Relationship Between Low‐Density Lipoprotein Cholesterol, Free Proprotein Convertase Subtilisin/Kexin Type 9, and Alirocumab Levels After Different Lipid‐Lowering Strategies

Abstract

BackgroundAlirocumab undergoes target‐mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (PCSK9). Statins increase PCSK9 levels; the effects of nonstatin lipid‐lowering therapies are unclear. Every‐4‐weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved.Methods and ResultsLow‐density lipoprotein cholesterol (LDL‐C), PCSK9, and alirocumab levels were assessed in subjects (LDL‐C >130 mg/dL, n=24/group) after a 4‐week run‐in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean LDL‐C reductions from day −1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%. LDL‐C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free PCSK9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free PCSK9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo.ConclusionsAlirocumab 150 mg every 4 weeks produced maximal LDL‐C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid‐lowering therapies appear to increase PCSK9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid‐lowering therapies concomitantly.Clinical Trial Registration URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735.

Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study

“…In line with previous studies,17, 18 alirocumab 150Q4W (and 75Q2W) led to a rapid and robust reduction in mean free PCSK9 levels, which persisted for at least 3 weeks (as shown between weeks 9 and 11) following alirocumab 150Q4W administration. With administration of alirocumab 75Q2W, mean free PCSK9 levels remained below 25% of baseline levels throughout the 4‐week period.…”

“…Alirocumab 150 mg Q4W monotherapy demonstrated a 47.4% reduction in LDL‐C levels from baseline in a phase 1 study 17. However, in an early phase 2 study of patients with heterozygous familial hypercholesterolemia on statin, there was only an incremental LDL‐C reduction of 28.9% at week 12 with alirocumab 150 Q4W 18.…”

Efficacy of alirocumab according to background statin type and dose: pooled analysis of 8 ODYSSEY Phase 3 clinical trials

“…Background statin seems to have more of an impact on alirocumab efficacy when longer dosing intervals are used (every 4 weeks [Q4W] vs Q2W). Phase 2 studies indicated that efficacy was not fully maintained over the dosing interval when alirocumab 150 mg Q4W was co-administered with a statin2122, probably because of statin-induced increases in PCSK9 levels leading to increased alirocumab clearance19. However, efficacy was stable with the 150 mg Q2W dose when co-administered with a statin2122, and has also been shown to be relatively stable with a dose of 300 mg Q4W23.…”

“…Therefore, higher PCSK9 concentrations through increased PCSK9 production are thought to increase the clearance of alirocumab19. Statin therapy increases circulating levels of PCSK9 through the statin-mediated activation of the transcription factor sterol regulatory element-binding protein-2, which leads not only to increased expression of the LDLR gene but also of the PCSK9 gene920.…”

“…Statin therapy increases circulating levels of PCSK9 through the statin-mediated activation of the transcription factor sterol regulatory element-binding protein-2, which leads not only to increased expression of the LDLR gene but also of the PCSK9 gene920. The efficacy of monoclonal antibodies to PCSK9 could therefore potentially be impacted by higher versus lower statin doses due to increased PCSK9 levels and target-mediated clearance19. We investigated whether LDL-C reductions following alirocumab treatment were affected by background statin dose and type of statin, using pooled data from the ODYSSEY clinical trials programme which was mainly conducted on a background of maximally tolerated statin.…”