PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE …PCSK9: GENÉTICA Y ESTRUCTURA MOLECULAR...

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-B2

1. Abifadel M et al. Nat Genet 2003;34:154–1562..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

• ↓ riesgo EAC 6-46 % tras reducción LDL-c 11-15 % por mutación gen PCSK9

● Estudio en Zimbabwe. Hooper AJ et al. Atherosclerosis 2007;193:445–448.

• 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 %

1. Chan JC et al. Proc Natl Acad Sci USA 2009;106:9820–9825.

https://www.praluenthcp.com/mechanism-of-action

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)

1. Gupta et al. PLoS ONE.2010;5:e106822. 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.

Goldberg AC. J Clin Lipidol 2010;4:350-356.

PCSK9: MECANISMO DE ACTUACIÓN

Shimada et al. European Heart Journal (2015) 36, 2415–2424

INHIBIDORES PCSK9: MECANISMO DE ACCIÓN


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 patients

Study duration LDL-C

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 LONG TERM

Alirocumab Hypercholesterolaemia not adequately controlled with current lipid-modifying therapy, and high

CVD risk

2341 24 weeks −61.9


PCSK9: 0DDYSEY MONOPatients with hypercholesterolaemia on no statins, compared with ezetimibe

• 103 pacientes con hipercol.

• Alirocumab vs ezetimiba• 24 semanas

Roth EM et al. Int J Cardiol. 2014 Sep;176(1):55-61

ODDYSEY COMBO I

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.

Hypercholesterolaemia not adequately controlled (with maximum dose of a statin with or without other lipid-modifying therapy), and high CVD risk

EVOLOCUMAB: ESTUDIOSTrial name PCSK9

inhibitorPopulation 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

GAUSS-2 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

TESLA Part B Evolocumab Patients with hoFH, not on apheresis, 420 mg Q4W

49 12 weeks −30.9


ESTUDIO DESCARTES

Bloom DJ et al. N Engl J Med. 2014 May 8;370(19):1809-19.

A 52-week placebo-controlled trial of evolocumab in hyperlipidemia

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.

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

PCSK9: HIPERCOLESTEROLEMIA FAMILIAR. ESTUDIO TESLA PARTE B

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.

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


Patients with hoFH, not on apheresis, 420 mg Q4W

Number of patients

49

Study duration

12 weeks

PCSK9. EFECTO DOSIS DEPENDIENTESafety 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-2Effect of Evolocumab or Ezetimibe Added to Moderate- or High-Intensity Statin Therapy on LDL-C Lowering in Patients With HypercholesterolemiaThe LAPLACE-2 Randomized Clinical Trial

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Yuichi J. Shimada, and Christopher P. Cannon Eur Heart J 2015;36:2415-2424Robinson JG et al. JAMA. 2014 May 14;311(18):1870-82


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

2067

Study duration

12 weeks

PCSK9. INTERVALO POSOLÓGICO

Yuichi J. Shimada, and Christopher P. Cannon Eur Heart J 2015;36:2415-2424

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)

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):1809-19Robinson JG et al. JAMA. 2014 May 14;311(18):1870-8Roth EM et al. Int J Cardiol 2014;176:55–61.

PCSK9. TOLERANCIA• ODYSSEY MONO

• 1/52 pacs. reacción local a la inyección (vs 2/51 placebo) a las 24 semanas

• OSLER• 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;209:189–1943. Toth PP Expert Rev Cardiovasc Ther 2008;6:955–969

.

PCSK9. ESTUDIOS EN MARCHAName of

studyMonoclonal

antibodyPatient population Study objectives and follow-up period

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)

To determine the effects of evolocumab every 4 weeks on atherosclerotic disease burden (per cent atheroma volume measured by intravascular ultrasonography), at 72 weeks

FOURIER Evolocumab Clinical CVD, high risk of recurrent CVD event, and LDL-C level ≥70 mg/dL or non-HDL-C ≥100 mg/dL (no specification regarding statin therapy)

To assess the effect of evolocumab every 2 or 4 weeks plus a statin vs. placebo plus a statin on major CVD 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

ODYSSEY OUTCOMES

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

PCSK9. ESTUDIOS EN MARCHAName of

studyMonoclonal


SPIRE-HF Bococizumab Heterozygous FH; high or very high CVD risk; LDL-C level >70 mg/dL and Tg level ≤400 mg/dL (with statin therapy)

To compare the effect of bococizumab and a statin vs. placebo and a statin on LDL-C level in patients with heterozygous FH, at 12 weeks

SPIRE-HR Bococizumab High or very high CVD risk; LDL-C level >70 mg/dL and Tg level ≤400 mg/dL (with statin therapy)

To compare the effect of bococizumab and a statin vs. placebo and a statin on LDL-C level, at 12 weeks

SPIRE-LDL Bococizumab High or very high CVD risk; LDL-C level >70 mg/dL and Tg level ≤400 mg/dL (with statin therapy)

To compare the effect of bococizumab and a statin vs. placebo and a statin on LDL-C level, at 12 weeks

SPIRE-1 Bococizumab High CVD risk; LDL-C level ≥70 mg/dL and <100 mg/dL, or non-HDL-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 PUBLICADOSName of study Monoclonal


ODYSSEY ALTERNATIVE

Alirocumab Statin intolerance; primary hypercholesterolaemia (heterozygous FH or non-FH); and moderate, high, or very high CVD risk (no statin therapy)

To evaluate the efficacy and safety of alirocumab vs. ezetimibe and vs. atorvastatin, after 24 weeks of treatment

ODYSSEY OPTIONS I

Alirocumab Hypercholesterolaemia (heterozygous FH or non-FH) not adequately controlled (atorvastatin with or without other lipid-modifying therapy), and high CVD risk

To evaluate the reduction in LDL-C level by alirocumab as an add-on therapy to atorvastatin, vs. ezetimibe as an add-on therapy to atorvastatin, vs. doubling the atorvastatin dose, and vs. switching from atorvastatin to rosuvastatin, after 24 weeks of treatment

ODYSSEY OPTIONS II

Alirocumab Hypercholesterolaemia not adequately controlled (rosuvastatin with or without other lipid-modifying therapy), and high CVD risk

To evaluate the reduction in LDL-C level by alirocumab as an add-on therapy to rosuvastatin, vs. ezetimibe as an add-on therapy to rosuvastatin, and vs. doubling the rosuvastatin dose, after 24 weeks of treatment

ODYSSEY FH I Alirocumab Heterozygous FH not adequately controlled with current lipid-modifying therapy (no specification regarding statin therapy)

To evaluate the effect of alirocumab vs. placebo on LDL-C level after 24 weeks of treatment (including background statin or other lipid-modifying therapy)

ODYSSEY FH II Alirocumab Heterozygous FH not adequately controlled (with maximally tolerated statin with or without other lipid-modifying therapy)

To demonstrate the reduction in LDL-C level by alirocumab vs. placebo as an add-on therapy to stable, maximally tolerated daily statin (atorvastatin, 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


PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE …PCSK9: GENÉTICA Y ESTRUCTURA MOLECULAR...

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