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



Low-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.



Alirocumab 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.



URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735.
Sanofi, Paris, France.
Jacques
J
Rey
Sanofi, Paris, France franck.poitiers@sanofi.com.
Franck
F
Poitiers
Sanofi, Frankfurt, Germany.
Tobias
T
Paehler
Sanofi, Montpellier, France.
Aurélie
A
Brunet
Regeneron Pharmaceuticals, Inc, Tarrytown, NY.
A Thomas
AT
DiCioccio
Harvard Clinical Research Institute, Boston, MA.
Christopher P
CP
Cannon
Sanofi, Bridgewater, NJ.
Howard K
HK
Surks
Sanofi, Paris, France.
Jean-Louis
JL
Pinquier
Sanofi, Paris, France.
Corinne
C
Hanotin
Regeneron Pharmaceuticals, Inc, Tarrytown, NY.
William J
WJ
Sasiela
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000378:metabolism*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000069438:Ezetimibe / Q000008:administration & dosage; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9 / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D000069438:Ezetimibe; C571059:alirocumab; D011345:Fenofibrate
cholesterol; hypercholesterolemia; lipids; pharmacokinetics