Odyssey Mono

Effect of Alirocumab 75 mg Subcutaneously Every 2 Weeks as Monotherapy Versus Ezetimibe Over 24 Weeks

Eli M Roth; James M McKenney


Future Cardiol. 2015;11(1):27-37. 

In This Article

Abstract and Introduction


Alirocumab is a fully human monoclonal antibody to PCSK9. The ODYSSEY MONO study was the first alirocumab Phase III study to test a previously unused dose of 75 mg subcutaneously every 2 weeks in a population on no lipid-lowering therapy. A total of 103 patients were randomly assigned to alirocumab starting at 75 mg subcutaneously every 2 weeks or ezetimibe 10 mg per os every day with alirocumab dose uptitration at 12 weeks based on achieved LDL-cholesterol level at week 8 and followed to week 24. At the week-24 primary end point, the alirocumab intent-to-treat group showed a 47.2% (least square [LS] mean) reduction in LDL-cholesterol compared with a 15.6% (LS mean) reduction with ezetimibe (LS mean difference of 31.6%; p < 0.0001). Safety parameters and adverse events were similar between the two groups.


LDL-cholesterol (LDL-C) is considered to be a major modifiable risk factor for the development of atherosclerosis and cardiovascular disease (CVD),[1] the leading cause of death worldwide.[2] LDL-C is identified as the primary target of cholesterol-lowering therapy by North American[3,4] and European[5] guidelines. Statins are the recommended first-line therapy for lowering LDL-C. Despite LDL-C-lowering therapies, there are still many patients who cannot achieve a LDL-C level low enough to optimally prevent primary or recurrent cardiovascular (CV) events.[6] In addition, there is currently a greater recognition of the prevalence of heterozygous familial hypercholesterolemia as the most common genetic disorder in humans, and new data suggest an actual occurrence of approximately 1:200, suggesting a US adult population of 1 million and worldwide estimates of 14–34 million.[7] There is a need for additional lipid-lowering therapies (LLT) that can be used with a statin or instead of a statin for those who cannot tolerate statin therapy at any dose.[8]

PCSK9 was first reported to have a significant role in the regulation of LDL-C in 2003.[9,10] LDL receptors (LDLr) typically bind an LDL particle, become internalized and then return to the cell surface after releasing the LDL particle to a lysosome for degradation. This LDLr recycling is estimated to occur over 100 times per LDLr.[11] PCSK9 binds to the LDLr and prevents LDLr recycling by preventing release of the LDL particle, causing degradation of both the LDL particle and LDLr. Inhibiting PCSK9 causes increased LDLr numbers because of increased recycling and decreased destruction, with a resultant decrease in LDL-C. Several monoclonal antibodies (mAbs) to PCSK9 have now entered Phase III testing and promising Phase I and II results have been reported.[12]

Alirocumab (formerly SAR236553/REGN727) is a fully human mAb to PCSK9 being developed jointly by Sanofi (France) and Regeneron (NY, USA). Phase I and II studies have been completed and previously described.[13–16] The Phase II studies utilized 150 mg of alirocumab as the most common dose and provided limited data in patients not receiving statin therapy. Computer modeling based on Phase II data suggested that a 75-mg dose of alirocumab subcutaneously (sc.) every 2 weeks (Q2W) should yield an approximate 50% reduction in LDL-C as a monotherapy.[17] The first completed Phase III study, entitled ODYSSEY MONO, tested the new lower 75-mg dose of alirocumab sc. Q2W as a monotherapy versus ezetimibe 10 mg per os (po.) every day (q.d.) as a control.[18]