PCSK9 inhibitors.

PURPOSE OF REVIEW: To summarize the therapeutic strategies to inhibit PCSK9 and to describe the main results obtained in phase I and II trials with monoclonal antibodies targeting PCSK9.

RECENT FINDINGS: Among the various approaches for PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDL receptor by monoclonal antibodies. Promising preclinical studies have also been reported with other strategies, including inhibition of PCSK9 synthesis by gene silencing agents. The two most advanced monoclonal antibodies in development are SAR236553/REGN727 and AMG145. In phase II, these two monoclonal antibodies administered subcutaneously are well tolerated and effective to decrease atherogenic lipoproteins. A dramatic decrease in LDL cholesterol up to 70% can be obtained. The efficacy has been evaluated so far in addition to statins in hypercholesterolemic patients with or without familial hypercholesterolemia, in patients with intolerance to statin therapy and in monotherapy.

SUMMARY: The short-term efficacy, safety and tolerability of two monoclonal antibodies to PSCK9 have been demonstrated in several phase II trials. These PCSK9 inhibitors are now tested in larger phase III studies to provide insights into the long-term safety and clinical efficacy of this very promising approach.