Evolving Scientific Insights into the

Novel Therapeutic Target of PCSK9

Prof. John J.P. Kastelein, MD PhD FESC

Dept. of Vascular Medicine

Academic Medical Center / University of Amsterdam

The Netherlands

2

PCSK9: Protein and Function

PCSK9: The Enzyme Proprotein Convertase Subtilisin Kexin type 9

Lambert et al. (2009) Atherosclerosis

H N S

PCSK9: The Chaperone

(Binds to the LDLR)

EGFA

domain

PCSK9 LDLR

CHRD

Prodomain

Catalytic

domain

Seidah et al. (2014) Circ Res

Endocytosis

PCSK9-LDLR Binding LDLR Conformation

Kd=750±80nM (at pH 7,5) Open (at pH 7,5)

Kd= 10±1nM (at pH 5,5) Closed (at pH 5,5) alone

Open (at pH5,5) bound to PCSK9 Surdo et al. (2011) EMBO Reports

PCSK9 Targets the LDLR to the Lysosome for

Degradation

LDLR Endosome Merge

+ P

CS

K9

PCSK9 Reduces LDLR Cell Surface Expression

Dose Dependently

MFI: median fluorescence intensity

* p<0,05, ** p<0,01 vs. condition no PCSK9 (0)

Lambert et al. (2014) J Am Coll Cardiol

PCSK9:

A Natural Inhibitor of the LDL Receptor

Lambert et al. (2012) J. Lipid Res.

8

PCSK9: Genetics and

Consequences

GOF and LOF in the PCSK9 gene

Davignon, J et al. 2010 Curr. Athero Reports 12: 308-315

10

PCSK9: Gain of Function

PCSK9: Gain of Function Mutations

11

PCSK9 Gain of Function Mutations:

Clinical Phenotype

12

● FH-associated pathognomonic clinical signs

● Coronary artery disease

● Premature myocardial infarction

● Stroke

FH caused by PCSK9 GOF mutations leads to a

clinical phenotype similar to that due to

mutations in the LDL-R and ApoB genes

13

PCSK9: Loss of Function

PCSK9 Loss of Function Mutations:

Clinical Phenotype

14Cohen et al. NEJM 2006;354:1264-72

15

Kathiresan S. N Engl J Med 2008; 358:2299-2300

PCSK9 R46L Reduces Risk of Early-Onset MI in

European and American Cohorts

Replication of Findings on PCSK9 R46L and

C679X for Reduced CAD risk in 56,000

Caucasians and Blacks

Peloso GM et al. Am J Hum Genet 2014;94:223-32

17

AJHG 2006;79:514-2332 yo woman Compound heterozygote for 2 LOF alleles in PCSK9LDL-C 0.36 mmol/LFertile, college educated, physically coordinated (fitness instructor)

Atherosclerosis 2007;193:445-8African womanHomozygous C679XLDL-C 0.40 mmol/LHealthy with children

PCSK9 Loss of Function Mutations and very low LDL-C from Birth

18

PCSK9: Target for

Pharmacotherapy?

Target Identification by Genetics:

PCSK9

19Schunkert H et al. Nature Genetics 2011;43:333-338

Manhattan Plot of the 13 Susceptibility

Loci for CAD

20Schunkert H et al. Nature Genetics 2011;43:333-338

• PCSK9 is a natural circulating inhibitor of the LDLR that targets the receptor for degradation following endocytosis.

• PCSK9 and LDLR genes are co-regulated by intracellular cholesterol content and statin treatment.

• Targeting plasma PCSK9 is conceptually a promising approach to lower LDL-C levels in monotherapy as well as on top of statins.

• Phase III trials of Alirocumab and Evolocumab indicate a reduction of CVD risk.

PCSK9 in Brief: