M. John Chapman BSc (Hons), Ph.D., D.Sc., FESC
Director Emeritus, INSERM,
Research Professor, University of Pierre and Marie Curie
Past-President, European Atherosclerosis Society
Pitié-Salpetriere University Hospital,
Paris, France
Fernando-Cruz Foundation Symposium,
Hospital Clinico San Carlos, Madrid 2015
Management of Hypercholesterolemia beyond Statins :
ODYSSEY and OSLER Trials
PCSK9 Inhibitors:
From Target Discovery to Phase III to the Clinic
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
PCSK9 (NARC-1) discovered
PCSK9 GOF mutations
associated with ADH*
PCSK9 LOF Mutations found with 28% LDL-C and 88% CHD risk
Humans null for PCSK9 have LDL-C ~15 mg/dL
Plasma PCSK9 binds to LDL-R
First Patientswith FH
/ non-FH treated with PCSK9i mAb
1st FDA / EMEA PCSK9i filing
Adenoviral expression in mice
PCSK9 KO mouse LDL-C
First subject treated with PCSK9 mAb
LDL-C in mice andnon-human primates treated
with anti-PCSK9 mAb
First publication
POC in patients
* ADH: Autosomal Dominant Hypercholesterolemia; Seidah NG. Proc Natl Acad Sci US 2003;100(3):928-33, Abifadel M. Nat Genet 2003;34(2):154-6, Maxwell KN. Proc Natl Acad Sci US 2004;101(18):7100-5, Rashid S. Proc Natl Acad Sci US 2005;102(15):5374-79, Lagace TA et al. JCI 2006;116:2995-3005 Cohen JC. N Engl J Med 2006;354(12):1264-72, Zhao Z. Am J Hum Genet 2006;79(3):514-23, Hooper AJ. Atherosderosis 2007;193(2):445-8, Chan JC. Proc Natl Acad Sci US 2009;106(24):9820-5: Stein et at N Engl J Med 2012;366:1108-18;Stein modified from Swergold, Regeneron.
• Cell membrane component
• Steroid hormone precursor
• Vitamin D precursor
• Bile acid precursor
• LXR agonist (oxysterols)
CHOLESTEROL
NY-160626.038/020131YlsjoLS1
CHOLESTEROL HOMEOSTASIS
WHOLE BODY
ExcretionDietary
Cholesterol
Biliary
Cholesterol
Intestine Liver
Peripheral
Tissue
Cholesterol
Pool
Synthesis
Cholesterol
Pool
Synthesis
Cholesterol
Pool
Synthesis
Skin
Cholesterol
Pool
Synthesis
Cholesterol
Pool
Synthesis
Endocrine
Glands
CM
VLDL LDL
nascentHDL HDL
Biliary
Cholesterol
600 mg/j
Bile
Acids
400 mg/j
Steroïd
Hormones
50 mg/j
Skin
Sterols
85 mg/j
NPC1L1
NPC1L1
Inflammation- macrophages
- T lymphocytes
- mast cells
Courtesy: Erling Falk
Thin cap
Cholesterol
crystals
Thin cap, rupture-prone atherosclerotic plaque
Lipid-rich core
LDL is causalin the pathophysiology of atherosclerotic vascular
disease
•INTERHEART
•Familial hypercholesterolemia
•RCTs with statins and cholesterol absorption inhibition
•Mendelian randomisation studies
•PCSK9 genetics
•Origin of Plaque components
•Modulation of Plaque composition and size by Statins
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 VIIIV
A
B
C
Control of plasma LDL- cholesterol levels:
Key role of the cellular LDL receptor
http://www.iemrams.spb.ru/english/molgen/fh-en/domain-e.htm. [Accessed 6 August 2015]
LDLR
ER Golgi
Coated vesicle
Endosome(H+)
Lysosome(H+)
Recyclingvesicle
Plasma LDL degradation by the LDL Receptor pathway
Coated pit
LDL
Which factors principally control
levels of LDL receptor activity in the liver ?
Control of hepatic LDL-Receptor activity
- Intracellular levels of cholesterol
(reflecting uptake of cholesterol contained in LDL,
VLDL and chylomicron remnants, and HDL), endogenous
cholesterol synthesis, cholesterol conversion to bile acids, and
excretion of bile acids and biliary cholesterol)
via the SREBP pathway
- PCSK9
- the IDOL pathway
Control of hepatic LDL-Receptor activity
- Intracellular levels of cholesterol
(reflecting uptake of cholesterol contained in LDL,
VLDL and chylomicron remnants, and HDL), endogenous
cholesterol synthesis, cholesterol conversion to bile acids, and
excretion of bile acids and biliary cholesterol)
via the SREBP pathway
- PCSK9
- the IDOL pathway
What is PCSK9 ?
How was PCSK9 identified as a key
gene in cholesterol homeostasis ?
What is PCSK9?
• Expressed in liver, kidney, intestine
• Undergoes autocatalytic cleavage in the ER to active conformation
• Appears to play the role of an intracellular protein chaperone
http://www.genecards.org/cgi-bin/carddisp.pl?gene=PCSK9/. [Accessed 19 July 2011]
Abifadel M, et al. Nature Genet 2003;34:154–6.
Abifadel M, et al. Hum Mutat 2009;30:520–9.
Chromosome:
• 1p32.3
Gene:
• 12 exons
• cDNA 3617 bp
Protein:
• 692 amino acids
Horton JD, et al. Trends Biochem Sci 2007;32:71–7.
Chen SN, et al JACC 2005;45:1611–9.
A PCSK9 GAIN-of-Function mutation causes
Autosomal Dominant Hypercholesterolaemia
Abifadel M, et al. Nat Genet 2003;34:154–6.
Affected family members with:
• Total cholesterol in 90th percentile
• Tendon xanthomas
• CHD
• Early MI
• Stroke
Absence of PCSK9 Leads to Marked Increase in LDL-R
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
Role of PCSK9 in regulation of
the surface expression of LDL receptors
LDL particles
LDL-R
PCSK9 secretion
PCSK9 routes LDL-R for lysosomal degradation
LDL-R recycling blocked
Chan JC, et al. Proc Natl Acad Sci USA 2009;106:9820–5..
Regulation of PCSK9 is dynamic
1. Horton JD, et al. J Lipid Res. 2009;50:S172–7.
2. Lopez D. Biochem Biophys Acta 2008;1781:184–91.
3. Abifadel M, et al. Hum Mutat. 2009;30: supplementary information.
4. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010:3–23.
5. Miao et al, ATVB. 2015;35:1589-1596.
• Dietary and cellular cholesterol4
• Bile acids3,4
Plasma PCSK9 levelDownregulates PCSK9
Upregulates PCSK9
• Cholesterol depletion2,3
• SREBP2 1,3,4
• Statins3,4
Is there a major flaw In the MOA of
statins ?
Mechanism of statin-mediated upregulationof the LDLR gene via SREBP2
Statin SREBP2
LDLRLysosomal
degradation
LDL-C
Hepatocyte
Mechanism of statin-mediated upregulation
of the LDLR and PCSK9 genes via SREBP2
Statin SREBP2
LDLR PCSK9Lysosomal
degradation
LDL-C
Hepatocyte
Adapted from Konrad RJ et al. Lipids Health Dis 2011;10:38.
PCSK9
How do genetic mutations/variants in
PCSK9 relate to LDL-C levels and CV risk ?
Can PCSK9 be targeted to reduce LDL-C
and CVD ?
Genetic variants of PCSK9 exert
distinct roles in regulating LDL-C levels
PCSK9 Gain of Function
= Less LDLRs
PCSK9 Loss of Function
= More LDLRs
Already in JC
presentation but I will
get better picture
quality for both
PCSK9 secretion
Plasma
Lysosomal degradation of LDLR Recycling of LDLR
Golgi apparatus
Nucleus
Gain-of-functionmutation
Plasma
Loss-of-functionmutation
Gain-of-function PCSK9 Loss-of-function PCSK9
Control 105
D35Y
L108R
S127R
F216L
R218S
D374Y
249
266
287
227
216
350
Poirier S, Mayer G. Drug Des Devel Ther 2013;7:1135–48.
RARE
Elevated LDL-C levels in patients
with GAIN-of-Function PCSK9 mutations
Poirier S, Mayer G. Drug Des Devel Ther 2013;7:1135–48.
Control
R46L
R97
G106R
Y142X
C679X
86
58
89
53
68
105
FREQUENT
Low LDL-C levels in patients
with LOSS-of-Function PCSK9 mutations
Loss-of-Function PCSK9 mutations are associated
with low LDL-C and low prevalence of CHD events
Adapted from Cohen JC et al. N Engl J Med 2006;354:1264–72.
30
20
10
09.7%
PCSK9142x or
PCSK9679X
No Yes
12
8
4
0
0 50 100 150 200 250 300
30
20
10
00 50 100 150 200 250 300
No nonsense
mutation(n = 3278)
50th Percentile
Plasma LDL-C in black subjects (mg/dL)
Fre
qu
en
cy (
%)
1.2%
PCSK9142x or
PCSK9679X
(n=85)
Coro
na
ry H
ea
rt D
ise
ase
(%
)
Mean 138 mg/dL
Mean 100 mg/dL
(-28%)
88% reduction in risk of CHD
events during 15-year follow-up
• Individuals who completely lack PCSK9 and
have very low LDL-C levels are healthy
• Therefore, inhibition of PCSK9 may be
a safe pharmacologic approach
to dyslipidaemia management
Bind plasma PCSK9
• Monoclonal antibodies
− Evolocumab, now EMEA approved (Amgen)
− Alirocumab, now FDA approved (Regeneron/Sanofi)
− Bococizumab (Pfizer)
• Adnectins (Adnexis/BMS)
Reduce PCSK9 synthesis
• siRNA (Alnylam)
Approaches to reducing PCSK9 interaction with the LDLR
Lambert G, et al. J Lipid Res. 2012. 53: 2515–24.
http://www.lilly.com/SiteCollectionDocuments/Pipeline/Clinical%20Development%20Pipeline/index.html. [Accessed 6 August 2015]
Impact of an anti-PCSK9 monoclonal antibody on LDL-R
expression
Chan JC, et al. Proc Natl Acad Sci USA 2009;106:9820–5.
LDLR recycling
LDLR PCSK9
Increased LDLR surface concentration
Anti-PCSK9 mAb
Alirocumab: Dynamic Relationship Between mAb Levels, PCSK9 and LDL-C
-70
-60
-50
-40
-30
-20
-10
0
0
20
40
60
80
100
120
140
160
180
200
0 500 1000 1500 2000 2500
LD
L-C
mean %
change
2 W
Total alirocumab
Free PCSK9
LDL-CFre
e/tota
l P
CS
K9 C
onc. (n
g/m
L)
Tota
l alir
ocum
ab (
ng/m
L)
X 0
.01
Time (hours)
Stein EA et al. New Engl J Med 2012;366:1108–18.
Familial Hypercholesterolemia (HeFH and HoFH)• LDL-C levels often far from goal, even with potent statins
and combination therapies • Life-long exposure to high LDL-C; considered high risk
even w/o additional risk factors
High CV Risk Patients• Patients not at LDL-C goal with currently available LLT
(even high doses of potent statins) and persistent high risk
Statin Intolerant Patients • LDL-C levels often far from goal, due to intolerance• Patients unable to tolerate at least 2 statins, including
one at the lowest dose
The CV Risk Pyramid :
Greatest clinical needs
Metabolic
syndrome
Chronic
kidney
disease
(SHARP)
Type 2
diabetes
Ischaemic
Stroke
Acute Coronary
Syndromes
Very high and
high risk
Dyslipidaemic
patient
populations
Stable;
Unstable
CAD
Non-FH
hyperchol
Chapman, MJ. Unpublished.
FH
Auto-immune
disorders
Overview of ODYSSEY Phase 3 Clinical Trial Program
ODYSSEY FH II (NCT01709500; CL1112)
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=250; 18 months
14 global phase 3 trials including >23,500 patients across >2,000 study centers
HeFH population HC in high CV risk population Additional populations
ODYSSEY HIGH FH (NCT01617655; EFC12732)
LDL-C ≥160 mg/dL
N=105; 18 months
ODYSSEY ALTERNATIVE (NCT01709513; CL1119)
Patients with defined statin intolerance
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=250; 6 months
ODYSSEY OPTIONS II (NCT01730053; CL1118)
Patients not at goal on moderate dose rosuvastatin
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=300; 6 months
ODYSSEY MONO (NCT01644474; EFC11716)
Patients on no background LMTs
LDL-C ≥100 mg/dL
N=100; 6 months
ODYSSEY OPTIONS I (NCT01730040; CL1110)
Patients not at goal on moderate dose atorvastatin
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=350; 6 months
ODYSSEY COMBO I (NCT01644175; EFC11568)
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=306; 12 months
ODYSSEY FH I (NCT01623115; EFC12492)
LDL-C ≥ 70 mg/dL OR LDL-C ≥100 mg/dL
N=471; 18 months
ODYSSEY LONG TERM (NCT01507831; LTS11717)
LDL-C ≥70 mg/dL
N=2,100; 18 months
ODYSSEY OUTCOMES (NCT01663402; EFC11570)
LDL-C ≥70 mg/dL
N=18,000; 64 months
Add-on to max-tolerated statin
(± other LMT)
Add-on to max-tolerated statin
(± other LMT)
*ODYSSEY COMBO II (NCT01644188; EFC11569)
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=660; 24 months
FH=familial hypercholesterolemia; HC=hypercholesterolemia; LMT=lipid-modifying therapy; OLE=open-label extension.
*For the ODYSSEY COMBO II other LMT not allowed at entry.
ClinicalTrials.gov. ODYSSEY Phase 3 Trials. http://clinicaltrials.gov. Accessed February 12, 2014.
ODYSSEY CHOICE I (NCT01926782; CL1308)
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=700; 12 months
ODYSSEY CHOICE II (NCT02023879; EFC13786)
Patients not treated with a statin
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=200; 6 months
ODYSSEY OLE (NCT01954394; LTS 13463)
Open-label study for FH from EFC 12492,
CL 1112, EFC 12732 or LTS 11717
N≥1000; 30 months
Evolocumab Clinical Trial Program
33
Program to
Reduce LDL-C and
Cardiovascular
Outcomes
Following
Inhibition of
PCSK9
In Different
Populations
(Latin):
•To advance
•To make progress
Evolocumab’s PROFICIO clinical trial program addresses key areas of
unmet need in the management of dyslipidaemia
HeFH, heterozygous hypercholesterolaemia; HoFH, homozygous hypercholesterolaemia. Clintrials.gov. * Amgen data on file.
Combinationtherapy
Statin intolerant
Monotherapy
HeFH
Long-term safety and efficacy
Open-labelextension
HoFH/ Severe FH
SecondaryPrevention
Atherosclerosis
Phase 2(n=631)
Phase 3(n=2067)
Phase 2(n=411)
Phase 3(n=615)
Phase 2(n=160)
Phase 3(n=331)
Phase 2(n=168)
Phase 2(n=1104)
Phase 3(n=3671)*
Phase 3(n=905)
Phase 3(n=27,564)
Phase 3(n=970)
Phase 2/3(n=300)
Phase 2/3(n=58)
NeurocognitionPhase 3
(n=1971)*
Phase 3(n=511)*
Phase 3(n=307)
Completedtrials
>35,000 patients
SPIRE Phase 3 Bococizumab Clinical Development ProgrammeUnmet Needs in the Management of CVD in High Risk Patients
SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events) N=~30,000
SPIRE HR (n=300)
On statinHigh risk of CV event
LDL-C ≥70 or ≥100 mg/dL
SPIRE LDL (n=1,932)
On statinHigh risk of CV event
LDL-C ≥70 mg/dL
SPIRE FH (n=300)
HeFH (genetic diagnosis or Simon Broome Criteria),
LDL >70 mg/dL
SPIRE Lipid Lowering Studies SPIRE CV Outcome Studies
SPIRE LL (n=690)
On statinHigh / very high risk of
CV eventLDL-C ≥100 mg/dL
SPIRE SI (n=150)
Statin intolerantLDL-C ≥70 mg/dL
SPIRE-1 (n=17,000)
High Risk Primary and Secondary Prevention
LDL-C ≥70 to <100 mg/dLon statins (or statin
intolerant)
SPIRE-2 (n=9,000)
High Risk Primary and Secondary PreventionLDL-C ≥100 mg/dL on
statins (or statin intolerant)
NCT#: https://clinicaltrials.gov
SPIRE HR: NCT01968954
SPIRE LDL: NCT01968967
SPIRE HF: NCT01968980
SPIRE-LL: NCT02100514
SPIRE-SI: NCT02135029
SPIRE-1: NCT01975376
SPIRE-2: NCT01975389Studies on PCSK9 Inhibition and the
Reduction of Vascular Events
Overview of ODYSSEY Phase 3 Clinical Trial Program
ODYSSEY FH II (NCT01709500; CL1112)
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=250; 18 months
14 global phase 3 trials including >23,500 patients across >2,000 study centers
HeFH population HC in high CV risk population Additional populations
ODYSSEY HIGH FH (NCT01617655; EFC12732)
LDL-C ≥160 mg/dL
N=105; 18 months
ODYSSEY ALTERNATIVE (NCT01709513; CL1119)
Patients with defined statin intolerance
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=250; 6 months
ODYSSEY OPTIONS II (NCT01730053; CL1118)
Patients not at goal on moderate dose rosuvastatin
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=300; 6 months
ODYSSEY MONO (NCT01644474; EFC11716)
Patients on no background LMTs
LDL-C ≥100 mg/dL
N=100; 6 months
ODYSSEY OPTIONS I (NCT01730040; CL1110)
Patients not at goal on moderate dose atorvastatin
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=350; 6 months
ODYSSEY COMBO I (NCT01644175; EFC11568)
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=306; 12 months
ODYSSEY FH I (NCT01623115; EFC12492)
LDL-C ≥ 70 mg/dL OR LDL-C ≥100 mg/dL
N=471; 18 months
ODYSSEY LONG TERM (NCT01507831; LTS11717)
LDL-C ≥70 mg/dL
N=2,100; 18 months
ODYSSEY OUTCOMES (NCT01663402; EFC11570)
LDL-C ≥70 mg/dL
N=18,000; 64 months
Add-on to max-tolerated statin
(± other LMT)
Add-on to max-tolerated statin
(± other LMT)
*ODYSSEY COMBO II (NCT01644188; EFC11569)
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=660; 24 months
FH=familial hypercholesterolemia; HC=hypercholesterolemia; LMT=lipid-modifying therapy; OLE=open-label extension.
*For the ODYSSEY COMBO II other LMT not allowed at entry.
ClinicalTrials.gov. ODYSSEY Phase 3 Trials. http://clinicaltrials.gov. Accessed February 12, 2014.
ODYSSEY CHOICE I (NCT01926782; CL1308)
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=700; 12 months
ODYSSEY CHOICE II (NCT02023879; EFC13786)
Patients not treated with a statin
LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL
N=200; 6 months
ODYSSEY OLE (NCT01954394; LTS 13463)
Open-label study for FH from EFC 12492,
CL 1112, EFC 12732 or LTS 11717
N≥1000; 30 months
Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT01623115; ODYSSEY FH II: NCT01709500.
Placebo Q2W SC
R
n=323 (FH I); n=167 (FH II)
n=163 (FH I); n=82 (FH II)
HeFH patients on
max tolerated statin
± other lipid-
lowering therapy
OLE
/8 w
eek F
U
Alirocumab 75 mg Q2W SC with potential ↑ to 150 mg Q2W SC(single 1-mL injection using prefilled pen for self-administration)
AssessmentsW0 W8 W16 W36
W52
Double-Blind Treatment Period (78 Weeks)
Primaryefficacy endpoint
W64
W4 W12 W24 W78
LDL-C ≥1.81 mmol/L
[70 mg/dL]
(history of CVD)
or
2.59 mmol/L
[100 mg/dL]
(no history of CVD)
Dose ↑ if LDL-C >70 mg/dL
at W8
Pre-specified analysisEfficacy: All Patients To W52Safety: Baseline-W78 (all patients at least W52)
Per-protocol dose ↑ possible based
on pre-specified LDL-C level
ODYSSEY FH I and FH II Study Design
Kastelein, ESC 2014
†Patients should receive either rosuvastatin 20-40 mg, atorvastatin 40-80 mg daily, or simvastatin 80
mg daily unless not tolerated and/or appropriate other dose given according to the judgement of the
investigator.
‡High-intensity statin: atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily.
Lipid Medication and LDL-C at Baseline
Any statin†, % (n) 100% 100% 100% 100%
High-intensity statin‡, % (n) 80.8% (261) 82.8% (135) 86.2% (144) 87.8% (72)
Ezetimibe, % (n) 55.7% (180) 59.5% (97) 67.1% (112) 64.6% (53)
LDL-C, mean (SD), mmol/L
[mg/dL]
3.7 (1.3)
[144.7 (51.2)]
3.7 (1.2)
[144.4 (46.8)]
3.5 (1.1)
[134.6 (41.3)]
3.5 (1.1)
[134.0 (41.6)]
All patients on background
of max-tolerated statin ±
other lipid-lowering
therapy
FH I FH II
Alirocumab
(N=323)
Placebo
(N=163)
Alirocumab
(N=167)
Placebo
(N=82)
Kastelein, ESC 2014
Alirocumab Significantly Reduced LDL-C from
Baseline to Week 24 versus Placebo
LS
me
an
(S
E)
% c
ha
ng
e f
rom
ba
se
lin
e t
o W
ee
k 2
4
LS mean
difference (SE)
vs. placebo:
N=163
Alirocumab
N=322
−57.9% (2.7)
P<0.0001
N=81N=166
−51.4% (3.4)
P<0.0001
FH IPlacebo
FH II
43.4%
had dose
increase
at W12
38.6%
had dose
increase
at W12
Primary Endpoint: % Change from Baseline to Week 24 in LDL-C
Intent-to-treat (ITT) Analysis Kastelein, ESC 2014
Evolocumab’s PROFICIO clinical trial program addresses key areas of
unmet need in the management of dyslipidaemia
HeFH, heterozygous hypercholesterolaemia; HoFH, homozygous hypercholesterolaemia. Clintrials.gov. * Amgen data on file.
Combinationtherapy
Statin intolerant
Monotherapy
HeFH
Long-term safety and efficacy
Open-labelextension
HoFH/ Severe FH
SecondaryPrevention
Atherosclerosis
Phase 2(n=631)
Phase 3(n=2067)
Phase 2(n=411)
Phase 3(n=615)
Phase 2(n=160)
Phase 3(n=331)
Phase 2(n=168)
Phase 2(n=1104)
Phase 3(n=3671)*
Phase 3(n=905)
Phase 3(n=27,564)
Phase 3(n=970)
Phase 2/3(n=300)
Phase 2/3(n=58)
NeurocognitionPhase 3
(n=1971)*
Phase 3(n=511)*
Phase 3(n=307)
Completedtrials
>35,000 patients
Evolocumab Q2W or QM:
consistent LDL-C reductions across different studies
Results are for the mean of weeks 10 and 12 except for DESCARTES, which are for week 52.MENDEL-2: Koren MJ, et al. J Am Coll Cardiol 2014;63:2531–40; LAPLACE-2: Robinson JG, et al. JAMA 2014;311:1870–82; RUTHERFORD-2: Raal FJ, et al.
Lancet 2015;385:331–40; DESCARTES: Blom DJ, et al. N Engl J Med 2014;370:1809–19; GAUSS-2: Stroes E, et al. J Am Coll Cardiol 2014;63:2541–8.
MonotxMENDEL-2
N=614
MonotxMENDEL-2
N=614
CombotxLAPLACE-2
N=1896
HeFHRUTHERFORD-2
N=329
SIGAUSS-2N=307
Long TermDESCARTES
N=901
CombotxLAPLACE-2
N=1896
Evolocumab 140 mg Q2W Evolocumab 420 mg QM
Treatment difference for
% change from baseline
in LDL-C
Evolocumab vs placebo:consistent reduction in LDL-C, Q2W and QM
Evolocumab vs ezetimibe:consistent reduction in LDL-C, Q2W and QM
Evolocumab’s PROFICIO clinical trial program addresses key areas of
unmet need in the management of dyslipidaemia
HeFH, heterozygous hypercholesterolaemia; HoFH, homozygous hypercholesterolaemia. Clintrials.gov. * Amgen data on file.
Combinationtherapy
Statin intolerant
Monotherapy
HeFH
Long-term safety and efficacy
Open-labelextension
HoFH/ Severe FH
SecondaryPrevention
Atherosclerosis
Phase 2(n=631)
Phase 3(n=2067)
Phase 2(n=411)
Phase 3(n=615)
Phase 2(n=160)
Phase 3(n=331)
Phase 2(n=168)
Phase 2(n=1104)
Phase 3(n=3671)*
Phase 3(n=905)
Phase 3(n=27,564)
Phase 3(n=970)
Phase 2/3(n=300)
Phase 2/3(n=58)
NeurocognitionPhase 3
(n=1971)*
Phase 3(n=511)*
Phase 3(n=307)
Completedtrials
>35,000 patients
Figure 2
Raal FJ et al. Lancet 2015; 385: 331–40
Efficacy of LDL-C lowering by Evolocumab in heterozygous FH patients : RUTHERFORD-2
Evolocumab 140 mg Q2W Evolocumab 420 mg QM
Raal FJ, et al. Lancet 2014; doi.org/10.1016/S0140-6736(14)61399-4 and supplementary material.
45
On treamentresidual
LDL= 280 mg/dL
46Raal et al ISA 2015
TAUSSIG
Cuchel et al, EHJ 2014
Evolocumab’s PROFICIO clinical trial program addresses key areas of
unmet need in the management of dyslipidaemia
HeFH, heterozygous hypercholesterolaemia; HoFH, homozygous hypercholesterolaemia. Clintrials.gov. * Amgen data on file.
Combinationtherapy
Statin intolerant
Monotherapy
HeFH
Long-term safety and efficacy
Open-labelextension
HoFH/ Severe FH
SecondaryPrevention
Atherosclerosis
Phase 2(n=631)
Phase 3(n=2067)
Phase 2(n=411)
Phase 3(n=615)
Phase 2(n=160)
Phase 3(n=331)
Phase 2(n=168)
Phase 2(n=1104)
Phase 3(n=3671)*
Phase 3(n=905)
Phase 3(n=27,564)
Phase 3(n=970)
Phase 2/3(n=300)
Phase 2/3(n=58)
NeurocognitionPhase 3
(n=1971)*
Phase 3(n=511)*
Phase 3(n=307)
Completedtrials
>35,000 patients
Sabatine et al. N Engl J Med 2015; March 15: online
OSLER Program
LAPLACE-TIMI 57
(n=629)
MENDEL-1
(n=406)
GAUSS-1
(n=157)
RUTHERFORD-1
(n=167)
LAPLACE-2
(n=1896)
MENDEL-2
(n=614)
GAUSS-2
(n=307)
RUTHERFORD-2
(n=329)
YUKAWA-1
(n=307)
THOMAS-1
(n=149)
THOMAS-2
(n=164)
DESCARTES
(n=901)
Phase 2
trials
Phase 3
trials
MONO-
THERAPY
HYPERCHOL
ON A STATIN
STATIN-
INTOL
HETEROZYG
FAM HYPERCHOL
OTHER
Median follow-up of 11.1 months (IQR 11.0-12.8)
7% discontinued evolocumab early
96% completed follow-up
Evolocumab
plus standard of care
(n=2976)
Standard of care alone
(n=1489)
Randomized2:1
Irrespective of treatment assignment
in parent study
4465 patients (74%) elected to enroll
into OSLER extension study program1324 from Ph2 trials into OSLER-1
3141 from Ph3 trials into OSLER-2
Eligible if medically stable
and on study drug
Trial Sponsor: Amgen
Sabatine et al. N Engl J Med 2015; March 15: online
LDL Cholesterol
Evolocumab plus standard of care
Standard of care alone
61% reduction (95%CI 59-63%), P<0.0001
Absolute reduction: 73 mg/dL (95%CI 71-76%)
N=4465 N=1258 N=4259 N=4204 N=1243 N=3727
(Parent study) (OSLER)
Sabatine et al. N Engl J Med 2015; March 15: online
Other Lipid Parameters
52% in Non-HDL-C
5.9
-46.1-50
-40
-30
-20
-10
0
10
Chan
ge fr
om
Bas
elin
e (%
)
P<0.001
47% in ApoB
5.5
-41.7-50
-40
-30
-20
-10
0
10
Chan
ge fr
om
Bas
elin
e (%
)
P<0.001
26% in Lp(a)
0.0
-25.5-30
-25
-20
-15
-10
-5
0
5
Chan
ge fr
om
Bas
elin
e (%
)
P<0.001
13% in Triglycerides
3.5
-9.1
-15
-10
-5
0
5
10
Chan
ge fr
om
Bas
elin
e (%
)
P<0.001
7% in HDL-C 4% in ApoA1
1.7
8.7
0
2
4
6
8
10
Chan
ge fr
om
Bas
elin
e (%
)
2.6
6.8
0
1
2
3
4
5
6
7
8
Chan
ge fr
om
Bas
elin
e (%
)
P<0.001P<0.001
Standard of care alone
Evolocumab plus standard of careWeek 12 data; values are means
except for TG and Lp(a) which are medians
Evolocumab 140 mg Q2W or 420 mg Q4W:
Effect of Baseline TG on TG response
N 1228 429 137
TG <150 mg/dL TG 150-250 mg/dL TG >250 mg/dL
Mean TG 99.2 mg/dL Mean TG 186.8 mg/dL Mean TG 328.7 mg/dL
Mean
% C
han
ge f
rom
Baselin
e
With permission from Dr E. Stein
Sabatine et al. N Engl J Med 2015; March 15: online
Cardiovascular Outcomes
0
1
2
0 30 60 90 120 150 180 210 240 270 300 330 365
HR 0.47
95% CI 0.28-0.78
P=0.003
Composite Endpoint: Death, MI, UA hosp,
coronary revasc, stroke, TIA, or CHF hosp
Evolocumab plus standard of care(N=2976)
Standard of care alone(N=1489)
0.95%
2.18%
3
Days since Randomization
Cu
mu
lati
ve
In
cid
en
ce
(%
)
788
1550
776
1534
731
1446
703
1393
682
1352
667
1335
321
642
127
252
0
0
No. at Risk
Placebo
Alirocumab
Weeks
Mean treatment
duration: 65 weeks
Placebo + max-tolerated statin ± other LLT0.10
0.08
0.06
0.04
0.02
0.00
96847260483624120
Esti
mate
d p
rob
ab
ilit
y o
f even
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
†Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic
stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy
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)
Post-hoc Adjudicated Cardiovascular TEAEs (Same as primary endpoint of ongoing ODYSSEY OUTCOMES trial†)
Robinson et al. N Enl J Med 2015; March 15: online
0
50
100
150
200
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Cu
mu
lati
ve L
DL-
C (
mm
ol)
Years Age
HOZ Untreated Treat at 10yrs Non FH Treat at 18yrs
35yrs
53yrs
48yrs
55yr
12.5yrs
Start high dose statin
Start lowdose statin
Threshold
for CHD
Female sex
Smoking
Hypertension
Diabetes
Triglycerides
HDL-C
Lipoprotein(a)
Without FH
Homozygous FH Heterozygous FH
Age in years
Nordestgaard et al, EHJ 2013; EAS Consensus Panel
Coronary disease & death before age 20
Untreated coronary disease before age 55/60
Sabatine et al. N Engl J Med 2015; March 15: online
Safety
Evolocumab
+ stnd of care
(N=2976)
Standard of
care alone
(N=1489)
Adverse events (%)
Any 69.2 64.8
Serious 7.5 7.5
Leading to discontinuation of evolocumab 2.4 n/a
Injection-site reactions 4.3 n/a
Muscle-related 6.4 6.0
Neurocognitive 0.9 0.3
Laboratory results (%)
ALT or AST >3×ULN 1.0 1.2
Creatine kinase >5×ULN 0.6 1.2
Sabatine et al. N Engl J Med 2015; March 15: online
Adverse Events by Achieved LDL-C
Evolocumab subjects stratified by
minimum achieved LDL-C All
EvoMab
(n=2976)
Stnd of
Care
Alone
(n=1489)
<25
mg/dL
(n=773)
25 to <40
mg/dL
(n=759)
<40
mg/dL
(n=1532)
≥40
mg/dL
(n=1426)
Adverse Events (%)
Any 70.0 68.1 69.1 70.1 69.2 64.8
Serious 7.6 6.9 7.2 7.8 7.5 7.5
Muscle-related 4.9 7.1 6.0 6.9 6.4 6.0
Neurocognitive 0.5 1.2 0.8 1.0 0.9 0.3
Lab results (%)
ALT/AST >3×ULN 0.9 0.8 0.8 1.3 1.0 1.2
CK >5×ULN 0.4 0.9 0.7 0.5 0.6 1.2
Phase 3 Trials: Alirocumab, Evolocumab, Bococizumab
EUHQ-NP-145-0715-109452
References to support data: see slide notes No head-to-head studies available. No direct study comparison intended. This overview is intended to be used for scientific illustrative purposes only.
Patient Pop’n Evolocumab (PROFICIO program) Alirocumab (ODYSSEY program) Bococizumab (SPIRE program)
Trial N Dur’n (m)Predicted Pt
Exposure (Y)
Min B/L
LDL-C
(mg/dL)
TrialN Dur’n (m)
Predicted
Pt
Exposure
(Y)
Min B/L LDL-
C (mg/dL)Trial N Dur’n (m)
Predicted
Pt
Exposure
(Y)
Min B/L LDL-
C (mg/dL)
HeFHRUTHERFORD-2 327 3 51 ≥100
FH I 471 18 471 ≥70
FH 300 12 200 >70FH II 250 18 250 ≥70
HAUSER (paeds) 150 6 50 ≥130 HIGH FH 105 18 105 ≥160
HoFHTESLA 50 3 8 ≥130
.TAUSSIG (OL) 300 60 1000 ≥100
Combo Therapy LAPLACE-2 1896 3 258 ≥80
COMBO I 316 12 209 ≥ 70 HR 600 12 400 >70
COMBO II 720 24 958 ≥70
OPTIONS I 345 6 51 ≥70 LDL 1932 12 1288 >70
OPTIONS II 300 6 150 ≥70
Monotherapy MENDEL-2 614 3 71 ≥100 MONO 103 6 24 ≥70 AI 300 3 50 ≥70
Statin IntoleranceGAUSS-2 307 3 47 None
ALTERNATIVE 314 6 47 ≥70 SI 150 6 23 ≥70
GAUSS-3 511 36 984 None
Long termDESCARTES 901 12 600 ≥75 LONG-TERM 2341 18 2341 ≥70
LL 690 12 460 ≥100
OSLER-2 (OL) 3671 24 5904 None OLE (OL) 1200 28 2800 None
Atheroma GLAGOV 970 18 970 ≥60
Totals Patients 10462 Predicted Pt Yrs ~ 9943 Patients 5465 Predicted Pt Yrs ~ 7302 Patients 3972 Predicted Pt Yrs ~ 2421
CVD Outcomes FOURIER 27,564 Event driven NA ≥70 OUTCOMES 18,000Event
drivenNA ≥70
SPIRE-1 17,000Event
drivenNA ≥70 & <100
SPIRE-2 9,000Event
drivenNA ≥100
Neurocognitive
eventsEBBINGHAUS 1971 in
FOURIER
End of
FOURIERN/A ≥70
†For Predicted Pt Exposure, where randomization is unknown, assumed 2:1 in favour of active comparator; ‡Assumed 1:1:1 random ization; §Patients from 4 studies: FH1, FH2, High FH and Long-term.
PCSK9 mAb Outcomes Trials
59
StudyFOURIER
ODYSSEY
OUTCOMESSPIRE-1 SPIRE-2
Who? Patients aged 40-
85 with history of
clinically evident
CVD at high risk for
recurrent event
Patients aged ≥40
hospitalized for
ACS recently (<52
weeks)
Background lipid lowering treatment and
at high risk of a CV event
N 27,500 18,000 17,000 9000
Primary
endpt
Time to CV death,
MI, hospitalization
for UA, stroke, or
coronary revasc,
whichever occurs
first
Time to CHD
death, any non-
fatal MI, fatal and
non-fatal ischemic
stroke,
hospitalization for
UA
Confirmed major cardiovascular event
[CV death, non- fatal MI, non-fatal
stroke, and hospitalization for UA
needing urgent revascularization]
LDL-C ≥70 mg/dL (or non-
HDL-C ≥100
mg/dL)
≥70 mg/dL ≥70 and <100
mg/dL (or non-
HDL-C ≥100 mg/dL
and <130 mg/dL)
≥100 mg/dL (or
non HDL C ≥130
mg/dL)
PCSK9 Education and Research Forumis the major, globally-recognized academic resource
of independent knowledge
of PCSK9 science
and its translation to therapeutic innovation.
Register at www.pcsk9forum.org
OSLER-1: Phase 2 programmeOpen-label Study of Long-term Evaluation Against LDL-C
Patients with hyperlipidaemia and mixed
dyslipidaemia
• Completed a qualifying
evolocumab Phase 2
parent study
• Eligible if medically
stable and on study drug
• Age ≥ 18 to ≤ 75 years
• n=1104
R
A
N
D
O
M
I
Z
E
D
Evolocumab 420 mg
QM + standard of care
(n=736)
Standard of care alone
(n=368)
2:1, irrespective
of treatment
assignment in
parent study
1
At Week 52, patients in the evolocumab +
SOC group achieved an LDL-C reduction of
52% (SE, 1%)
Koren et al. Circulation 2014;129:234–43.
OSLER subpopulations:
patients with T2DM, IFG or MetS
Presented by Henry RR, et al. American
Association of Clinical Endocrinologists, Las
Vegas, NV. May 2014.
Disease categorization (parent-study baseline):
• T2DM (n=72): By patient history
• IFG (n=95): No T2DM, but presence of FPG ≥ 110 mg/dL
and < 126 mg/dL
• MetS (n=291): No T2DM, and presence of ≥ 3 IDF
criteria
1
OSLER: Conclusions
In patients with T2DM, IFG or MetS:
• Evolocumab (420 mg monthly) treatment
reduced LDL-C by up to 52% (P < 0.001) at week 52
– Reductions were comparable to those observed in patients
without these three conditions
• Evolocumab dosed monthly demonstrated encouraging
safety and tolerability at 1 year of treatment
Presented by Henry RR, et al. American
Association of Clinical Endocrinologists, Las
Vegas, NV. May 2014.
1
Time course of plasma levels of FPG and HbA1C
Presented by Henry RR, et al. American
Association of Clinical Endocrinologists, Las
Vegas, NV. May 2014.
1
135
125
115
105
95
85
135
125
115
105
95
85
135
125
115
105
95
85
135
125
115
105
95
85
Med
ian
FP
G (
mg
/dL
)
7.5
7
6.5
6
5.5
5
7.5
7
6.5
6
5.5
5
7.5
7
6.5
6
5.5
5
7.5
7
6.5
6
5.5
5
Patients
with
T2DM
Patients
with MetS
Patients
with IFG
Patients
without
MetS, IFG
or T2DM
Med
ian
Hb
A1c (
%)
PCSK9 inhibition :
The Future
1) Cardiovascular outcomes in Phase III trials
2) Impact on atherosclerotic vascular disease (AVD)
3) Impact of TGRL, remnant and Lp(a) lowering, and possibly
HDL raising, on progression of AVD and CV events
3) Long term, real life, safety data from post-marketing
surveillance
4) Evaluation of efficacy in other patient populations at high risk