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Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses
Journal article   Open access   Peer reviewed

Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses

Jennifer G. Robinson, Michel Farnier, John J.P. Kastelein, Eli M. Roth, Marja-Riitta Taskinen, Helen M. Colhoun, Aurelie Brunet, A. Thomas DiCioccio, Guillaume Lecorps, Robert Pordy, …
Journal of clinical lipidology, Vol.13(6), pp.979-988.e10
11/2019
DOI: 10.1016/j.jacl.2019.10.004
PMID: 31708410
url
https://doi.org/10.1016/j.jacl.2019.10.004View
Published (Version of record) Open Access

Abstract

Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150 mg Q2W. Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production. [Display omitted] •Changes in proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein cholesterol (LDL-C) assessed after administration of alirocumab 75 or 150 mg every 2 weeks.•Patients on background statin had higher baseline levels of PCSK9 vs no statin.•Alirocumab resulted in reduced PCSK9 with corresponding LDL-C reduction by week 4.•Dose increase from 75 to 150 mg every 2 weeks further reduced PCSK9 and LDL-C.•Results were consistent with the known mechanism of PCSK9 inhibition.
 Cardiovascular Clinical trial Low-density lipoprotein cholesterol Monoclonal antibody PCSK9 Pharmacokinetic

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