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
PCSK9
El aclaramiento del cldl requiere del reciclado del receptor LDL 1. Brown MS, et al. Proc Natl Acad Sci U S A. 1979;76:3330-3337. 2. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547. 3. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438.
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;48:1488-1498. 2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177. 3. Zhang DW, et al. J Biol Chem. 2007;282:18602-18612.
Inhibición de PCSK9
Inhibidores de PCSK9 en desarrollo
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;106:9820-9825.
SAR 236/Alirocumab
Free/Total PCSK9 Conc. (ng/ml) Total REGN727 (ng/ml) X 0.01 LDL--C mean % change PCSK9-041812000 Alirocumab: Dynamic Relationship Between mab Levels, PCSK9 and LDL-C Free PCSK9, Total Alirocumab Concentration and Mean % Change LDL-C vs Time 200 0 180 160 140-10 -20 120-30 100 80-40 60 40 20-50 -60 0 0 500 1000 1500 2000 2500 Time (hours) Total REGN727/SAR236553 free PCSK9 LDL-c -70 CONFIDENTIAL NOT FOR PROMOTIONAL USE DO NOT COPY OR DISTRIBUTE
(SAR 236/Alirocumab)
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 -66.1-56.4-33.7 8 <1 MENDEL2 Monotherapy -47.2-44.2-29.3-12.0 10 11 LAPLACE-TIMI 571 On statin w/ or w/o ezetimibe -50.3-42.0-19.4 5 4 420 mg Q4W RUTHERFORD3 Heterozygous FH -56.4-46.2-31.5-19.9 7 2 MENDEL2 Monotherapy -52.5-42.5-29.2-3.3 6 5 GAUSS4 Statin intolerance -50.7-42.1-23.6-14.2 9 9 Data expressed as % change vs placebo (except reference 4: % change vs baseline) 1. Giugliano RP et al. Lancet 2012; 380: 2007 17; 2. Koren MJ et al. Lancet 2012; 380: 1995 2006; 3. Raal F et al. Circulation 2012; 126: 2408 17; 4. Sullivan D et al. JAMA 2012; 308: 2497 506.
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) 471 18 496 100 250 18 250,5 100 105 18 106,5 160 306 12 210 70 660 24 960 70 350 6 50 70 300 6 50 70 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-2 300 3 46 100 SPIRE-HF 300 12 200 70 LAPLACE-2 1700 3 231 80 100 6 25.5 100 MENDEL-2 600 3 92 100 250 6 50 70 2100 18 2340 70 GAUSS-2 300 3 46 None GAUSS-3 500 3 NA NA DESCARTES 905 12 602 75 OSLER Open label 3515 12+ TBD TBD Minimum LDL-C Levels (mg/dl) SPIRE-HR 600 18 600 70 SPIRE-LDL 1600 18 1600 70 PLANNED SPIRE-LL 939 12 626 >100 Total Number of Patients 4892 4538 patient-years In double-blind placebo controlled trials Total Number of Patients 7820 1017 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 18000 Event Driven N/A 70 FOURIER 22500 Event Driven N/A 70 SPIRE-1 12000 SPIRE-2 6300 Event Driven Event Driven N/A 70 & <100 N/A >100 ClinicalTrials.gov. available at: http://clinicaltrials.gov. Accessed May 20, 2014. 12
PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial
Combo II
Combo II
Combo II
Combo II
Alternative
Alternative
Long Term
Long Term
Long Term
Long Term
Long Term
Long Term
Long Term
Long Term
Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B):a randomised, double-blind, placebo-controlled trial
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) 471 18 496 100 250 18 250,5 100 105 18 106,5 160 306 12 210 70 660 24 960 70 350 6 50 70 300 6 50 70 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-2 300 3 46 100 SPIRE-HF 300 12 200 70 LAPLACE-2 1700 3 231 80 100 6 25.5 100 MENDEL-2 600 3 92 100 250 6 50 70 2100 18 2340 70 GAUSS-2 300 3 46 None GAUSS-3 500 3 NA NA DESCARTES 905 12 602 75 OSLER Open label 3515 12+ TBD TBD Minimum LDL-C Levels (mg/dl) SPIRE-HR 600 18 600 70 SPIRE-LDL 1600 18 1600 70 PLANNED SPIRE-LL 939 12 626 >100 Total Number of Patients 4892 4538 patient-years In double-blind placebo controlled trials Total Number of Patients 7820 1017 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 18000 Event Driven N/A 70 FOURIER 22500 Event Driven N/A 70 SPIRE-1 12000 SPIRE-2 6300 Event Driven Event Driven N/A 70 & <100 N/A >100 ClinicalTrials.gov. available at: http://clinicaltrials.gov. Accessed May 20, 2014. 53
PCSK9