ODYSSEY ALTERNATIVE: Efficacy And Safety of the Proprotein Convertase Subtilisin/kexin Type 9 Monoclonal Antibody, Alirocumab, versus Ezetimibe, in Patients With Statin Intolerance as Defined by a Placebo Run-in and Statin Rechallenge Arm

Presented at the AHA congress 2014 by:  Patrick M Moriarty (Univ of Kansas Medical Ctr, Kansas City, KS)

Background

In patients who cannot tolerate statins, it is a challenge to reach LDL-c targets. These patients therefore have a high cardiovascular (CV) risk. 10-25% of patients in clinical practice report statin intolerance (SI), often with myalgia as the main reason. A majority (63.2%) of patient with previous SI does, however, tolerate statins at a next attempt.
Alirocumab is a monoclonal antibody directed against PCSK9, of which earlier studies of the ODYSSEY trial programme have shown that it lowers LDL-c levels.
Large, well-conducted randomised studies of cholesterol-lowering agents in statin-intolerant patients are lacking. The ODYSSEY ALTERNATIVE therefore randomised statin-intolerant patients with LDL-c>70 mg/dL (at very high CV risk) or >100 mg/dL (at moderate/high risk) to a SC injection with alirocumab 75/150 mg Q2W plus placebo PO QD, or to ezetimibe 10 mg plus placebo SC Q2W or atorvastatin 20 mg PO QD plus placebo SC Q2W. Patients were treated doubleblindly for 24 weeks, after a 4-week run-in period with placebo PO QD plus placebo SC Q2W in which patients who reported muscle-related symptoms discontinued. Depending on CV risk, dose of alirocumab was increased if LDL-c in week 8 was higher than 70 or 100 mg/dL.

Main results

• In comparison with ezetimibe, alirocumab lowered LDL-c levels significantly between baseline and week 24 (intention to treat: -45.0% (absolute change: -84+4.1 mg/dL)  vs. -14.6% (-33+4.2 mg/dL), P<0.0001), on-treatment: -52.2% (-96+3.9 mg/dL) vs. -17.1% (-38+4.2 mg/dL), P<0.0001). 

• The LDL-c reduction reached with alirocumab was stable between week 4 and 24. Both in week 12 and in 2eek 24 the difference in LDL-c levels as compared with ezetimibe-treated patients was 58 mg/dL.

• Significantly more statin-intolerant patients reached LDL-c targets with alirocumab, as compared with ezetimibe at a target of <70 mg/dL at very high risk or <100 mg/dL  at moderate/high risk (42% vs. 4%, P<0.0001), or at a general target of LDL-c < 100 mg/dL (61% vs. 10%, P<0.0001).

• Also other lipid parameters (non-HDL-c, ApoB, Lp(a)) were significantly reduced with alirocumab as compared with ezetimibe, both in the intention-to-treat and in the on-treatment analysis.

• The number of treatment-emergent side effects (among which serious ones) did not differ significantly between treatment groups. A Kaplan-Meier estimate on the time to first muscle-related event showed that alirocumab gave significantly fewer muscle-related side effects than treatment with atorvastatin (ATV vs. ALI: HR: 1.63, 95%CI: 1.02-2.62, P=0.042).

Conclusion

In a population of statin-intolerant patients with very high baseline LDL-c levels (~190 mg/dL) self-injection of alirocumab gave significantly larger LDL-c reductions than ezetimibe. 50% of patients did not need dose uptitration to 150 mg Q2W in week 12. 42% of patients randomised to alirocumab reached their LDL-c target in week 24.
Alirocumab was better tolerated in this study than atorvastatin: fewer people had muscle-related side-effects.