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PCSK-9 antibodies:Lipids and Beyond ?
Erik Stroes, MD Academic Medical Center
Amsterdam, The Netherlands
May 21st, 2016
Disclosures: Lecturing fees from
• Amgen, Sanofi, Merck, Chiesi, Novartis, Cerenis
No stocks
No patents
2
Outline
Best lipid target
Need for more LDL-c lowering
‘Study’ evidence
Competition
Lipoprotein Pathways for MI
Epidemiology Genetics Therapy
HDL-raising therapy
Common variants: no effect on MI
Rare variants: no effect on MI Failed
Plasma Level
TG
MI R
isk
Plasma Level
HDL
MI R
isk
LDLRPCSK9NPC1L1
StatinsPCSK9 AbsEzetimibe
Common variants: Yes
Rare variants: LPL, APOC3,
APOA5, ANGPTL4
?
Plasma Level
LDL
Courtesy S Katherisan
Lower lifetime LDL provides more protection than later LDL lowering
Ference et al. J Am Coll Cardiol 2015;65:1552–1561.
0
Lower LDL-C (mg/dL)
Prop
ortio
nal r
educ
tion
in C
HD
risk
(log
scal
e) 30%
20%
10%
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0
PCSK9 46Lrs11591147
GISSI-PA to Z
SEARCH
ALLHAT-LLT
LDLRrs6511720
NPC1L1 LDL-C scoreHMGCR LDL-C score
Genetically lower LDL-C
Pharmacologically lower LDL-C
IMPROVE-IT
Combined NPC1L1 & HMGCR LDL-C score
HMGCR LDL-C scoreNPC1L1 LDL-C score
18.2% reduction in CHD risk for each 1mmol/L (38mg/dL) lower LDL-C
54.5% reduction in CHD risk for each 1mmol/L (38mg/dL) lower LDL-C
LDLRrs2228671
NPC1L1 rs217386
PCSK9 rs2479409
ABCG5/8rs4299376
HMGCR rs12916
PCSK9rs11206510
Outline
Best lipid target
Need for more LDL-c lowering
‘Study’ evidence
Competition for LDL-c lowering
Need for additional LDL‐C lowering therapies
I. Guidelines set LDL-C goals in high risk patients
II. Special populations do not achieve LDL-C goals
III. More patients with adverse effects on statins
I. ESC guidelines: LDL-c target levels
Ray KK et al.
Eur Heart J 2014
I. After a CV event, 1:5 patients achieve LDL-C <70mg/dLdespite statin prescription and good adherence
EUROASPIRE IV
Kotseva et al. Eur J Prev Cardiol 2015;Feb 16. pii:2047487315569401.www.escardio.org/The-ESC/Press-Office/Press-releases/Last-5-years/EUROASPIRE-IV-reveals-success-and-challenges-in-secondary-prevention-of-CVD-acro. Accessed 22 Jan 16.
87
58
210
10
20
30
40
50
60
70
80
90
100
Lipid-lowering drugs LDL-C <100mg/dL LDL-C <70mg/dL
Prev
alen
ce (%
)
II. Heterozygous Familial Hypercholesterolemia is a common disease
HeFH is characterised by:
Markedly elevated LDL-C levels from before birth1
Atherosclerotic plaque formation at an early age2–4
High incidence of MI and stroke2–5
HeFH is caused by mutations in genes involved in LDLR endocytic and recycling pathways1,6
LDLR (most common)
APOB and PCSK9
1. Nordestgaard et al. Eur Heart J 2013;34:3478–3490. 2. Versmissen et al. BMJ 2008;337:a2423. 3. Elis et al. Am J Cardiol 2011;108:223–226. 4. Raal et al. Circulation 2011;124:2022–2027. 5. Reiner et al. Eur Heart J 2011;32:1769–1818. 6. De Backer et al. Atherosclerosis 2015;241:169–175.
HeFH worldwide prevalence
14 to 34 million1
1:2001
Individuals are affected
II. Familial hypercholesterolaemia patients reach LDL-C threshold levels for CHD at an early age
Cuchel et al. Eur Heart J 2014;35:2146–2157.Nordestgaard et al. Eur Heart J 2013;34:3478–3490.
Without FH
55 years
12.5 years
35 years
Heterozygous FHHomozygous FH
0
Age in years
Cum
ulat
ive
LDL-
C (m
mol
) 200
150
100
50
0
Threshold for CHD
603 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
mmol/L
mg/dL
LDL-C
10
1315
390
500580
0
5
0
190
111
3444
61213
1943
71
0 20 40 60
MexicoBrazilChile
JapanCanada
USAOman
ItalyTaiwanFrance
Hong KongAustralia
South AfricaDenmarkSlovakiaBelgium
SpainUK
SwitzerlandIcelandNorway
Netherlands
Based onprevalence 1 in50021%
of HeHF patients achieved the LDL-C treatment goal of <2.5mmol/L1
II. HeFH is under-diagnosed and undertreated
In many countries
<10%of patients are
diagnosed2
1. Pijlman et al. Atherosclerosis 2010;209:189–194.2. Nordestgaard et al. Eur Heart J 2013;34:3478–3490.
<
Diagnosed FH (estimated) as % of estimated number in each country
0.40.40.41.21.61.61.62.4
4.85.2
7.617.2
28.40 20 40 60
MexicoBrazilChile
JapanCanada
USAOman
ItalyTaiwanFrance
Hong KongAustralia
South AfricaDenmarkSlovakiaBelgium
SpainUK
SwitzerlandIcelandNorway
Netherlands
Based onprevalence 1 in500Based onprevalence 1 in200
21%of HeHF patients achieved the LDL-C treatment goal of <2.5mmol/L1
II. HeFH is under-diagnosed and undertreated
In many countries
<10%of patients are
diagnosed2
1. Pijlman et al. Atherosclerosis 2010;209:189–194.2. Nordestgaard et al. Eur Heart J 2013;34:3478–3490.
Diagnosed FH (estimated) as % of estimated number in each country
II. FH and Cardiovascular risk
Nordestgaard, Eur Heart J 2013
III. Special populations ‐ Statin intoleranceDiscontinuation due to Statin‐Associated Side Effects
Observational studies: Most frequent: statin‐attributed muscle symptoms (SAMS)
Gastro‐intestinal discomfort
Fatigue
Peripheral neuropathy
Insomnia
Neurocognitive symptoms
Carter AA et al. BMJ. 2013;346:f2610; Mancini GB et al. Can J Cardiol. 2013;29(12):1553‐68; Richardson K et al. Ann Intern Med. 2013 Nov 19;159(10):688‐97
III. Muscle symptoms associated with statins are common in observational studies
Bruckert et al. Cardiovasc Drugs Ther 2005;19:403–414.
10.914.9
18.2
5.1
0
10
20
Pravastatin Atorvastatin Simvastatin Fluvastatin
Patie
nts
with
mus
cula
r sy
mpt
oms
(%)
PRIMO: 7,924 patients with hyperlipidaemia receiving high-dosage statin therapy
III. Statin intolerance may be less common than suggested by observational data
STOMP was powered to assess statin-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 404.9 3.5% 3.7%
PROSPER 5,804 3.2 1.2% 1.1%CARDS 2,838
Atorvastatin10
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 PlaceboSTOMP 440 Atorvastatin 80 0.5 19 10 P=0.05
III. Successful statin re-challengein vast majority
Blinded challenge1
361 patients intolerant to ≥ 2 statins
Randomized to ezetimibe, alirocumab, atorvastatin
Results:atorva challenge: 22% muscle symptoms 75% free of AE’sezetimibe challenge: 20% muscle symptoms 75% free of AE’salirocumab challenge: 16% muscle symptoms 82% free of AE’s
Statin rechallenge2
From 107.835 records – 18.778 statin-attributed AE (40% muscle s.)
From 11.124 discontinued – 6.579 rechallenged
Results:92% successfully used ‘a statin’ for > 12 months after rechallenge
1. Moriarty, AHA 2014; 2. Zheng, Ann Int Med 2013;
Exclude other causes of muscle symptoms and interactions
Statin rechallenge Continue statin
Establish highest tolerable statin dose:very low dose, different statin, more potent
statin, alternate day dosing
Add ezetimibe and option for PCSK9 inhibitor
2–4 weeks statin washout
III. Algorithm for treating patients with statin-associated muscle symptoms
Stroes et al. Eur Heart J 2015;36(17):1012–22.
No symptomsSymptoms recur
Not at recommended LDL-C
III. Statin discontinuation leads to reduced survival
Side effects are the most common reason patients discontinue statins1
Survival is reduced in patients who discontinue, even compared to those on non-daily statin doses2
1. Cohen et al. J Clin Lipidol 2012;6:208-15. 2. Mampuya et al. Am Heart J 2013;166:597–603.
Surv
ival
(%)
Years
Statin continued/daily doseStatin continued/non-daily doseStatin discontinued
Outline
Best lipid target
Need for more LDL-c lowering
‘Study’ evidence for PCSK9 antibodies
Competition for LDL-c lowering
LDLR
PCSK9
3. C-terminus2. Prodomain1. Catalytic domain
PCSK9
A serine proprotein convertase1
Expressed in hepatocytes, kidney mesenchymal cells, intestinal ileum and colon epithelia, CNS2
Regulates hepatic LDLRs, which bind and internalise LDL particles2
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.
1
2
3
Plasma LDL-C is controlled by hepatic low density lipoprotein receptor (LDLR) levels
Brown et al. Proc Natl Acad Sci USA 1979;76:3330–3337.
Recycling of LDL-R
Increased LDL-R surface concentration
LDL particles
LDL-R
PCSK9 reduces LDLR recycling, thereby increasing plasma LDL-C
Horton et al. J Lipid Res 2009;50:S172–S177.
LDL particles
LDL-R
PCSK9 secretion
PCSK9 routes LDL-R for lysosomal degradation
LDL-R recycling blocked
Loss-of-function variants in PCSK9, with lifetime low LDL-C, are associated with a lower risk of CV events
Serum LDL-C
GeneticPCSK9 LDL-R
Yes
12
No
8
4CH
D(%
)
0
CHD
88%
P=0.008Plasma LDL-C in black subjects (mg/dL)
Cohen et al. N Engl J Med 2006;354;1264–1272.
30
20
10
(N=85)
50th percentile with no nonsense mutation
Freq
uenc
y (%
)
050 100 300150 200 250
Nonsense mutation
Nonsense mutation
PCSK9 is a new therapeutic targetType Compound Company
mAb
Evolocumab (Repatha®)AMG145 Amgen
Alirocumab (Praluent®)REGN7272/SAR236553 Sanofi/Regeneron
BococizumabRN-316/PF-04950615 Pfizer/Rinat
RG7652 (MPSK3169A) Roche/GenentechLY3015014 Eli Lilly
Adnectin Ad. BMS-962476 BMS-AdnexussiRNA ALN-PCS Alnylam Pharmaceuticals
Vaccine AFFITOPE AT04A+adjuvantAFFITOPE AT06A+adjuvant AFFiRiS AG
Small molecule – Shifa Biomedical Corp
Mimetic peptideEGF-A peptide Merck & Co.
Prodomain and C-terminal domain interaction disruption
School of Medicine, University of South Carolina, USA
Antibody-based therapeutics have a long history
www.nobelprize.org/nobel_prizes/medicine/laureates/1901/behring-article.html. Accessed 10 Jan 2016. www.nobelprize.org/nobel_prizes/medicine/laureates/1908/ehrlich-bio.html. Accessed 10 Jan 2016.Zhou et al. Annu Rev Pharmacol Toxicol 2011;51:359–372. www.nobelprize.org/nobel_prizes/medicine/laureates/1972/. Accessed 10 Jan 2016.Caravella et al. Curr Comput Aided Drug Des 2010;6:128-138.www.nobelprize.org/nobel_prizes/medicine/laureates/1984/. Accessed 10 Jan 2016.Ecker et al. MAbs 2015;7:9–14.
1890 1901 1962 1984 19861908
Serum therapy used as treatment against diphtheria and tetanus
• Side-chain theory predicted substances todaycalled antibodies
• First idea of a "magic bullet"
Discovery of antibody chemical structure
Development of hybridoma technology
Production of first monoclonal antibody
César Milstein
Emil Adolf von Behring
Gerald Edelman
Rodney Porter
Paul Ehrlic
hGeorges Köhler
>40 Ab-based therapies approved in the EU
>300 in development
1972 1975
Nobel prizes
Discovery milestones
2015
0
Study Day28 56
0
50
500
100
300
400
200
14 70 8442
LDL-C
Mean C
hange (%)
0
150
350
450
250
Total evolocumab
Free PCSK9
LDL-C
Free
PC
SK9
conc
entr
atio
n (n
g/m
L)Fr
ee E
volo
cum
abco
ncen
trat
ion
(ng/
mL
x 0.
01)
Pharmacokinetics and pharmacodynamics of PCSK9-ab: changes in PCSK9 and LDL-C levels
in response to evolocumab
Stein EA , Annu. Rev. Med. 2014. 65:417–31.
160
140
120
100
80
60
40
20
0
Overview of the ODYSSEY Phase 3 Program (Alirocumab)
Fourteen global Phase 3 trials including >23,500 patients across >2000 study centers
ODYSSEY FH II (NCT01709500; CL1112)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=249; 18 months
HeFH population HC in high CV-risk population Additional populations
ODYSSEY HIGH FH (NCT01617655; EFC12732)LDL-C ≥160 mg/dL n=107; 18 months
ODYSSEY ALTERNATIVE (NCT01709513; CL1119)Patients with defined statin intoleranceLDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=314; 6 months
ODYSSEY OPTIONS II (NCT01730053; CL1118)Patients not at goal on moderate-dose rosuvastatinLDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=305; 6 months
ODYSSEY MONO (NCT01644474; EFC11716)Patients on no background LLTsLDL-C ≥100 mg/dLn=103; 6 months
ODYSSEY OPTIONS I (NCT01730040; CL1110)Patients not at goal on moderate-dose atorvastatinLDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=355; 6 months
ODYSSEY COMBO I (NCT01644175; EFC11568)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=316; 12 months
ODYSSEY FH I (NCT01623115; EFC12492)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=486; 18 months
ODYSSEY LONG TERM (NCT01507831; LTS11717)LDL-C ≥70 mg/dL n=2341; 18 months
ODYSSEY OUTCOMES (NCT01663402; EFC11570)LDL-C ≥70 mg/dLn=18,000; 64 months
Add-on to max tolerated statin (± other LLT)
Add-on to max tolerated statin (± other LLT)
*ODYSSEY COMBO II (NCT01644188; EFC11569)LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=720; 24 months
*For ODYSSEY COMBO II other LLT not allowed at entry
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 statinLDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dLn=200; 6 months
ODYSSEY OLE (NCT01954394; LTS 13463) Open-label study for FH from EFC 12492,CL 1112, EFC 12732 or LTS 11717n ≥1000; 30 months
FamilialHypercho-lesterolemia
High-risk ‘progressive’
CV-disease
Statinintolerance
Alirocumab
Alirocumab in hyperlipidemic CV-patients
Week
118.9 mg/dL(+0.8%)
48.3 mg/dL(−61.0%)
123.0 mg/dL(+4.4%)
53.1 mg/dL(−56.8%)
Placebo
Cal
cula
ted
LDL-
C, L
S m
ean
(SE)
, mg/
dL
Achieved LDL-C Over Time All patients on background of maximally tolerated statin ± other lipid-lowering therapy
Difference
−61.9%
0 4 8 12 16 24 36 52
Difference
−61.3%
Robinson J, N Engl J Med 2015
-62.1%-56.3%
-0.5%
7.0%
-70-60-50-40-30-20-10
01020
HeFHNon-HeFH
Alirocumab in Familial hypercholesterolemia
All patients on background of maximally tolerated statin± other lipid-lowering therapy
PlaceboAlirocumab
n=271 n=145n=1259 n=635
LS m
ean
(SE)
% c
hang
e fr
om
base
line
to W
eek
24
-62.3%
-52.3%
9.3%
-8.7%
-70
-60
-50
-40
-30
-20
-10
0
10
20
≥160 mg/dL<160 mg/dL
n=84 n=35n=187 n=110
HeFH population by baseline LDL-C
20
0−10−20−30−40
−60−50
10
−70
Robinson J, N Engl J Med 2015
Alirocumab in statin-intolerance
Moriarty PM, et al. AHA 2014
Alirocumab*
0
-60
-50
-10
-40
-20
-30
LS M
ean
(SE)
% C
hang
e fr
om
Bas
elin
e to
Wee
k 24
LS Mean Difference (SE) vs Ezetimibe:-30.4 (3.1); P<0.0001
-14.6%
-45.0%
n=122n=126
% Change from Baseline to WK 24 in LDL-C(ITT, primary endpoint)
Ezetimibe
Alirocumab and safetySubanalysis in patients with LDLc < 25mg/dl
% of patientsAll pts on background of maximally tolerated statin ± other LLT
ALI (n=1550)
ALI with2 consecutive
LDL-C <25 mg/dL
(n=562, 37%)
PBO (n=788)
Nasopharyngitis 12.6 10.0 12.7
URTI 7.0 5.7 8.0
Injection-site reaction 5.7 3.6 3.4
Influenza 5.4 4.1 5.5
Diarrhea 5.3 3.9 5.1
Urinary tract infection 5.2 5.5 6.2
Bronchitis 5.2 5.2 4.7
Myalgia 4.9 3.0 3.0
Headache 4.8 1.8 5.6
Back pain 4.7 5.0 6.0
Arthralgia 4.5 3.2 6.0
Muscle spasms 3.7 2.8 3.2
Fatigue 3.0 3.0 3.8
Pain in extremity 3.0 2.1 4.4
Hypertension 3.5 2.0 3.4Robinson J, N Engl J Med 2015
Alirocumab and Incidence of Cardiovascular Events¶
Robinson JG et al. N Engl J Med 2015;372:1489-1499
0Time (weeks)
0
0.06
0.02
0.04
52 78 86
0.03
0.05
0.01
PlaceboAlirocumab*
Cum
ulat
ive
Prob
abili
ty o
f Eve
nt
6412 24 36
Cox model analysisHR = 0.52 (95% CI, 0.31-0.90)Nominal P-value = .02
*27/1550
**26/7883.3%**
1.7%*
¶post-hoc analysis not specified in the study protocol
Combo-therapy
Statin-intolerant
Mono-therapy
HeFH
Long-term safety and
efficacyOpen-labelextension
HoFH
Phase 2(N = 168)
Phase 3(N = 300)
Phase 2(N = 629)
Phase 3(N = 1700)
Phase 2(N = 1400)
Phase 2/3(N ≤67)
Phase 2/3(N = 125)
Phase 2(N = 406)
Phase 3(N = 600)
Phase 3(N = 905)
Phase 3(N = 27,500)
Secondary
prevention Phase 3
(N = 950)
Phase 2(N = 157)
Phase 3(N = 300)
Athero
Phase 3(N ≥3500)
Phase 3(N = 500)
PROFICIO Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations
FamilialHypercho-lesterolemia
High ‘progressive’ CV-disease
Statinintolerance
Evolocumab in hyperlipidemic CV-patients DESCARTES
UC
LD
L-C
per
cent
cha
nge
from
bas
elin
e, m
ean
(±SE
)
Baseline Week 12 Week 52
-80-70-60-50-40-30-20-10
01020
Number of patients:
Study week
599 582 542302 294 264
Placebo QM (N = 302) Evolocumab 420 mg QM (N = 599)
-50.1%
6.8%
Treatment difference57%
Blom et al. N Engl J Med 2014;370:1809–19
Evolocumab in statin intoleranceGAUSS3
511 patients with a history of intolerance to multiple statins due to muscle-related adverse effects
Atorvastatin 20 mg Placebo
PlaceboAtorvastatin 20 mg
Participants entered Phase B only if they had muscle symptoms on atorvastatin, but not placebo, or CK ≥ 10 x ULN during statin
treatment
PhaseA
PhaseB
Daily oral ezetimibe 10 mgMonthly SC evolocumab 420 mg
2 1
10 weeks
10 weeks
24 weeks
Nissen S, Stroes E, et al. JAMA 2016
Baseline Characteristics
Characteristic Phase A(n=491)
Phase B (n=218)Ezetimibe
(n=73)Evolocumab (n=145)
Age (years) 61 59 59
Male Gender 50% 47% 54%
Coronary Heart Disease 35% 29% 33%
NCEP-ATP III High Risk 63% 52% 58%
Intolerance to ≥ 3 statins 82% 82% 82%
Total Cholesterol (mg/dL) 301 308 307
LDL-C (mg/dL) 212 222 219
HDL-C (mg/dL) 51 50 50Nissen S, Stroes E, et al. JAMA 2016
Phase A: Study Drug Discontinuation Events
Intolerable Muscle Symptoms N = 491
On atorvastatin, but not placebo 209 (42.6%)*
On placebo, but not atorvastatin 130 (26.5%)
On both placebo and atorvastatin 48 (9.8%)
No symptoms on either treatment 85 (17.3%)
Did not complete Phase A 20/511
Bypassed Phase A due to CK elevation≥ 10 x ULN 19 (3.9%)*
Nissen S, Stroes E, et al. JAMA 2016
LDL-C Values Over Time During Phase BLDL-C Values Over Time During Phase B
-70
-60
-50
-40
-30
-20
-10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Perc
ent C
hang
e in
LD
L-C
(%)
Weeks Following Randomization in Phase B
Ezetimibe
Mean reduction 16.7%(LDL-C = 181 mg/dL)
Mean reduction 53.0%(LDL-C = 104 mg/dL)
Nissen S, Stroes E, et al. JAMA 2016
Achievement of Common LDL-C Target LevelsAchievement of Common LDL-C Target Levels
LDL-C < 100 mg/dL*LDL-C < 100 mg/dL*LDL-C < 70 mg/dLLDL-C < 70 mg/dL
1.4%
29.9%
0%
20%
40%
60%
80%
100%
Ezetimibe Evolocumab
Perc
ent o
f Pat
ient
s (%
)
1.8%
64.1%
0%
20%
40%
60%
80%
100%
Ezetimibe Evolocumab
Perc
ent o
f Pat
ient
s (%
)
Nissen S, Stroes E, et al. JAMA 2016
Conclusion
GAUSS-3 demonstrates that muscle-related intolerance is reproducible during blinded statin rechallenge in more than 40% of patients with a history of symptoms
Development of alternative approaches to LDL-C reduction for these patients is an important medical priority
Evolocumab and safetyOSLER
Evolocumab subjects stratified by minimum achieved LDL-C All
EvoMab(n=2976)
SOC Alone(n=1489)<25
mg/dL(n=773)
25 to <40 mg/dL(n=759)
<40mg/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
Sabatine MS et al. N Engl J Med 2015;372:1500-1509
Sabatine MS et al. N Engl J Med 2015;372:1500-1509
Evolocumab and Cardiovascular Events¶
OSLER
0
1
2
0 30 60 90 120 150 180 210 240 270 300 330 365
HR 0.4795% CI 0.28-0.78P=0.003
Composite Endpoint: Death, MI, UA hosp, coronary revasc, stroke, TIA, or CHF hosp
3
Days since Randomization
Cum
ulat
ive
Inci
denc
e (%
)
Evolocumab plus standard of care(N=2976)
Standard of care alone(N=1489)
0.95%*
2.18%**
*29/2976
**31/1489
¶CVD clinical outcomes (prespecified, exploratory): adjudicated by TIMI Study Group CEC, blinded to treatmentIncluded death, myocardial infarction, unstable angina requiring hospitalization, revascularization, stroke or transient ischemic attack and Heart failure requiring hospitalization
Evolocumab Alirocumab Bococizumab
Sponsor Amgen Sanofi / Regeneron Pfizer
Trial FOURIER ODYSSEY Outcomes SPIRE I SPIRE II
Sample size 27,500 18,000 17,000 9,000
Patients MI, stroke or PAD 4-52 wks post-ACS High risk of CV event
Statin Atorva ≥20 mg or equiv Evid-based med Rx Lipid-lowering RxLDL-C
mg/dL(mmol/L) ≥70 (≥1.8) ≥70 (≥1.8) 70-99 (1.8-2.6) ≥100 (≥2.6)
PCSK9i Dosing Q2W or Q4W Q2W Q2W
Endpoint 1: CV death, MI, stroke, revasc or hosp for UA,
Key 2: CV death, MI, or stroke
CHD death, MI, ischemic stroke, or hospfor UA
CV death, MI, stroke, or urgent revasc
Recruitment Status Completed June 2015 Projected for Dec 2015 ?
Completion Q4 /2016 Q3 /2017 ? /2017
PCSK9 Inhibitor CVD Outcomes Trials
www.clinicaltrials.gov
Outline
Best lipid target
Need for more LDL-c lowering
‘Study’ evidence
Competition for LDL-c lowering
The competitive landscape for LDLc lowering
• Apo B mRNA antisense
• Microsomal Triglyceride Transfer Protein inhibitors
• Cholesteryl-ester transfer protein inhibitors
ApoB antisense reduces LDL-c in patients with statin intolerance
–2%
–47%
Akdim, Stroes, Eur H J 2012
Safety and tolerability issuesfor apoB antisense
Injection site reactions (target-independent)
Hepatic steatosis (target-dependent)
Heterogeneity of response (target-dependent)
the competitive landscape of LDLc lowering
• Apo B mRNA antisense drugs
• Microsomal Triglyceride Transfer Protein inhibitors
• Cholesteryl-ester transfer protein inhibitors
Efficacy and safety of lomitapide in HoFH open-label phase 3 study (n=29)
Dose escalation biweekly: 5–60 mg
LDL-C 50%, ApoB 49%, TC 45% (23/29 completer population)
Change in LDL-C (%) Percentage of hepatic fat in the liver
Mean (98% CI)0 42 6 8 10 12 14 16 18 20 22 24 26
20
0
–20
–40
–60
–80
–100
Study week
LDL-CTCApoB
Baseline Week 26 Week 56 Week 78
25
20
15
10
5
0
Study week
Hep
atic
fat (
%)
Mea
n (
SD) %
ch
ange
from
bas
elin
e
Cuchel M et al. Lancet 2013; 381: 40–6.
Safety and tolerability issuesfor MTP-inhibition using Lomitapide
Gastrointestinal complaints Reported by 27 (93%) of 29 patients Decreased by maintaining strict fat-restriction
Transaminase elevations 10 (34%) of 29 patients had elevation in ALT/ AST ≥3x ULN
Hepatic fat 18 (78%) of patients exhibited increase in hepatic fat > 5%
3 (13%) of patients exhibited increase in hepatic fat >20%
The competitive landscape of LDLc lowering
• Apo B mRNA antisense drugs
• Microsomal Triglyceride Transfer Protein inhibitors
• Cholesteryl-ester transfer protein inhibitors
CETP inhibition by Anacetrapib lowers LDL-cin patients with Heterozygous FH
Kastelein JJ et al. Lancet 2015Kastelein JJ et al. Lancet 2015
Mea
n %
cha
nge
from
bas
elin
e
ACCELERATEEvacetrapib reduces LDLc by 37%
55Nicchols S, ACC 2016
ACCELERATEEvacetrapib does not reduce CV-events
56Nicchols S, ACC 2016
There is a need for additional LDL-c lowering therapies getting to targetFamilial hypercholesterolemiaStatin intolerance
PCSK9-antibodies lower LDLcPotently and prolongedFew side effectsBeneficial CV-signal in post-hoc analyses
Other options less attractive due toSide effects: ISRs, liver fat, gastro-intestinal, … Lack of potency
Summary: PCSK9 antibodies: Lipids and beyond
Take Home
LDL-c lowering is currently best target in CV therapy
Statin/ezetimibe is always number ‘1’ option
PCSK9-antibodies offer potent and safe LDLc loweringin patient groups currently facing residual LDLc-burden
Keeping CVD-therapy affordable necessitates restricteduse of PCSK9-ab in selected patient groups:Fam hypercholesterolemia, statin-intolerance and …very high CV risk with residual LDLc burden
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