pcsk-9 inhibition -...

PCSK-9 inhibition

New Therapy in Cardiovascular Risk Reduction

Nathalie Meyten

[email protected]

CVD

Cancer

Respratory

Injuries

Other

CVD is the leading cause of mortality in Europe

European Cardiovascular Disease Statistics, 2012 edition.

> 4.000.000 deaths each year

from CVD in Europe

CVD is the leading cause

of mortality in Europe

On average 11,000 Europeans die of CVD

each day, an average of

1 death every 8 seconds

1. World Heart Federation. Cardiovascular disease risk factors. 2. Dekker et al. Circulation 2005;112:666–673. 3. Bhatt et al. JAMA 2010;304:1350–1357. 4. Lagrand et al. Circulation 1999;100:96–102. 5. Go et al. N Engl J Med 2004;351:1296–1305. 6. Grundy et al. J Am Coll Cardiol 1999;34:1348–1359.

Increased CV risk

Prior CV event/manifest

atherosclerosis3

Smoking, physical inactivity1

Hypertension1

Age, ethnicity, gender, family history/genetic

variations1

Obesity1

Type 2 diabetes1

High CRP,4 chronic kidney disease5

Metabolic syndrome2

Lipid disorders1

(LDL-C↑, HDL-C↓, TG↑)

LDL-C is a major risk factor of CVD LDL-C levels are associated with greater CVD morbidity and mortality

LDL-C remains THE target for lipid-modifying therapy in CVD

ESC / EAS guidelines for control of LDL-C

Perk J et al. Eur Haert J 2012;33:1635-1701.

SCORE Rela4ve risk calculated using tables that take into account sex, smoking status, SBP and cholesterol

Cholesterol metabolism

Majority of circula4ng LDL-‐C is synthesized in the liver by HMG-‐CoA reductase Removal of LDL-‐C from the circula4on is primarily via hepa4c LDL receptors

Treatment of dyslipidemia Benefits of intensive statin therapy are well documented since 1994 Scandinavian Simvastatin Survival Landmark Study Statins improved survival in CVD

No increased risk for any specific non-‐CV cause of death

Cholesterol Treatment Trialists’ Collaboration. Lancet 2010;376:1670–1681.

-‐27% -‐25% -‐24%

-‐20%

-‐16%

-‐10%

-30%!

-25%!

-20%!

-15%!

-10%!

-5%!

0%!

Non-fatal MI

Coronary revascularisation

Major coronary

event

Coronary death

Stroke All-cause mortality

Change in risk over 1 year per 1mmol/L (38mg/dL) LDL-C reduction

Treatment of dyslipidemia Novel compounds (torcetrapib – laropiprant -‐ dalcetrapib…) were prematurely halted due to safety concerns and or lack of efficacy

Fibrates and nico4nic acids failed to improve CVD events in conjunc4on with op4mal sta4n therapy Removed from guidelines

Apheresis lowers LDL-‐C Requires 4me and resource costs and venous access Adverse effects : nausea, hypotension, headache, abdominal or chest pain iron-‐deficiency anaemia, post-‐procedural bleeding, infec4on

Barter et al NEJM 2007; Schwartz et al NEJM 2012; Landray et al NEJM 2014; ACCORD Study NEJM 2010; FIELD Study Lancet 2005; AHA Guidelines J Am Coll Cardio 2014 Page et al. Best Pract Res Clin Endocrinol Metab 2014;28:387–403. Thompson et all. Atheroscler Suppl 2013;14:67–70. . Thompson et al. Curr Opin Lipidol 2010;21:492–498. . Schuff-Werner et al. Clin Res Cardiol Suppl 2012;7:7–14. van Buuren et al. Clin Res Cardiol Suppl 2012;7:24–30.

Treatment of dyslipidemia

Ezetimibe Ezetimibe has been the only drug shown to further improve outcomes for dyslipidemic patients IMPROVE-IT was a double-blind, randomized controlled trial of 18.144 patients who had been hospitalized for acute coronary syndrome within the preceding 10 days.

Cannon. Presented at the American Heart Association Annual Scientific Sessions, 17 Nov 2014

Even

t rate (%

)

Years since randomisa4on

0

40

30

20

10

0 7 1 2 3 4 5 6

Treatment of dyslipidemia

ITT: Hazard ra4o, 0.936 (95% CI, 0.89–0.99) P=0.01

Simvasta4n (on-‐treatment) Simvasta4n-‐eze4mibe (on-‐treatment)

Simvasta4n (ITT) Simvasta4n-‐eze4mibe (ITT)

On-‐treatment: Hazard ra4o, 0.924 (95% CI, 0.87–0.98) P=0.012

Cannon. Presented at the American Heart Association Annual Scientific Sessions, 17 Nov 2014

Eze4mibe added to sta4n reduces CV events compared with sta4n alone

Greater reductions in LDL-C levels are associated with greater reductions in CV event rates No lower LDL-C limit in reducing CV events

CTTC. Lancet 2005;366:1267–1278. CTTC. Lancet 2010;376:1670–1681. Cannon et al. N Engl J Med 2015;372:2387 – 2397.

50%

40%

30%

20%

10%

0%

19 39 58 77

Reduc4on in LDL-‐C (mg/dL)

Prop

or4o

nal Red

uc4o

n in Event Rate (SE)

IMPROVE-‐IT

CTT-‐meta-‐analysis

Lower even be>er

Limitations of current management of dyslipidemie

CV

events, %

100

80

60

40

20

0

Residual events Prevented events

4S LIPID CARE HPS WOS JUPITER AF/Tex

1º Preven4on High risk 2º Preven4on

Circula4on 1999;99:736–743. Lancet 1995;345:1274–1275. N Engl J Med 1998;339:1349–1357. J Am Coll Cardiol 1999;33:125–130. N Engl J Med 1995;333:1301–1307. JAMA 1998;279:1615–1622. Lancet 2010;376:333–339.

Significant residual CV risk remains in pa4ents on treatment with evidence –based care


EUROASPIRE IV

Kotseva et al. Eur J Prev Cardiol 2015;Feb 16. pii:2047487315569401 Karalis et al Cholesterol 2012; Reiner et al Atherosclerosis 2013;

87

58

21 0

10

20

30

40

50

60

70

80

90

100

Lipid-lowering drugs LDL-C <100mg/dL LDL-C <70mg/dL

Pre

vale

nce

(%)

1:5 pa4ents achieve LDL-‐C < 70mg/dL aoer CV event despite sta4n and good adherence

1 1 1 3 4 4 4 6

12 13

19 43

71

0 20 40 60

Mexico Brazil Chile Japan

Canada USA

Oman Italy

Taiwan France

Hong Kong Australia

South Africa Denmark Slovakia Belgium

Spain UK

Switzerland Iceland Norway

Netherlands

Based on prevalence 1 in 500

21% achieved LDL-C goal of < 100mg/dL 1


1.  Pijlman et al. Atherosclerosis 2010;209:189–194. 2.  Nordestgaard et al. Eur Heart J 2013;34:3478–

3490.

Diagnosed FH (es4mated) as % of es4mated number in each country

<1

Heterozygote familial hypercholesterolemia is underdiagnosed and undertreated

• Posssible genetic basis • Pharmacokinetic factors • Poor adherance to statin therapy

Statin-induced myopathy Digestive problems Mental fuzziness Rarely liver damage


Kim et al Genome Biol 2014; Stroes et al Eur Heart J 2015; Finegold etla Eur J Prev Cardiol 2014

Variable respons between individuals

Incidence of statin intolerance in RCT is lower than 5-18% suggested by observational data

STOMP was powered to assess sta4n-‐associated muscle symptoms2

Trial details1 Myalgia1

Trial Total No. Agent Dose, mg Duration, yr Statin Placebo

4S 4,444 Simvastatin 20–40 5.4 3.7% 3.2% WOSCOPS 6,595

Pravastatin 40 4.9 3.5% 3.7%

PROSPER 5,804 3.2 1.2% 1.1% CARDS 2,838

Atorvastatin 10

3.9 4.0% 4.8% ASPEN 2,410 4.0 3.0% 1.6% SPARCL 4,731 80 4.9 5.5% 6.0% JUPITER 17,802 Rosuvastatin 20 1.9 7.9% 6.9%

1. Newman et al. JAMA 2015;313:1011–1012. 2. Parker et al. Circulation 2013;127:96–103.

No imbalance

Trial details2 Myalgia2

Trial Total No. Agent Dose, mg Duration, yr Statin Placebo

STOMP 420 Atorvastatin 80 0.5 19 10 P=0.05

•  Statins have revolutionized the management of LDL-C

•  Statins provide marked reductions in LDL-C and

clinically significant reductions in CV events in high risk patients

•  Ezetimibe added to statin reduces CV events compared with statin alone

•  IMPROVE-IT: No lower limit for LDL-C lower even better

•  Most patients do not achieve their goal LDL-C on statins

•  Need for a consistently effective, well-tolerated treatment that will provide reductions in LDL-C beyond those with a statins

Current management of LDL-C

LDLR

PCSK9

3. C-‐terminus 2. Prodomain 1. Cataly4c domain

PCSK9 Proprotein subtilisin / kexin type 9

Serine proprotein convertase1

Expressed in hepatocytes, kidney mesenchymal cells, ileum and colon epithelia, central nervous system2

Regulates hepa4c LDLRs, which bind and internalise LDL par4cles3

LDL Receptor and PCSK9 expression are both upregulated when cellular cholesterol levels are low

Sta4n therapy induces PCSK9 expression

1. Abifadel et al. Hum Mutat 2009;30:520–529. 2. Seidah et al. Proc Natl Acad Sci USA 2003;100:928–933.

3. Horton et al. J Lipid Res 2009;50:S172–S177. Goldstein et al. Arterioscler Thromb Vasc Biol 2009;29:431–438. Dubuc et al. Arterioscler Thromb Vasc Biol 2004;24:1454–

1459.

1

2

3

Plasma LDL-C is controlled by hepatic LDL receptor levels In absence of PCSK9 LDL-receptor is recycled to the plasma membrane

Brown et al. Proc Natl Acad Sci USA 1979;76:3330–3337.

Recycling of LDLR

Increased LDLR surface concentraJon

LDL parJcles

LDLR

PCSK9 Prevents LDL-receptor recycling Targets it for lysosomal degradation resulting in decreased LDLReceptors Increasing plasma LDL-C

Horton et al. J Lipid Res 2009;50:S172–S177.

LDL parJcles

LDLR

PCSK9 secreJon

PCSK9 routes LDLR for lysosomal degradaJon

LDLR recycling blocked

Discovery of PCSK9

PCSK9 genetic variants demonstrate importance in regulating LDL

1Abifadel et al. Hum Mutat 2009;30:520–529. 2,Dadu et al. Nat Rev Cardiol 2014;11:563–575.

3. Benn et al. J Am Coll Cardiol 2010;55:2833–2842.

PCSK9 gain of function = Fewer LDLRs1 (rare2) GOF variant Population Characteristics

D374Y British, Norwegian families, 1 Utah family Premature CHD, tendon xanthomas, severe hypercholesterolaemia

S127R French, South African, Norwegian patients Tendon xanthomas; CHD, early MI, stroke

D129G New Zealand family Brother died at 31 from MI; strong family history of CVD

PCSK9 loss of function = More LDLRs3 (common3) LOF variant Population LDL-C CHD risk

R46L ARIC, DHS ↓ 15% ↓ 47%

Y142X or C679X ARIC, DHS ↓ 28%–40% ↓ 88%

R46L CGPS ↓ 11% ↓ 46%

PCSK9 • PCSK9 is a serine proprotein convertase that reduces hepatic LDLR

levels and increases plasma LDL-C

• Genetic variants of PCSK9 demonstrate its importance in regulating LDL levels

Loss-of-function variants are associated with a lower risk of CV events

• PCSK9 represents a therapeutic target in dyslipidaemia

Binding of plasma PCSK9 by monoclonal antibodies

Reducing PCSK9 expression by silencing RNA

Vaccination against PCSK9

Adnectin

• Several PCSK9 inhibitors have been licensed recently or are in development

PCSK9 inhibition is an important new therapeutic target Type Compound Company

mAb

Evolocumab (Repatha®) AMG145 Amgen

Alirocumab (Praluent®) REGN7272/SAR236553 Sanofi/Regeneron

Bococizumab RN-316/PF-04950615 Pfizer/Rinat

RG7652 (MPSK3169A) Roche/Genentech

LY3015014 Eli Lilly

Adnectin Ad. BMS-962476 BMS-Adnexus

siRNA ALN-PCS Alnylam Pharmaceuticals

Vaccine AFFITOPE AT04A+adjuvant AFFITOPE AT06A+adjuvant AFFiRiS AG

Small molecule – Shifa Biomedical Corp

Mimetic peptide

EGF-A peptide Merck & Co.

Prodomain and C-terminal domain interaction disruption

School of Medicine, University of South Carolina, USA

Therapeutic monoclonal antibodies

Act via indirect or direct mechanisms

Cancer Principles and Practice of Oncology. Vol 1. 8th ed. 2008:537–548. Principles of Anticancer Drug Development. 1st ed. 2010:535–567.

Cell-‐mediated cytotoxicity

(NK/macrophage)

Altering intracellular

signalling pathways

Indirect Direct

Complement-‐dependent cytotoxicity (CDC)

Membrane aqack complex

Neutralising soluble an4gens


Weiner. J Immunother 2006;29:1–9. Yang et al. Crit Rev Oncol Hematol 2001;38:17–23. WHO INN (International Nonproprietary Names) Working Document 05.179

Mouse (0% human)

Fully human (100% human)

Humanised (> 90% human)

Chimeric (65% human)

-umab -zumab -ximab -omab Generic suffix

Low High Potential for immunogenicity

Examples: Infliximab Trastuzumab Evolocumab

IgG is the class of choice for an4body produc4on


Administered IV, IM or SC1

- An4bodies are degraded by gastrointes4nal proteolysis aoer oral delivery

- Systemic absorp4on most likely occurs via the lympha4c system

Biodistribu4on of an4bodies following administra4on depends mainly on the 4ssue structure and capillary endothelium2

Clearance of an4bodies3 is via:

1. Lobo et al. J Pharm Sci 2004;93:2645–2668. 2. Tabrizi et al. AAPS J 2010;12:33–43. 3. Tabrizi et al. Drug Discov Today 2006;11:81–88.

Re4culoendothelial system Target-‐mediated disposi4on

Evolocumab (Amgen) Repatha® 2-‐weekly (140 mg dose) or monthly (420 mg dose) administra4on (PROFICIO)

Alirocumab (Sanofi/Regeneron) Praluent ® 2-‐weekly (75–150 mg) (ODYSSEY)

Bococizumab (Pfizer) Phase III clinical evalua4on (SPIRE)

PCSK9 inhibition due to monoclonal antibodies

Combination therapy

Monotherapy

Statin intolerant

HeFH

HoFH/Severe FH

Long-term safety and efficacy

Open-label extension

Atherosclerosis

Secondary Prevention

Neurocognition

Phase 3 (n=2,067)

Phase 3 (n=615)

Phase 3 (n=307)

Phase 3 (n=511)

Phase 3 (n=331)

Phase 2/3 (n=300)

Phase 3 (n=905)

Phase 3 (n=3,141)

Phase 3 (n=968)

Phase 3 (n=27,564)

Phase 3 (n=1,972)

Phase 2 (n=631)

Phase 2 (n=411)

Phase 2 (n=160)

Phase 2 (n=168)

Phase 2/3 (n=58)

Phase 2 (n=1,324)

Completed trials

>35,000 patients

Evolocumab PROFICIO trial programme

Evolocumab in a pre-filled autoinjector pen

27-‐gauge needle

SC injec4on into abdomen, thigh or upper arm region

Evolocumab must not be administered IV or IM

420mg dose is given as 3 × 140mg doses administered consecu4vely within 30 minutes

Severe renal impairment (eGFR<30mL/min/1.73m2): not studied

Hepa4c impairment: reduc4on in total evolocumab exposure may lead to reduced LDL‑C reduc4on

Close monitoring may be warranted

Severe (Child–Pugh C): not studied

Yellow safety guard

Orange cap off

Grey start

button

Window

Medicine

Orange cap

on

Before use

After use

Repatha 140mg solution for injection in pre-filled pen. Summary of Product Characteristics,

Alirocumab ODYSSEY trial fase III program

>23.000 patients

A decade aoer the discovery of PCSK9… Fase I Landmarkstudy by Stein et al N Eng J Med 2012 Effect of a Monoclonal An4body to PCSK9 on LDL cholesterol Alirocumab reduces LDL-‐C > 60% in both healthy volunteers and pa4ents with FH Summer 2015 European Medicines Agency

Approval alirocumab and evolocumab for inacceptable lipid control despite op4mal sta4n homozygous FH sta4n-‐intolerant pa4ents

PCSK9-inhibiting monoclonal antibodies from bench to bed…

Effects of PCSK9-inhibiting antibodies on lipids Meta-‐analysis Navarese et al Ann Intern Med 2015 clinical poten4al of an4body PCSK9 inhibi4on in >10.000 pa4ents in> 20 phase II-‐III trials with alirocumab and evolocumab

Navarese, et al. Ann Intern Med. 2015

Effects of PCSK9-inhibiting ab on lipids

LDL- C percentage of change from baseline Reduc4on in LDL -‐C with an4-‐PCSK9 compared with placebo was significantly greater than that compared with eze4mibe

Navarese, et al. Ann Intern Med. 2015

Overall reduc4on in LDL-‐C of almost 50% with PCSK9 an4bodies compared with no an4-‐PCSK9 treatment

Zhang XL et al; BMC Med. 2015

Overall reduc4on in LDL-‐C of allmost 50% with PCSK9 an4bodies compared with no an4-‐PCSK9 treatment

Effects of PCSK9 inhibiting antibodies on lipids Meta-‐analysis Zang et al BMC 2015

Effects of PCSK9-inhibiting mab on lipids

Sabatine et al. N Engl J Med 2015;372:1500–1509.

LDL–

C (m

g/dL

)

Standard therapy

Weeks

Evolocumab

Baseline

1,219 2,508 n = 394

864 Standard therapy Evolocumab

Open-‐Label Study of Long-‐Term Evalua4on against LDL-‐C,4465 pa4ents Extension study of par4cipants who had completed phase II or III studies of evolocumab

61 % LDL-‐C reduc4on

Effect of bococizumab on LDL cholesterol in a 12-‐week study in sta4n-‐treated pa4ents with hypercholesterolaemia

Ballantyne CM, Neutel J, Cropp A et al.. Am J Cardiol 2015;115:1212-‐21.

Effects of PCSK9-inhibiting ab on lipids Long-‐term safety and efficacy data on bococizumab are limited…

Conclusions from PCSK9 inhibition trials Mean LDL-C reductions of approximately 50-60 %

Persisted during follow-up Similar effects across different doses, patient populations Independent of statin use

Mean LDL-C reduction of approximately 36 % compared to ezetimibe

Increased HDL-C by approximately 6 %

Lowered lipoprotein(a) by approximately 26 % (placebo- and ezetimibe-controlled trials)

Similar effect with evolocumab, alirocumab, and bococizumab Effect of PCSK9 inhibition depends on the LDLR mutation in homozygote familial hypercholesterolemiae

Ñ  All trials confirmed the beneficiThe use of PCSK9 monoclonal an4bodies was associated with mean LDL-‐C reduc4ons of al effect of PCSK9 inhibi4on with evolocumab and alirocumab on LDL-‐C levels. approximately 50 % [19, 20]. These results persisted

Preliminary CV outcome data PCSK9 inhibitors Meta-‐analysis Navasere et al.

significant reduc4on of myocardial infarc4on (0.6 % PCSK9 inhibitor versus 1% no an4-‐PCSK9 treatment)

Pre-‐specified preliminary analysis of ODYSSEY LONG TERM trial (2,341 pa4ents treated with alirocumab for at least 52 weeks) The incidence of the primary composite cardiovascular outcome was significantly reduced

Evolocumab associated with lower rate of CV events (4465 patients, open label OSLER1-2)

60 adjudicated events of death, MI, unstable angina requiring hospitalisa4on, heart failure requiring hospitalisa4on or coronary revascularisa4on, stroke or transient ischaemic aqack

0 30 60 90 120 150 180 210 240 270 300 330 365

Days since randomisation

0

1

2

HR 0.47 95% CI 0.28–0.78

P=0.003

Evolocumab plus standard of care (n=2,976)

Standard of care alone (n=1,489)

0.95%

2.18%

3

Cum

ulat

ive

CV

eve

nt in

cide

nce

(%)

Sabatine et al. N Engl J Med 2015;372:1500–1509.

Preliminary CV outcome data PCSK9 inhibitors Preliminary analyses suggest

Sta4s4cally significant reduc4on in all-‐cause mortality Non-‐significant reduc4on in CVD mortality

Because of the limited number of events, long-‐term clinical outcome studies should be awaited…

Randomized large outcome trials are in progress Will addi4onal LDL lowering translate into CV benefit ?

FOURIER: Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk

>27,500 pa4ents with clinically evident CVD (prior MI, stroke or PAD) Age 40 to 85 years, ≥1 other high-‐risk features* Primary endpoint: CV death, MI, hospitalisa4on for unstable angina, stroke, coronary revascularisa4on

Sabatine et al. Am Heart J 2015; doi: 10.1016/j.ahj.2015.11.015.

Screening, placebo run-in, and lipid stabilisation

period

Effective statin therapy (atorvastatin ≥20mg or an equivalent statin dose ±

ezetimibe)

Results before 2017

Evolocumab SC Q2W or QM

~13,750 subjects

Placebo Q2W or QM

~13,750 subjects

LDL-C ≥70mg/dL

or non-HDL-C ≥100mg/dL

End

of s

tudy

(e

vent

-driv

en)

*History of clinically evident CVD at high risk for a recurrent event, fasting LDL-C ≥70mg/dL or non-HDL-C ≥100mg/dL, or fasting triglycerides ≤400mg/dL

GLAGOV: GLobal Assessment of plaque reGression with a PCSK9 antibOdy as measured by intraVascular ultrasound

•  Lowering LDL-‐C with evolocumab is expected to reduce the atheroma burden

•  IVUS imaging enables measurement of the changes in the atheroma burden

Puri et al. Am Heart J 2016; doi: 10.1016/j.ahj.2016.01.019

Placebo SC monthly

Max. 6 weeks Day 1 Week 36 Week 64 Week 24 Week 12 Week 4 Week 52 Week 76 Week 78

2–4 weeks

Randomisation

1:1

Evolocumab 420mg SC QM

End

of s

tudy

, 201

6 Screening and placebo run-in period, n=970

Clinically indicated coronary angiogram

IVUS based on coronary angiogram

results SC injection of 3 mL

placebo

Up to 4 week lipid

stabilisation period

Assigned to atorvastatin background

therapy

Primary endpoint: nominal change in PAV from baseline to 78 weeks post randomiza4on

Tolerability and safety of PCSK9 inhibitors

•  Well tolerated •  An4-‐drug an4bodies were rare and unproblema4c

Absence of neutralising an4bodies •  Safety and tolerability profile is comparable to that of control

•  Achieving very low LDL-‐C levels is not associated with safety concerns

How low can we go ???

3 pa4ents with Loss of func4on PCSK9 muta4on have a LDL-‐C of 14 mg/dl and are healthy and fer4le….

Tolerability and safety of PCSK9 inhibitors No increase in adverse events at very low LDL-C

Evolocumab-‐treated subjects in OSLER programme were stra4fied by minimally achieved LDL-‐C

Adverse events (AEs), % LDL-C

<25mg/dL (N=773)

LDL-C 25 to <40mg/dL

(N=759)

LDL-C <40mg/dL (N=1,532)

LDL-C ≥40mg/dL (N=1,426)

Any AE 70.0 68.1 69.1 70.1 Serious AEs 7.6 6.9 7.2 7.8 Muscle-related AE 4.9 7.1 6.0 6.9 CK >5 x ULN 0.4 0.9 0.7 0.5 ALT or AST >3 x ULN 0.9 0.8 0.8 1.3 Neurocognitive AE 0.5 1.2 0.8 1.0

Sabatine et al. N Engl J Med 2015;372:1500–1509 Supplementary Appendix.

.00%

.500%

1.00%

1.500%

2.00%

2.500%

3.00%

3.500%

4.00%

4.500%

Control (N=2,080) Evolocumab (N=3,946) SOC (N=1,489) Evolocumab (N=2,976)

Inje

ctio

n-si

te re

actio

ns (%

)

Tolerability and safety of PCSK9 inhibitors Injection-site reactions remain low in the short and long term

N/A

Integrated parent studies Integrated interim open-label extension studies Year 1

Toth et al. J Am Coll Cardiol 2015;65:A1351.!

Tolerability and safety of PCSK9 inhibitors Alirocumab ODYSSEY LONG TERM trial

Bococizumab Phase II: adverse events similar in placebo and bococizumab groups

Ballantyne CM, A et al. Am J Cardiol 2015 Saba4ne MS, Giugliano RP, Wivioq SD et al. N Engl J Med 2015 Robinson JG, Farnier M, Krempf M et al. N Engl J Med 2015;

Tolerability and safety of PCSK9 inhibitors Cognition Cogni4ve impairment has been reported rarely in sta4n users

• Formal studies provide conflic4ng results1–6

Cholesterol is needed for synap4c forma4on and func4on • But virtually all brain cholesterol is synthesised locally

Both sta4ns and PCSK9 lower LDL-‐C • But lower LDL-‐C may protect the CNS by preven4ng or slowing cerebrovascular disease

• And PCSK9 inhibitors and PCSK9 do not cross the intact blood-‐brain barrier

1. Muldoon et al. Am J Med 2000;108:538–546. 2. Muldoon et al. Am J Med 2004;117:823–829. 3. Jukema et al. J Am Coll Cardiol 2012;60:875–881.4. Richardson et al. Ann Intern Med 2013;159:688–697. 5. Swiger et al. Mayo Clin Proc 2013;88:1213–1221. 6. Ott et al. J Gen Intern Med 2015;30:348–358.

EBBINGHAUS: Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in high cardiovascUlar risk Subjects (FOURIER substudy)

Ongoing trial to show effect of evolocumab on cogni4ve health

EBBINGHAUS. https://clinicaltrials.gov/ct2/show/NCT02207634?term=ebbinghaus+and+evolocumab&rank=1. Accessed 10 Jan 2016.

Evolocumab SC Q2W or QM

+ effective statin dose

Placebo Q2W or QM

+ effective statin dose

Results before 2017

Randomisation

Randomised into study FOURIER

~2,000 patients

Excludes patients with current or known past

diagnosis of dementia or mild cognitive impairment

End

of s

tudy

(e

vent

-driv

en)

Take home

LDL-‐C is the major risk factor for the development of atherosclero4c plaques and CVD

LDL-‐C remains the key target of lipid-‐modifying therapy

Lowering LDL-‐C reduces CV events

No lower limit of LDL-‐C levels for reducing major CV events has been iden4fied

IMPROVE-‐IT confirmed the ‘lower is even beqer’ paradigm regarding LDL-‐C levels and CVD risk

Take home

The hepa4c LDL receptor is the most important mechanism of removal of LDL cholesterol from the circula4on Reducing the ac4vity or expression of PCSK9 increases the number of LDL receptors, which reduces circula4ng LDL cholesterol People with muta4ons of the PCSK9 gene that decrease its ac4vity have lifelong low LDL-‐C and a lower risk of CV events than the general popula4on Muta4ons of the PCSK9 gene that increase its ac4vity can give rise to the familial hypercholesterolaemia phenotype

Take home

Sta4ns reduce LDL-‐C and CV risk, and are the first-‐line treatment for pa4ents with dyslipidaemia

Sta4n intolerance is of par4cular concern in pa4ents at high CV risk

Eze4mibe plus sta4n reduces LDL-‐C and CV risk versus sta4n alone

Apheresis lowers LDL-‐C, but can be inconvenient and expensive

PCSK9 inhibitors reduced LDL-‐C by > 50% in randomized trials in pa4ents with hypercholesterolaemia Substan4al reduc4ons in LDL -‐C were also seen in pa4ents with familial hypercholesterolaemia PCSK9 inhibitors are effec4ve when added to other lipid-‐modifying treatment, including high-‐intensity sta4n therapy Preliminary data on CV outcomes provide a possible improvement in long-‐term cardiovascular prognosis with these agents in pa4ents with hypercholesterolemiae The tolerability and safety profiles of these agents so far support long-‐term administra4on for hypercholesterolemia

Take home

Take home Which patients will benefit ? People with familial hypercholesterolaemia

Avoid early onset of cardiovascular disease No optimal control of LDL-cholesterol on current therapies

People with statin intolerance People at high CV risk who are not at their LDL-C goal

Primary or Secundary prevention

Take home

Statins will likely remain the basis of lipid lowering treatment in the foreseeable future due to their relatively low costs, oral availability, and their established beneficial safety profile and clinical efficacy PCSK9 inhibition may provide a dramatic improvement in our ability to get high-risk patients to their LDL cholesterol goal Discussion on the potential role of PCSK9 will therefore focus on the desired balance between additional absolute CV risk reduction and costs

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pcsk-9 inhibition -...

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