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


This was the first study with alirocumab at the 75-mg dose sc. Q2W utilizing self-injection in a population not receiving statin background therapy and also utilizing an uptitration scheme based on LDL-C response. The results demonstrate alirocumab resulted in a highly effective reduction in LDL-C of approximately 50%, as projected from Phase II study results, and also resulted in 70% (32/46) of patients achieving a LDL-C of <70 mg/dl (<1.8 mmol/l) at week 12 from a baseline LDL-C of 141 mg/dl (3.6 mmol/l; 46 patients had a week-12 visit in the study). Furthermore, the study demonstrated that the difference between alirocumab and ezetimibe in lowering LDL-C (47.2 vs 15.6%, respectively, after 24 weeks of treatment in the ITT evaluation) is highly significantly different (p < 0.0001). There were no meaningful differences between alirocumab and ezetimibe in terms of safety parameters. Numerically, more patients receiving alirocumab experienced nasopharyngitis and diarrhea and more had glucose levels above 126 mg/dl (>7 mmol/l) than in those receiving ezetimibe. Again, there was no pattern of change in glucose or HbA1c from screening to week 24 as previously described in the safety section. Ongoing Phase III ODYSSEY studies with much larger numbers of patients will help further document the safety of alirocumab.

The group receiving an uptitration of alirocumab to 150 mg sc. Q2W had higher LDL-C baseline levels, as may be expected. Alirocumab levels rose to approximately double the blood concentration and PCSK9 levels declined further. However, LS mean LDL-C levels at week 24 were not appreciably different between the uptitrated and non-uptitrated alirocumab groups. This may have been because the suppression in PCSK9 was already substantial when the dose was increased but some (albeit small) additional reduction would have been expected. In the Phase II dose-ranging study, 100 mg sc. Q2W and 150 mg sc. Q2W resulted in LS mean LDL-C reductions of 64 and 72%, respectively, after 12 weeks of treatment.[14] However, the dose-ranging study was conducted on the background of statin therapy, which is known to increase PCSK9 levels by 35–45%, and this may accentuate the LDL-C lowering achieved when the PCSK9 mAb is administered.[21] A doubling of the PCSK9 mAb dose is an approach to enhancing the duration of the LDL-C lowering, especially in patients receiving no background lipid-modifying therapy, as more mAbs would be available to neutralize newly synthesized PCSK9. Based on this consideration, once-monthly administration of the 150-mg alirocumab dose is currently being tested in the ODYSSEY CHOICE II study.