Jennifer G Robinson1, Michel Farnier2, John J P Kastelein3, Eli M Roth4, Marja-Riitta Taskinen5, Helen M Colhoun6, Aurelie Brunet7, A Thomas DiCioccio8, Guillaume Lecorps9, Robert Pordy8, Marie T Baccara-Dinet7, Christopher P Cannon10. 1. University of Iowa, Iowa City, IA, USA. Electronic address: jennifer-g-robinson@uiowa.edu. 2. Lipid Clinic, Point Médical and Department of Cardiology, CHU Dijon-Bourgogne, Dijon, France. 3. Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. 4. The Sterling Research Group, Cincinnati, OH, USA. 5. Research Program Unit, Clinical and Molecular Metabolism, University of Helsinki, Finland. 6. University of Edinburgh, Edinburgh, UK. 7. Sanofi, Clinical Development, R&D, Montpellier, France. 8. Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA. 9. Sanofi, Chilly-Mazarin, France. 10. Harvard Clinical Research Institute, Boston, MA, USA.
Abstract
BACKGROUND: Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND:Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: 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). METHODS: 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. RESULTS: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. CONCLUSIONS: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.
Authors: Arianna Toscano; Maria Cinquegrani; Michele Scuruchi; Antonino Di Pino; Salvatore Piro; Viviana Ferrara; Carmela Morace; Alberto Lo Gullo; Egidio Imbalzano; Francesco Purrello; Giovanni Squadrito; Roberto Scicali; Giuseppe Mandraffino Journal: Biomolecules Date: 2022-04-09
Authors: Stephen J Nicholls; Steven E Nissen; Francesco Prati; Stephan Windecker; Yu Kataoka; Rishi Puri; Thomas Hucko; Helina Kassahun; Jason Liao; Ransi Somaratne; Julie Butters; Giuseppe Di Giovanni; Stephen Jones; Peter J Psaltis Journal: Cardiovasc Diagn Ther Date: 2021-02
Authors: Carlota Oleaga; Michael D Shapiro; Joshua Hay; Paul A Mueller; Joshua Miles; Cecilia Huang; Emily Friz; Hagai Tavori; Peter P Toth; Cezary Wójcik; Bruce A Warden; Jonathan Q Purnell; P Barton Duell; Nathalie Pamir; Sergio Fazio Journal: J Am Coll Cardiol Date: 2021-10-05 Impact factor: 24.094