and well-tolerated oral therapeutic agent.  This presentation will highlight how Merck’s discovery program was enabled by mRNA display screening to identify cyclic peptide starting points, and lead optimization efforts accelerated by our institutional strength in structure-based drug design and innovative medicinal chemistry.  We will outline the key structure activity relationship studies culminating in the discovery of MK-0616, and the clinical translation of oral PK/TE/PD in Phase 1 SAD/MAD studies.

Invention of MK-0616 a macrocyclic peptide oral PCSK9 inhibitor

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