Low-density lipoprotein cholesterol reduction by inhibition of PCSK9

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).

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.

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.