Despite the potency of high dose statins, many patients fail to reach targets for LDL cholesterol reduction.  Whilst the addition of a second agent such as niacin or ezetemibe results in an additional 10-20% reduction in cholesterol, there remains an unmet need for more potent therapies.  Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing their degradation and reducing the rate at which LDL cholesterol is removed from the circulation.  The injectable fully human monoclonal antibody SAR236553 binds PCSK9, resulting in increases in LDL receptor recycling and reductions in LDL cholesterol.  In this phase 2, multicenter, double-blind, placebo-controlled trial 92 patients who had LDL cholesterol levels of 2.6 mmol/l or higher despite statin therapy were randomised to 8 weeks treatment with atorvastatin 80 mg plus SAR236553 fortmightly, atorvastatin 10 mg plus SAR236553, or atorvastatin 80 mg plus placebo injections.  The primary end-point was the change in LDL at 8 weeks.  The least-squares mean (±SE) percent reduction in LDL was 73.2±3.5 with 80 mg of atorvastatin plus SAR236553, as compared with 17.3±3.5 with 80 mg of atorvastatin plus placebo (P<0.001) and 66.2±3.5 with 10 mg of atorvastatin plus SAR236553 (P<0.001). All the patients who received SAR236553, as compared with 52% of those who received 80 mg of atorvastatin plus placebo, attained an LDL cholesterol level of less than 2.6 mmol/l and at least 90% of patients who received SAR236553, as compared with 17% who received 80 mg of atorvastatin plus placebo, attained LDL cholesterol levels of less than 1.8 mmol/l.  There were no significant differences in adverse events seen between SAR236553 and placebo.

Conclusions

In this randomized study, the addition of the anti-PCSK9 antibody SAR236553 to either 10 mg or 80 mg of atorvastatin resulted in significantly greater reductions in LDL cholesterol than that attained with 80 mg of atorvastatin alone.  Larger and longer term studies are needed to determine the clinical safety and effectiveness of this novel therapy in improving outcomes from cardiovascular disease.

•  Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia. N Engl J Med. 2012 Oct 31. [Epub ahead of print]