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
CBFKARDIOLOGIE
Atherosclerosis development: subendothelial
LDL deposition - electron microscopy studies
Aldis JL, Nature. 2000 Feb 21;451(7181):904-13
Subendothelial LDL particlesTransmigration
of monocytes
CBFKARDIOLOGIE
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)
CBFKARDIOLOGIE
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)
CBFKARDIOLOGIE
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.
CBFKARDIOLOGIE
Stroes ES et al. Eur Heart J 2015 ;36:1012-1022
Statin Associated Muscle Symptoms (SAMS)
CBFKARDIOLOGIE
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).
CBFKARDIOLOGIE
Monoclonal AB
PCSK9 – mechanims to lower LDL
CBFKARDIOLOGIE
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
CBFKARDIOLOGIE
CBFKARDIOLOGIE
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
CBFKARDIOLOGIE
* 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
CBFKARDIOLOGIE
PCSK9 –Inhibition and cardiovascular events
NEJM 2015
CBFKARDIOLOGIE
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
CBFKARDIOLOGIE
Open-Label Study of Long-Term Evaluation
against LDL Cholesterol (OSLER)
NEJM 2015
CBFKARDIOLOGIE
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
CBFKARDIOLOGIE
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
CBFKARDIOLOGIE
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),
CBFKARDIOLOGIE
Network meta-analysis in primary
hypercholesterolemia
CBFKARDIOLOGIE
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
CBFKARDIOLOGIE
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
CBFKARDIOLOGIE
Neue ESC NSTE-ACS-Guidelines
Eur Heart J. 2016 Jan 14;37(3):267-315
CBFKARDIOLOGIE
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