Fernando Civeira Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis

Hospital Universitario Miguel Servet, Zaragoza

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

12 Curso de Lipidología y Factores de Riesgo Cardiovascular

FIPEC, Barcelona 27 de noviembre de 2014

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.

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.

PCSK9 controla la expresión del receptor LDL en la superficie de

hepatocito a través de la degradación lisosomal

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.

NP-ESP-AMG-361-2011

SAR 236/Alirocumab

CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE

PCSK9-041812000

Alirocumab: Dynamic Relationship Between

mAb Levels, PCSK9 and LDL-C

-70

-60

-50

-40

-30

-20

-10

0

0

20

40

60

80

100

120

140

160

180

200

0 500 1000 1500 2000 2500

LDL-

-C m

ean

% c

han

ge

Fre

e/T

ota

l PC

SK9

Co

nc.

(n

g/m

L)

Tota

l REG

N7

27

(n

g/m

L) X

0.0

1

Time (hours)

Free PCSK9, Total Alirocumab Concentration and Mean % Change LDL-C vs Time

Total REGN727/SAR236553 free PCSK9 LDL-c

(SAR 236/Alirocumab)

Efficacy of evolocumab (AMG 145): 140 mg every 2

weeks and 420 mg every 4 weeks (phase 2 trials)

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.

Data expressed as % change vs placebo (except reference 4: % change vs baseline)

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

420 mg Q4W

LAPLACE-TIMI 571 On statin w/ or w/o ezetimibe

-50.3 -42.0 – -19.4 5 4

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

Ensayos fase 3: Alirocumab, Evolocumab, Bococizumab

ClinicalTrials.gov. available at: http://clinicaltrials.gov. Accessed May 20, 2014.

12

Trial Type Alirocumab

Double-Blinded Trials

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)

Minimum LDL-C Levels

(mg/dL)

HeFH

ODYSSEY FH I

471 18 496 ≥100

RUTHERFORD-2 300 3 46 ≥100 SPIRE-HF 300 12 200 ≥70 ODYSSEY

FH II 250 18 250,5 ≥100

ODYSSEY HIGH FH

105 18 106,5 ≥160

Combo Therapy

ODYSSEY COMBO I

306 12 210 ≥ 70

LAPLACE-2 1700 3 231 ≥80

SPIRE-HR 600 18 600 ≥70

ODYSSEY COMBO II

660 24 960 ≥70

SPIRE-LDL 1600 18 1600 ≥70 ODYSSEY OPTIONS I

350 6 50 ≥70

ODYSSEY OPTIONS II

300 6 50 ≥70

Monotherapy ODYSSEY

MONO 100 6 25.5 ≥100 MENDEL-2 600 3 92 ≥100

Statin Intolerance

ODYSSEY ALTERNATIVE

250 6 50 ≥70 GAUSS-2 300 3 46 None

PLANNED GAUSS-3 500 3 NA NA

LTS ODYSSEY

LONG-TERM 2100 18 2340 ≥70

DESCARTES 905 12 602 ≥75

SPIRE-LL 939 12 626 >100 OSLER Open label

3515 12+ TBD TBD

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 Event Driven

N/A ≥70 & <100

SPIRE-2 6300 Event Driven

N/A >100

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

ClinicalTrials.gov. available at: http://clinicaltrials.gov. Accessed May 20, 2014.

53

Trial Type Alirocumab

Double-Blinded Trials

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)

Minimum LDL-C Levels

(mg/dL)

HeFH

ODYSSEY FH I

471 18 496 ≥100

RUTHERFORD-2 300 3 46 ≥100 SPIRE-HF 300 12 200 ≥70 ODYSSEY

FH II 250 18 250,5 ≥100

ODYSSEY HIGH FH

105 18 106,5 ≥160

Combo Therapy

ODYSSEY COMBO I

306 12 210 ≥ 70

LAPLACE-2 1700 3 231 ≥80

SPIRE-HR 600 18 600 ≥70

ODYSSEY COMBO II

660 24 960 ≥70

SPIRE-LDL 1600 18 1600 ≥70 ODYSSEY OPTIONS I

350 6 50 ≥70

ODYSSEY OPTIONS II

300 6 50 ≥70

Monotherapy ODYSSEY

MONO 100 6 25.5 ≥100 MENDEL-2 600 3 92 ≥100

Statin Intolerance

ODYSSEY ALTERNATIVE

250 6 50 ≥70 GAUSS-2 300 3 46 None

PLANNED GAUSS-3 500 3 NA NA

LTS ODYSSEY

LONG-TERM 2100 18 2340 ≥70

DESCARTES 905 12 602 ≥75

SPIRE-LL 939 12 626 >100 OSLER Open label

3515 12+ TBD TBD

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 Event Driven

N/A ≥70 & <100

SPIRE-2 6300 Event Driven

N/A >100

PCSK9