PCSK9 inhibitors : How do they work ? John Chapman BSc (Hons), - - PowerPoint PPT Presentation

PCSK9 inhibitors : How do they work ?

John Chapman BSc (Hons), Ph.D., D.Sc., EFESC

Director Emeritus, INSERM, Research Professor, University of Pierre and Marie Curie, Past-President, European Atherosclerosis Society Pitié-Salpetriere University Hospital, Paris, France

Which factors are central to the physiological control of circulating LDL-C levels ?

• LDL receptor
• PCSK9 - (Proprotein convertase subtilisin kexin 9)

EXONS DOMAINS

Ligand binding (292 aa) Epidermal growth factor precursor homology (400 aa) O-linked sugars (58 aa) Cytoplasmic (50 aa)

DOMAINS

Ligand binding (292 aa) NH2 COOH Membrane- spanning (22 aa) 2 3 4 5 6 I II III V VI VII IV A B C http://www.iemrams.spb.ru/english/molgen/fh-en/domain-e.htm. [Accessed 6 August 2015]

The cellular LDL receptor

LDL Receptor Function and Life Cycle

D H S

SP

Prodomain

Catalytic domain C-terminal

692

Autocatalytic cleavage

Abifadel et al. (2003) Nat Genet 34:154

undergoes autocatalytic cleavage to take up its active conformation for LDLR binding

PCSK9:

Horton JD, et al. J Lipid Res. 2009;50:S172-S177.

LDLR PCSK9

Ligand-binding domain EGF-like repeats

b

propeller Catalytic domain Prodomain Carboxyl- terminus

PCSK9 and the LDL Receptor

Role of PCSK9 in Regulation of LDL-R Expression

PCSK9 knockout mice : hepatic LDL-R levels Immunoblot Immunofluorescence against LDL-R

PCSK9 decreases number of LDL-R : LDL-C

Rashid S et al. PNAS 2005;102:5374–5379

Absence of PCSK9 Leads to Marked Increase in LDL-R

Adapted from Cohen JC et al. N Engl J Med 2006;354:1264–72. 30 20 10

9.7% PCSK9142x or PCSK9679X

No Yes 12 8 4 0 50 100 150 200 250 300 30 20 10 0 50 100 150 200 250 300

No nonsense mutation

(n = 3278) 50th Percentile Plasma LDL-C in black subjects (mg/dL) Frequency (%)

1.2% PCSK9142x or PCSK9679X

(n=85) Coronary Heart Disease (%)

Mean 138 mg/dL Mean 100 mg/dL (-28%) 88% reduction in risk of CHD events during 15-year follow-up

Loss-of-Function PCSK9 mutations are associated with low LDL-C and low prevalence of CHD events

• Individuals who completely lack PCSK9 and have

very low LDL-C levels (approx. 15 mg/dL) are healthy

• Therefore, inhibition of PCSK9 represents a safe

pharmacologic approach to management of hypercholesterolemia and CVD prevention

Evolocumab and Alirocumab

• Fully human PCSK9

monoclonal antibodies

• Less likely to have immune

side effects:

• Neutropenia
• Thrombocytopenia
• Hemolytic anemia
• Hypersensitivity reactions

For illustration purposes only

mAb

Impact of an PCSK9 mAb on LDL Receptor Expression

• 70
• 60
• 50
• 40
• 30
• 20
• 10

20 40 60 80 100 120 140 160 180 200 500 1000 1500 2000 2500 LDL-C mean % change

2 W

Total MAB Free PCSK9 LDL-C Free/total PCSK9 Conc. (ng/mL) Total alirocumab (ng/mL) X 0.01 Time (hours)

Stein EA et al. New Engl J Med 2012;366:1108–18.

LDL-C

PCSK9 mAb

PCSK9 Inhibition by Monoclonal antibodies: Dynamic Relationship Between mAb Levels, PCSK9 and LDL-C

Mechanism of statin-mediated upregulation of the LDLR gene via SREBP2

Statin

SREBP2 LDLR Lysosomal degradation LDL-C Hepatocyte

Mechanism of statin-mediated upregulation of the LDLR and PCSK9 genes via SREBP2

Statin

SREBP2 LDLR PCSK9

Lysosomal degradation LDL-C

Hepatocyte

Adapted from Konrad RJ, et al. Lipids Health Dis 2011;10:38.

Key Messages

• MABs to PCSK9 efficaciously remove the target from plasma, resulting in enhanced LDL

receptor numbers (espec. in liver).

• Ag: Ab complex removal occurs primarily through the high capacity RES system, mainly in

liver and spleen.

• Circulating MAB levels directly determine plasma PCSK9 concentrations, and thence those of

LDL-C.

• The amount of the MAB injected can be increased to provide target saturation for up to one

month with a single subcutaneous injection.

• Genetically-determined absence of PCSK9 is not deleterious to health.
• MABs to PCSK9 are typically used with concomitant statin therapy in very high risk patients,

allowing 60% additional LDL-C reduction.