El tratamiento de la hipercolesterolemia desde la perspectiva de una nueva familia de agentes hipolipemiantes anti-pcsk9

Transcripción

1 12 Curso de Lipidología y Factores de Riesgo Cardiovascular FIPEC, Barcelona 27 de noviembre de 2014 Nuevos horizontes en el control de la hipercolesterolemia: El tratamiento de la hipercolesterolemia desde la perspectiva de una nueva familia de agentes hipolipemiantes anti-pcsk9 Fernando Civeira Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis Hospital Universitario Miguel Servet, Zaragoza

2 PCSK9

3 El aclaramiento del cldl requiere del reciclado del receptor LDL 1. Brown MS, et al. Proc Natl Acad Sci U S A. 1979;76: Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106: Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:

4 PCSK9 controla la expresión del receptor LDL en la superficie de hepatocito a través de la degradación lisosomal 1. Qian YW, et al. J Lipid Res. 2007;48: Horton JD, et al. J Lipid Res. 2009;50:S172-S Zhang DW, et al. J Biol Chem. 2007;282:

5 Inhibición de PCSK9

6 Inhibidores de PCSK9 en desarrollo

7 Bloquear la interacción receptor LDL y PCSK9 podría disminuir el cldl 1. Chan JC, Piper DE, Cao Q, et al. Proc Natl Acad Sci U.S A. 2009;106:

8 SAR 236/Alirocumab

9 Free/Total PCSK9 Conc. (ng/ml) Total REGN727 (ng/ml) X 0.01 LDL--C mean % change PCSK Alirocumab: Dynamic Relationship Between mab Levels, PCSK9 and LDL-C Free PCSK9, Total Alirocumab Concentration and Mean % Change LDL-C vs Time Time (hours) Total REGN727/SAR free PCSK9 LDL-c -70 CONFIDENTIAL NOT FOR PROMOTIONAL USE DO NOT COPY OR DISTRIBUTE

10 (SAR 236/Alirocumab)

11 Efficacy of evolocumab (AMG 145): 140 mg every 2 weeks and 420 mg every 4 weeks (phase 2 trials) Dose Trial Patient population LDL-C (%) ApoB (%) Lp(a) (%) TG (%) HDL-C (%) ApoA1 (%) 140 mg Q2W LAPLACE-TIMI 571 On statin w/ or w/o ezetimibe <1 MENDEL2 Monotherapy LAPLACE-TIMI 571 On statin w/ or w/o ezetimibe mg Q4W RUTHERFORD3 Heterozygous FH MENDEL2 Monotherapy GAUSS4 Statin intolerance Data expressed as % change vs placebo (except reference 4: % change vs baseline) 1. Giugliano RP et al. Lancet 2012; 380: ; 2. Koren MJ et al. Lancet 2012; 380: ; 3. Raal F et al. Circulation 2012; 126: ; 4. Sullivan D et al. JAMA 2012; 308:

12 Ensayos fase 3: Alirocumab, Evolocumab, Bococizumab Trial Type HeFH Combo Therapy Monotherapy Statin Intolerance LTS Alirocumab Double- Blinded Trials ODYSSEY FH I ODYSSEY FH II ODYSSEY HIGH FH ODYSSEY COMBO I ODYSSEY COMBO II ODYSSEY OPTIONS I ODYSSEY OPTIONS II ODYSSEY MONO ODYSSEY ALTERNATIVE ODYSSEY LONG-TERM N Duration (Mos) Patient Exposure (Yrs) Minimum LDL-C Levels (mg/dl) , , Evolocumab Double-Blinded Trials N Duration (Mos) Patient Exposure (Yrs) Minimum LDL-C Levels (mg/dl) Bococizumab Double-Blinded Trials N Duration (Mos) Patient Exposure (Yrs) RUTHERFORD SPIRE-HF LAPLACE MENDEL GAUSS None GAUSS NA NA DESCARTES OSLER Open label TBD TBD Minimum LDL-C Levels (mg/dl) SPIRE-HR SPIRE-LDL PLANNED SPIRE-LL >100 Total Number of Patients patient-years In double-blind placebo controlled trials Total Number of Patients patient-years In double-blind placebo controlled trials Total Number of Patients 3439 ~3000 patient-years (assumes 2:1 randomization, final number likely to be larger as anticipate additional trials) CVD Outcomes Trials ODYSSEY OUTCOMES Event Driven N/A 70 FOURIER Event Driven N/A 70 SPIRE SPIRE Event Driven Event Driven N/A 70 & <100 N/A >100 ClinicalTrials.gov. available at: Accessed May 20,

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21 PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial

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28 Combo II

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47 Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B):a randomised, double-blind, placebo-controlled trial

48 Ensayos fase 3: Alirocumab, Evolocumab, Bococizumab Trial Type HeFH Combo Therapy Monotherapy Statin Intolerance LTS Alirocumab Double- Blinded Trials ODYSSEY FH I ODYSSEY FH II ODYSSEY HIGH FH ODYSSEY COMBO I ODYSSEY COMBO II ODYSSEY OPTIONS I ODYSSEY OPTIONS II ODYSSEY MONO ODYSSEY ALTERNATIVE ODYSSEY LONG-TERM N Duration (Mos) Patient Exposure (Yrs) Minimum LDL-C Levels (mg/dl) , , Evolocumab Double-Blinded Trials N Duration (Mos) Patient Exposure (Yrs) Minimum LDL-C Levels (mg/dl) Bococizumab Double-Blinded Trials N Duration (Mos) Patient Exposure (Yrs) RUTHERFORD SPIRE-HF LAPLACE MENDEL GAUSS None GAUSS NA NA DESCARTES OSLER Open label TBD TBD Minimum LDL-C Levels (mg/dl) SPIRE-HR SPIRE-LDL PLANNED SPIRE-LL >100 Total Number of Patients patient-years In double-blind placebo controlled trials Total Number of Patients patient-years In double-blind placebo controlled trials Total Number of Patients 3439 ~3000 patient-years (assumes 2:1 randomization, final number likely to be larger as anticipate additional trials) CVD Outcomes Trials ODYSSEY OUTCOMES Event Driven N/A 70 FOURIER Event Driven N/A 70 SPIRE SPIRE Event Driven Event Driven N/A 70 & <100 N/A >100 ClinicalTrials.gov. available at: Accessed May 20,

49 PCSK9