Low-density lipoprotein cholesterol reduction by inhibition of PCSK9

PURPOSE OF REVIEW: To review the phase 1 and 2 trials with fully human monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 published in the last 18 months and provide comprehensive data that targeting proprotein convertase subtilisin/kexin type 9 very effectively reduces LDL-cholesterol (LDL-C). RECENT FINDINGS: The trials studied a number of different populations including patients with LDL receptor defects (heterozygous familial hypercholesterolemia) and non-familial hypercholesterolemia, background statin or diet only treatment, and those intolerant to statins. The LDL-C lowering has been large, consistent and greater than the largest reductions achievable by the most efficacious statins. These subcutaneously administered drugs produce very rapid reductions in LDL-C, maximal in 7 days, with dosing frequency that may be every 2 or 4 weeks. Unexpected, consistent and robust reductions in Lp(a) have also been reported. Based on these short-term trials of 8-12 weeks in over 1500 patients the drugs have been very well tolerated and the emergent safety profile has not identified any specific areas of concern. SUMMARY: Provided these compounds continue to exhibit an acceptable safety profile in ongoing phase 3 trials they will be as crucial to LDL-C control and reduction of cardiovascular disease, as statins.