While antibody inhibitors of proprotein convertase subtilisin/kexin 9 have begun to report proof-of-concept data as lipid-lowering agents, other approaches to PCSK9 inhibition are just now moving into the clinic. Small molecule programs could have an advantage based on oral dosing, while RNAi-based approaches may prove useful for patients with higher baseline levels of PCSK9.

The lead mAbs - REGN727 (SAR236553) from Regeneron Pharmaceuticals Inc. and Sanofi, and Amgen Inc.'s AMG 145 - have shown impressive reductions in LDL-C levels when added to statins. But they require subcutaneous injections once or twice a month (see Cover Story).