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Cardiovascular disease


Proprotein convertase subtilisin/kexin type 9 (PCSK9); low-density lipoprotein receptor (LDLR)

In vitro studies identified truncated analogs of the epidermal growth factor-like domain A (EGF-A) of LDLR that could aid the design of oral therapeutics to lower cholesterol. PCSK9 binds EGF-A on LDLR, inhibits receptor recycling and thus reduces removal of LDL from the blood. In binding assays, a truncated analog of EGF-A bound PCSK9 with a Kd of ~0.6 mM and inhibited its interaction with EGF-A with an IC50 of ~18 mM. In hepatocellular carcinoma cells, the truncated analogs induced LDLR recycling with an EC50 of ~25 mM. This study was performed in collaboration with Pfizer Inc., whose next steps include improving potency and biopharmaceutical properties.
Amgen Inc.'s evolocumab, Regeneron Pharmaceuticals Inc. and Sanofi's alirocumab and Pfizer's bococizumab are mAbs targeting PCSK9, and all are in Phase III testing to treat lipid disorders.
At least seven additional companies have PCSK9 inhibitors in clinical or preclinical development (see PCSK9 peptide inhibitors, page 4).

SciBX 7(5); doi:10.1038/scibx.2014.143
Published online Feb. 6, 2014

Patent status undisclosed; licensed to Pfizer; unavailable for licensing

Schroeder, C.I. et al. Chem. Biol.; published online Jan. 16, 2014;
Contact: David J. Craik, The University of Queensland, Brisbane, Queensland, Australia