Current Phase II proprotein convertase subtilisin/kexin 9 inhibitor therapies for dyslipidemia

Reduction of plasma low-density lipoprotein (LDL) cholesterol concentration with statins reduces adverse cardiovascular outcomes. However, lack of efficacy and intolerance of statins in many patients requires alternative treatments. Currently available non-statin alternatives include bile acid sequestrants, the cholesterol absorption inhibitor ezetimibe, niacin-based preparations and fibrates; however, each of these has limitations. Newer agents for LDL cholesterol reduction include the cholesterol ester transfer protein inhibitors, the microsomal triglyceride transfer protein inhibitor lomitapide, the apolipoprotein B antisense oligonucleotide mipomersen and several molecules that inhibit or interfere with proprotein convertase subtilisin/kexin 9 (PCSK9).

Among the various PCSK9 inhibitors, human data are available for monoclonal antibodies against PCSK9 of which the two most advanced are alirocumab (SAR236553/REGN727) and AMG 145. Phase II studies of these agents as monotherapy or in combination with statins have shown reductions of LDL cholesterol by > 70%, with acceptable safety and tolerability so far.

Despite their biochemical efficacy, clinical efficacy, reflected by reduction of cardiovascular end points, remains to be shown for two leading monoclonal antibodies against PSCK9. Other issues to be evaluated with these agents over the longer term include development of rare adverse effects and potential attenuation of efficacy.