PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9) : PASADO, PRESENTE Y FUTURO

PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9) : PASADO, PRESENTE Y FUTURO

PCSK9: GENÉTICA Y ESTRUCTURA MOLECULAR Serin-proteasa Gen 3617 pb en 1p32.3 Expresión abundante higado, riñon, GI, sistema nervioso Secuencia señalización. pro-dominio, dominio catalítico y un dominio C-terminal

PCSK9: IMPORTANCIA CLÍNICA Y MUTACIONES Primera mutación: Francia. Año 20031. HAD Ganancia función = Hipercol. Familiar LDL-c RCV Responsables 10-25 % HCF sin mutaciones LDL-R o APO-B 2 1. Abifadel M et al. Nat Genet 2003;34:154 156 2..Allard D et al. Hum Mutat 2005;26:497.

PCSK9: PÉRDIDA DE FUNCIÓN I LDL-c Dallas Heart Study. Cohen et al. Nat Genet 2005;37:161 165. Mutaciones sin sentido gen PCSK9 28 % niveles LDL-c vs población general Atherosclerosis Risk In Communities study. Cohen et al. N Engl J Med 2006;354: 1264 1272 Pérdida función ½ genes PCSK9 15-28 % LDL-c Pérdida función heterocigota eventos CV. HR para EAC a 15 años: 0.5 (IC95 % 0.32-0.79) para caucásicos y 0.11 (IC95 % 0.02-0.81) para afroamericanos

PCSK9: LDL-C Y EVENTOS. AFROAMERICANOS Cohen et al. N Engl J Med 2006;354: 1264 1272

PCSK9: LDL-C Y EVENTOS. CAUCÁSICOS Cohen et al. N Engl J Med 2006;354: 1264 1272

PCSK9: PÉRDIDA DE FUNCIÓN II Copenhagen Heart Study. Benn M et al J Am Coll Cardiol 2010;55:2833 2842 Estudio en Zimbabwe. Hooper AJ et al. Atherosclerosis 2007;193:445 448. riesgo EAC 6-46 % tras reducción LDL-c 11-15 % por mutación gen PCSK9 Mutación PCSK9 27 % LDL-c en mujeres africanas Heterocigosis PCSK9 riesgo arteriopatía periférica y menor grosor intima-media carotidea Mutaciones sin sentido en ambos genes [LDL-c] = 14-16 mg/dl

PCSK9: INHIBIDORES Anticuerpos monoclonales Pequeños ARN de interferencia (sirna) Oligonucleotidos antisentido (ASOs)

INHIBIDORES PCSK9: ANTICUERPOS MONOCLONALES Método más común de inhibición. Descubrimiento en 20091 Se unen a la región de interacción LDL-R PCSK9 inhibiendola Descensos de LDL-c. 20-50 % https://www.praluenthcp.com/mechanism-of-action 1. Chan JC et al. Proc Natl Acad Sci USA 2009;106:9820 9825.

NHIBIDORES PCSK9: ARN DE INTERFERENCIA ARN de cadena simple que se una al ARNm del PCSK9 Admon. IV en nanopartículas lipídicas Modelos murinos: silenciamiento de más de la mitad ARNm LDL-c 30 %1 Estudio fase 1 en voluntarios sanos2 70 % PCSK9 circulante 40 % LDL-c 1. Frank-Kamenetsky M. Proc Natl Acad Sci USA 2008;105:11915 11920. 2. Fitzgerald K wt al. Lancet 2014;383:60 68.

INHIBIDORES PCSK9: OLIGONUCLEÓTIDOS ANTISENTIDO Nucleótido corto que se une al RNAm Estudios en animales1,2 Reducciones de: RNAm 92 % [PCSK9] 85 % [LDL-c] 32 % - 50 % Un solo estudio en fase 1 (molécula SPC5001) terminado prematuramente por motivos desconocidos (un caso relacionado con IRA grave3) Goldberg AC. J Clin Lipidol 2010;4:350-356. 1. Gupta et al. PLoS ONE.2010;5:e10682 2. Grraham MJ et al. J Lipid Res 2007;48:763 767. 3. Van Poelgeest EP et al. Am J Kidney Dis. 2013 Oct;62(4):796-800.

PCSK9: MECANISMO DE ACTUACIÓN Shimada et al. European Heart Journal (2015) 36, 2415 2424

INHIBIDORES PCSK9: MECANISMO DE ACCIÓN Shimada et al. European Heart Journal (2015) 36, 2415 2424

INHIBIDORES PCSK9: FARMACOCINÉTICA Y FARMACODINÁMICA Yuichi J. Shimada, and Christopher P. Cannon Eur Heart J 2015;36:2415-2424

ALIROCUMAB: ESTUDIOS Trial name PCSK9 inhibitor Population and study design Number of Study duration patients ODYSSEY Mono Alirocumab Patients with hypercholesterolaemia on no statins, compared with ezetimibe 103 24 weeks 31.6 ODYSSEY COMBO I Alirocumab Hypercholesterolaemia not adequately controlled (with maximum dose of a statin with or without other lipid-modifying therapy), and high CVD risk 311 24 weeks 45.9 ODYSSEY COMBO II Alirocumab Hypercholesterolaemia not adequately controlled (maximum dose of a statin with or without other lipid-modifying therapy), and high CVD risk 707 24 weeks 29.7 ODYSSEY Alirocumab Hypercholesterolaemia not LONG TERM adequately controlled with current lipid-modifying therapy, and high CVD risk 2341 24 weeks 61.9 Shimada et al. European Heart Journal (2015) 36, 2415 2424 LDL-C

PCSK9: 0DDYSEY MONO Patients with hypercholesterolaemia on no statins, compared with ezetimibe Roth EM et al. Int J Cardiol. 2014 Sep;176(1):55-61 103 pacientes con hipercol. Alirocumab vs ezetimiba 24 semanas

ODDYSEY COMBO I Hypercholesterolaemia not adequately controlled (with maximum dose of a statin with or without other lipid-modifying therapy), and high CVD risk LDL-C values achieved vs. study time-points (ITT analysis). Percentages above Weeks 12 and 24 data points indicate LS mean (SE) percent change from baseline. Values above Weeks 24 and 52 indicate achieved LDL-C Eur Heart J. 2015 May 14; 36(19): 1186 1194.

EVOLOCUMAB: ESTUDIOS Trial name PCSK9 inhibitor Population and study design Number of patients Study duration LDL-C DESCARTES Evolocumab Patients with hyperlipidaemia 420 mg Q4W added to diet alone or to diet plus atorvastatin or to diet plus atorvastatin plus ezetimibe 901 52 weeks 57.0 LAPLACE-2 Evolocumab Patients with hypercholesterolaemia, 140 mg Q2W or 420 mg Q4W added to moderate- or high-intensity statin therapy, compared with ezetimibe or placebo 2067 12 weeks 59.2, 70.6 Evolocumab Patients with statin intolerance, 140 mg Q2W or 420 mg Q4W compared with ezetimibe 307 12 weeks 68.8, 69.7 MENDEL-2 Evolocumab Patients with hypercholesterolaemia on no statins, 140 mg Q2W or 420 mg Q4W compared with ezetimibe 614 12 weeks 54.8, 57.1 RUTHERFORD-2 Evolocumab Patients with hefh, 140 mg Q2W or 420 mg Q4W 329 12 weeks 59.2, 61.3 OSLER-2 Evolocumab Hypercholesterolaemia or mixed dyslipidaemia; completion of previous evolocumab study (no specification regarding statin therapy) 4465 12 weeks 61 49 12 weeks 30.9 GAUSS-2 TESLA Part B Evolocumab Patients with hofh, not on apheresis, 420 mg Q4W Shimada et al. European Heart Journal (2015) 36, 2415 2424

ESTUDIO DESCARTES A 52-week placebo-controlled trial of evolocumab in hyperlipidemia Population and study design Patients with hyperlipidaemia 420 mg Q4W added to diet alone or to diet plus atorvastatin or to diet plus atorvastatin plus ezetimibe Number of patients 901 Study duration 52 weeks Percent Reduction from Baseline in Low-Density Lipoprotein (LDL) Cholesterol Levels in the Evolocumab Group, as Compared with the Placebo Group, at Weeks 12 and 52, According to Background Lipid-Lowering Therapy. Bloom DJ et al. N Engl J Med. 2014 May 8;370(19):1809-19.

PCSK9: HIPERCOLESTEROLEMIA FAMILIAR. ESTUDIO TESLA PARTE B Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, doubleblind, placebo-controlled trial. Population and study design Patients with hofh, not on apheresis, 420 mg Q4W Number of patients 49 Study duration 12 weeks Mean percentage change in ultracentrifugation LDL cholesterol concentration from baseline to week 12 Raal FJ et al. Lancet. 2015 Jan 24;385(9965):341-50.

PCSK9. EFECTO DOSIS DEPENDIENTE Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. Change in Calculated LDL-C From Baseline to Week 12 by Stratified Atorvastatin Dose McKenney JM et al. J Am Coll Cardiol. 2012 Jun 19;59(25):2344-53

ESTUDIO LAPLACE-2 Cambio porcentual medio de LDL-c respecto al basal. Semanas 10 y 12 Effect of Evolocumab or Ezetimibe Added to Moderate- or High-Intensity Statin Therapy on LDL-C Lowering in Patients With HypercholesterolemiaThe LAPLACE2 Randomized Clinical Trial Atorva 80 Rosu 40 Atorva 10 Rosu 5 Simva 40 Population and study design 20 Patients with hypercholesterolaemia, 140 mg Q2W or 420 mg Q4W added to moderate- or high-intensity statin therapy, compared with ezetimibe or placebo Number of patients 10 0-10 -20-30 2067-40 -50 Study duration -60 12 weeks -70-80 Placebo cada 2 sem. Placebo mensual Evolocumab cada 2 sem Evolocumab mensual Yuichi J. Shimada, and Christopher P. Cannon Eur Heart J 2015;36:2415-2424 Robinson JG et al. JAMA. 2014 May 14;311(18):1870-82

PCSK9. INTERVALO POSOLÓGICO Change in low-density lipoprotein cholesterol with different alirocumab concentrations and intervals from baseline to week 12 (figure modified from McKenney et al. J Am Coll Cardiol 2012;59: 2344 2353) Yuichi J. Shimada, and Christopher P. Cannon Eur Heart J 2015;36:2415-2424

PCSK9. SEGURIDAD 36-75 % pacientes eventos adversos 2-6 % EA serios 2-10 % EA causaron discontinuación Elevación ALT/AST o CPK > 3 LSN en < 2 % No efectos relevantes de anticuerpos neutralizantes de los ipcsk9 Bloom DJ et al. N Engl J Med. 2014 May 8;370(19):1809-19 Robinson JG et al. JAMA. 2014 May 14;311(18):1870-8 Roth EM et al. Int J Cardiol 2014;176:55 61.

PCSK9. TOLERANCIA ODYSSEY MONO OSLER 1/52 pacs. reacción local a la inyección (vs 2/51 placebo) a las 24 semanas 1/38 pcs que experimentaron reacción local abandonaron el tratamiento DESCARTES 34/599 (5,7 %) reacción local (vs 15/302 (5,0 %) placebo) Solo 1 paciente abandonó el tratamiento ODDYSEY COMBO II 85 % pacs. continuaban con el tto. (o el placebo) al año.

PCSK9. POBLACIONES OBJETIVO Hipercolesterolemia Familiar1 80 % pacs. con HF no logran LDL-c < 100 mg/dl con ttos. convencionales2 Pacientes que no pueden alcanzar niveles objetivo de LDL-c a pesar de estatinas a altas dosis Intolerantes a estatinas 12 % pacientes tienen que interrumpir a estatinas 62 % abandonos : efectos adversos3. 1. Robinson JG et al. J Manag Care Pharm 2013;19:139 149. 2 Pijlman AH et al. Atherosclerosis 2010;209:189 194 3. Toth PP Expert Rev Cardiovasc Ther 2008;6:955 969

PCSK9. ESTUDIOS EN MARCHA Name of study Monoclonal antibody GLAGOV Evolocumab Coronary heart disease; clinical indication for coronary catheterization; and LDL-C level 80 mg/dl or, with additional risk factors, 60 and <80 mg/dl (no specification regarding statin therapy) FOURIER Evolocumab Clinical CVD, high risk of recurrent CVD event, To assess the effect of evolocumab and LDL-C level 70 mg/dl or non-hdl-c 100 every 2 or 4 weeks plus a statin vs. mg/dl (no specification regarding statin placebo plus a statin on major CVD therapy) events (CVD death, nonfatal myocardial infarction, unstable angina requiring hospitalization, stroke, or coronary revascularization), at 5 years TAUSSIG Evolocumab Homozygous FH or PCSK9 mutations; LDL-C level above ATP III target or receiving apheresis; and completion of previous evolocumab study (no specification regarding statin therapy) To assess the long-term safety and efficacy of evolocumab every 2 or 4 weeks on LDL-C level in patients with severe FH, at 5 years Alirocumab Recent (in the past 4 16 weeks) acute coronary syndrome event requiring hospitalization To compare the effect of alirocumab vs. placebo on CVD events (cardiovascular death, nonfatal myocardial infarction, fatal and non-fatal ischaemic stroke, and unstable angina requiring hospitalization), for up to 64 months ODYSSEY OUTCOMES Patient population Study objectives and follow-up period To determine the effects of evolocumab every 4 weeks on atherosclerotic disease burden (per cent atheroma volume measured by intravascular ultrasonography), at 72 weeks

PCSK9. ESTUDIOS EN MARCHA Name of study Monoclonal antibody Patient population Study objectives and follow-up period SPIRE-HF Bococizumab Heterozygous FH; high or very high To compare the effect of bococizumab and a statin vs. CVD risk; LDL-C level >70 mg/dl placebo and a statin on LDL-C level in patients with and Tg level 400 mg/dl (with statin heterozygous FH, at 12 weeks therapy) SPIRE-HR Bococizumab High or very high CVD risk; LDL-C To compare the effect of bococizumab and a statin vs. level >70 mg/dl and Tg level 400 placebo and a statin on LDL-C level, at 12 weeks mg/dl (with statin therapy) SPIRE-LDL Bococizumab High or very high CVD risk; LDL-C To compare the effect of bococizumab and a statin vs. level >70 mg/dl and Tg level 400 placebo and a statin on LDL-C level, at 12 weeks mg/dl (with statin therapy) SPIRE-1 Bococizumab High CVD risk; LDL-C level 70 mg/dl and <100 mg/dl, or nonhdl-c level 100 mg/dl and <130 mg/dl, with lipid-lowering therapy (no specification regarding statin therapy) To compare the effect of bococizumab vs. placebo on reducing the occurrence of major cardiovascular events, including cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization, at 5 years SPIRE-2 Bococizumab High CVD risk; LDL-C level 100 mg/dl or non-hdl-c level 130 mg/dl, with lipid-lowering therapy (no specification regarding statin therapy) To compare the effect of bococizumab vs. placebo on reducing the occurrence of major cardiovascular events, including cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization, at 5 years

PCSK9. ESTUDIOS COMPLETADOS NO PUBLICADOS Name of study Monoclonal Patient population Study objectives and follow-up period antibody ODYSSEY Alirocumab Statin intolerance; primary To evaluate the efficacy and safety of alirocumab vs. ALTERNATIVE hypercholesterolaemia ezetimibe and vs. atorvastatin, after 24 weeks of (heterozygous FH or non-fh); treatment and moderate, high, or very high CVD risk (no statin therapy) ODYSSEY Alirocumab Hypercholesterolaemia To evaluate the reduction in LDL-C level by OPTIONS I (heterozygous FH or non-fh) not alirocumab as an add-on therapy to atorvastatin, vs. adequately controlled ezetimibe as an add-on therapy to atorvastatin, vs. (atorvastatin with or without other doubling the atorvastatin dose, and vs. switching lipid-modifying therapy), and high from atorvastatin to rosuvastatin, after 24 weeks of CVD risk treatment ODYSSEY Alirocumab Hypercholesterolaemia not To evaluate the reduction in LDL-C level by OPTIONS II adequately controlled alirocumab as an add-on therapy to rosuvastatin, vs. (rosuvastatin with or without otherezetimibe as an add-on therapy to rosuvastatin, and lipid-modifying therapy), and high vs. doubling the rosuvastatin dose, after 24 weeks of CVD risk treatment ODYSSEY FH I Alirocumab Heterozygous FH not adequately To evaluate the effect of alirocumab vs. placebo on controlled with current lipidldl-c level after 24 weeks of treatment (including modifying therapy (no background statin or other lipid-modifying therapy) specification regarding statin therapy) ODYSSEY FH II Alirocumab Heterozygous FH not adequately To demonstrate the reduction in LDL-C level by controlled (with maximally alirocumab vs. placebo as an add-on therapy to tolerated statin with or without stable, maximally tolerated daily statin (atorvastatin, other lipid-modifying therapy) rosuvastatin, or simvastatin) therapy, with or without other lipid-modifying therapy, after 24 weeks of treatment

PCSK9. RETOS Coste-efectividad Coste primer año tras SCA 22.529$ Coste aféresis LDL-c para HF 45.000 100.000$ /año PCKS9 probablemente coste-efectivos en población alto riesgo Cumplimiento terapéutico Técnica de inyección Reacciones locales Seguridad a largo plazo Shimada et al. European Heart Journal (2015) 36, 2415 2424