PCSK9-inhibitor yields greater LDL-c reduction than conventional intensive lipid-lowering strategies

Bays H, Gaudet D, Weiss R et al.,
J Clin Endocrinol Metab. 2015 Jun 1:jc20151520. [Epub ahead of print]

Background

Despite receiving standard-of-care therapy, most patients with coronary heart disease (CHD) still do not reach LDL-c target [1]. Clinical outcome data suggest that further lowering of the LDL-c level may reduce the risk of CHD [2,3].
Strategies that have been shown to give additional LDL-c reductions include doubling the statin dose, switching to a higher-potency statin, and adding a nonstatin lipid-lowering drug.
Alirocumab is an investigational monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), that has been shown to reduce LDL-c levels by 40% to 70% when given as monotherapy, or in addition to statin therapy [4-7].
The ODYSSEY OPTIONS I trial directly compared the efficacy and safety of alirocumab in addition to atorvastatin, with other lipid-lowering strategies, namely A: addition of ezetimibe, B: doubling atorvastatin dose, or C: switching from atorvastatin 40 mg to rosuvastatin 40 mg. OPTIONS I was a multicentre, randomised, double-blind, double-dummy 24-week phase III trial in 355 patients with hypercholesterolaemia at high or very-high cardiovascular disease risk, on a stable dose of atorvastatin 20 mg or 40 mg.

Main results

• Add-on alirocumab reduced LDL-c levels at 24 weeks by 44.1% and 54.0% in the atorvastatin 20 and 40 mg regimens respectively, while add-on ezetimibe lowered LDL-c by 20.5% and 22.6%, doubling of atorvastatin by 5.0% and 4.8% and switching from atorvastatin 40 mg to rosuvastatin further lowered LDL-c by 21.4%.
• LDL-c reductions were stable from week 4 through week 24.
• Most (86%) patients treated with alirocumab add-on were maintained on the 75 mg Q2W dose after week 12, because they reached the predefined threshold of <70 or 100 mg/dL at week 8. 8.0% and 20.9% of patients on baseline atorvastatin 20 mg and 40 mg respectively, switched to 150 mg Q2W at week 12.
• Over 80% of high and very-high CVD risk patients achieved their protocol defined LDL-c goals of <70 and <100 mg/dL respectively with add-on alirocumab treatment (calculated LDL-c values).  
• The rates of treatment emergent adverse events (TEAEs), serious AEs and injection site reactions were comparable among all treatment regimes.
• 5 of 99 patients (5.1%) receiving alirocumab add-on therapy showed treatment-emergent antidrug antibody responses, 3 of which were persistent.

Download Bays ODYSSEY OPTIONS 1 2015 PACE.pptx

Conclusion

In patients at high CVD risk who are treated with atorvastatin 20 or 40 mg, adding alirocumab stably provided greater LDL-c reductions than adding ezetimibe or increasing the dose or intensity of the statin treatment. The impact of the further LDL-c lowering with alirocumab on CV events will be assessed in the ongoing ODYSSEY OUTCOMES study.

Find this article online at the J Clin Endocrinol Metab

References

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