Emerging low-density lipoprotein therapies: Targeting PCSK9 for low-density lipoprotein reduction.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the hepatocyte that regulates the surface expression of low-density lipoprotein (LDL) receptors by targeting them for lysosomal degradation. Statins enhance PCSK9 synthesis, an effect that blunts the LDL-cholesterol (-C)-lowering effectiveness of statins. Loss-of-function mutations in the PCSK9 gene produce life-long low levels of LDL-C and reduce cardiovascular risk. Monoclonal antibodies to PCSK9, which mimic the effects of genetic mutations by inhibiting PCSK9, are in clinical trial development. Two different commercial development programs have demonstrated significant success in lowering LDL-C in phase 1 and 2 trials with similar agents: REGN727/SAR236553 (REGN727) and, more recently, AMG 145. When administered subcutaneously at doses ranging from 50 to 150 mg every 2 weeks or 200 to 400 mg every 4 weeks, these agents produced similar dose-responses in LDL-C lowering. In hypercholesterolemic patients, LDL-C reductions ranged up to 60%, and, as would be expected, an even greater response was reported for statin-treated hypercholesterolemic patients-up to 70% decrease. LDL-C has typically shown a gradual increase after the nadir as monoclonal antibodies are cleared from the circulation. Results to date indicate that the PCSK9 monoclonal antibody approach appears safe, well-tolerated, and profoundly lowers LDL-C levels while also favorably altering apolipoprotein B, triglycerides, lipoprotein (a), and high-density lipoprotein-C. It is expected to meet an important clinical need for patients unable to achieve adequate LDL-C-lowering with currently available therapies.