CBFKARDIOLOGIE

ULF Landmesser

Berlin, 09th December 2014

Ulf LandmesserChairman, Department of Cardiology

Charité – Universitätsmedizin Berlin (CBF)

Statin intolerance and

PCSK9 inhibitors

SGK Annual Congress 2016

CBFKARDIOLOGIE

1) LDL cholesterol in prevention of

coronary disease

2) Statin intolerance – SAMS

3) Recent developments using

PCSK9 inhibition

Statin intolerance and

PCSK9 inhibitors

CBFKARDIOLOGIE

•Cell. 2015 Mar 26;161(1):161-72

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Atherosclerosis development: subendothelial

LDL deposition - electron microscopy studies

Aldis JL, Nature. 2000 Feb 21;451(7181):904-13

Subendothelial LDL particlesTransmigration

of monocytes

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Authors/Task Force Meeting. Eur Heart J 2013

Lipid-lowering agents:Patients with documented CAD should be treated

with statins.

The treatment target is:LDL-C < 1.8 mmol/L and/or

< 50% reduction (if the target level cannot be reached)

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Prevalence of raised BP*, elevated LDL-C**

and diabetes in CAD: EUROASPIRE

* SBP/DBP ≥ 140/90 mmHg (≥ 140/80 mmHg for patients with diabetes); LDL ≥ 1.8 mmol/L;***Fasting glucose ≥ 7 mmol/L for patients without history of diabetes

EUROASPIRE II

EUROASPIRE III

EUROASPIRE IV

P<0.0001

p=0.01

p=0.0004

p=0.78

CBFKARDIOLOGIE

1) LDL cholesterol in prevention of

coronary disease

2) Statin intolerance – SAMS

3) Recent developments using

PCSK9 inhibition

Statin intolerance and

PCSK9 inhibitors

CBFKARDIOLOGIE

Muscle symptoms

Liver toxicity

Proteinuria

Statintherapy

Neurocognitive

Symptoms ?

Dysglycemia

New onset

diabetes

Statin Associated Muscle Symptoms (SAMS)

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Definition of Muscle Symptoms

Myalgia:

muscle discomfort – no CK elevations

Myositis: muscle discomfort (‘inflamm.’) + CK elev.

mild: < 4-foldmoderate: 4–10-foldsevere: > 10-fold

Rhabdomyolysis: Myonecrosis + CK elevation and Myoglobinuria/serum creatine increase

.

Rosenson RS, et al. J Clin Lipidol 2014,8 (3 Suppl):S58–71.

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Stroes ES et al. Eur Heart J 2015 ;36:1012-1022

Statin Associated Muscle Symptoms (SAMS)

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Management of a patient with SAMSstep II: Use a standardized approach

Stroes Eur Heart J 2015

PCSK9 Inhibition ?

CBFKARDIOLOGIE

1) LDL cholesterol in prevention of

coronary disease

2) Statin intolerance – SAMS

3) Recent developments using

PCSK9 inhibition

Statin intolerance and

PCSK9 inhibitors

CBFKARDIOLOGIE

PCSK9 und LDL: Development towards clinical application

2001 2002 2003 2004 2005 2006 2007 2008 2010 2011 20122009

• Entdeckung PCSK9

(NARC-1)

• PCSK9 GOF-Mutationen

sind ursächlich für FH

• PCSK9 LOF-Mutationen:

28% LDL-C-Reduktion +

88% Risikoreduktion

kardiovaskulärer Ereignisse

• Individuen ohne PCSK9

haben einen LDL-C-Spiegel

von ~15 mg/dl

• Erste PCSK9-

Antikörper-Tests

in Affen

• Erster Mensch wird

mit einem PCSK9-

Antikörper behandelt

• Erste Patienten werden mit

einem PCSK9-Antikörper

behandelt

• Start der Phase

III Studien

• PCSK9-

Überexpression

in vitro

(LDL-C ↑)

• PCSK9 bindet an

den LDL-

Rezeptor

• PCSK9-

knockout

Maus (LDL-C ↓)

2013

• Seidah, N. G. et al., Circ. Res. 114, 1022-1036 (2014).

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Monoclonal AB

PCSK9 – mechanims to lower LDL

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Development of monoclonal antibodies

• I. N. Foltz et al., Circulation 127, 2222 (2013).

Muriner

Antikörper

100%

Maus-Proteine

Chimärer

Antikörper

ca. 33%

Maus-Proteine

Humanisierter

Antikörper

ca. 10%

Maus-Proteine

Vollhumaner

Antikörper

100%

menschliche Proteine

-

omab

-

ximab

-

zumab

-

umab

Generisch

e

Endung

Immunogenes Potentialhoch niedrig

CBFKARDIOLOGIE

PCSK9 Inhibitors: clinical trial programs

Nature Cardiology 2014

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Intolerance to ≥3 statins or 2 statins (one

of which was atorvastatin ≤10 mg/day) or

with a history of marked creatine kinase

elevation accompanied by muscle

symptoms while on a statin.

GAUSS-3

CBFKARDIOLOGIE

Date of download: 4/13/2016Copyright © 2016 American Medical

Association. All rights reserved.

From: Efficacy and Tolerability of Evolocumab vs Ezetimibe

in Patients With Muscle-Related Statin Intolerance:

The GAUSS-3 Randomized Clinical TrialJAMA. Published online April 03, 2016. doi:10.1001/jama.2016.3608

CBFKARDIOLOGIE

Date of download: 4/13/2016Copyright © 2016 American Medical

Association. All rights reserved.

From: Efficacy and Tolerability of Evolocumab vs Ezetimibe

in Patients With Muscle-Related Statin Intolerance:

The GAUSS-3 Randomized Clinical TrialJAMA. Published online April 03, 2016. doi:10.1001/jama.2016.3608

CBFKARDIOLOGIE

From: Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin

Intolerance: The GAUSS-3 Randomized Clinical Trial

JAMA. Published online April 03, 2016. doi:10.1001/jama.2016.3608

Time to First Occurrence of a Muscle-Related Adverse Effect Resulting in Discontinuation of Study Drug During

Period 1 and Period 2 of Phase A, GAUSS-3 Trial Atorvastatin dose, 20 mg daily; placebo indicates matching placebo.

GAUSS-3 indicates Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3.

Time to First Occurrence of a Muscle-Related Adverse Effect

Resulting in Discontinuation of Study Drug

CBFKARDIOLOGIE

Date of download: 4/13/2016Copyright © 2016 American Medical

Association. All rights reserved.

From: Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin

Intolerance: The GAUSS-3 Randomized Clinical Trial

JAMA. Published online April 03, 2016. doi:10.1001/jama.2016.3608

Mean Percent Change in Low-Density Lipoprotein Cholesterol Level During Randomized Treatment With Ezetimibe or Evolocumab,

GAUSS-3 Trial

Ezetimibe dose, 10 mg daily; evolocumab dose, 140 mg 3 times monthly (420 mg total dosage). GAUSS-3 indicates Goal

Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3. Error bars indicate 95% CIs.

CBFKARDIOLOGIEODYSSEY ALTERNATIVE

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* Unfähigkeit 2 verschiedene Statine aufgrund muskulärer Beschwerden zu tolerieren, eines davon bereits in der geringsten Dosierung.

Placebo Run-In-Phase

Treatment -Phase (24 Wochen)

Open Label Extension

Atorvastatin 20 mg PO QD + Placebo SC Q2W

n=63

Alirocumab 75/150 mg SC Q2W + Placebo PO QD

n=126

Randomisation

0 24-4 0

Ezetimib 10 mg PO QD + Placebo SC Q2W

n=125

Primärer Efficacy

Endpoint

ODYSSEY ALTERNATIVE

CBFKARDIOLOGIEODYSSEY ALTERNATIVE

CBFKARDIOLOGIEODYSSEY ALTERNATIVE

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PCSK9 –Inhibition and cardiovascular events

NEJM 2015

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27

Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment,

including 607 patients who completed W78 visit)

Intent-to-treat (ITT) analysis

No. at RiskPlaceboAlirocumab

Weeks

Mean treatment duration: 65 weeks

Placebo + max-tolerated statin ± other LLT

Cu

mu

lati

ve p

rob

abili

ty o

f e

ven

t

Alirocumab + max-tolerated statin ± other LLT

Cox model analysis:HR=0.46 (95% CI: 0.26 to 0.82)Nominal p-value = <0.01

847260483624120

0.06

0.05

0.04

0.02

0.01

0.00

0.03

788

1550

776

1534

731

1446

703

1393

682

1352

667

1335

321

642

127

252

NEJM 2015

PCSK9 –Inhibition and cardiovascular events:Post-hoc adjudicated cardiovascular TEAEs - safety analysis

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Open-Label Study of Long-Term Evaluation

against LDL Cholesterol (OSLER)

NEJM 2015

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Sabatine M | ACC 2015

OSLER

29

Treatment effect was apparent in all subgroups

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

Cum

ula

tive

In

cid

en

ce

(%

)

3

2

1

0

HR 0.47

95% CI 0.28-0.78

P=0.003 Standard of care alone

(N=1489)

Months since randomization

Evolocumab plus standard of care

(N=2976)

2.18%

0.95%

NEJM 2015

PCSK9 Hemmung und kardiovaskuläre Ereignisse:

OSLER Results – cardiovascular outcome

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Relative risk reduction of major adverse cardiovascular

events (MACE) by lipid-lowering strategy

Baris Gencer, and François Mach Eur Heart J

2015;36:1146-1148

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Network meta-analysis in primary

hypercholesterolemia

Our meta-analysis included 17 RCTs with 13 083 patients that were

randomized to PCSK9 inhibitors (n = 8250), placebo (n = 3957),

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Network meta-analysis in primary

hypercholesterolemia

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Network meta-analysis in primary

hypercholesterolemia

We only included neurocognitive adverse event data from studies that

specifically defined an outcome as an adverse neurocognitive event.

CBFKARDIOLOGIE

PCSK9 inhibition clinical outcome trials

Chapman J, Blankenberg S, Landmesser U. Eur Heart J 2016 (in press)

CBFKARDIOLOGIE

1) LDL cholesterol in prevention of

coronary disease

2) Statin intolerance – SAMS

3) Recent developments using

PCSK9 inhibition

Statin intolerance and

PCSK9 inhibitors

CBFKARDIOLOGIECBFKARDIOLOGIEThank you

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CBFKARDIOLOGIE

Date of download: 4/13/2016Copyright © 2016 American Medical

Association. All rights reserved.

From: Efficacy and Tolerability of Evolocumab vs Ezetimibe

in Patients With Muscle-Related Statin Intolerance:

The GAUSS-3 Randomized Clinical TrialJAMA. Published online April 03, 2016. doi:10.1001/jama.2016.3608

CBFKARDIOLOGIE

PCSK9 Inhibitors: clinical trial programs

Nature Cardiology 2014

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Neue ESC NSTE-ACS-Guidelines

Eur Heart J. 2016 Jan 14;37(3):267-315

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