PCSK-9...
Transcript of PCSK-9...
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
Limitations of current management of dyslipidemie
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
Limitations of current management of dyslipidemie
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
Limitations of current management of dyslipidemie
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
Therapeutic monoclonal antibodies
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
Therapeutic monoclonal antibodies
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
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*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
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, 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
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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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