Treatment of Severe FH Forms: PCSK9 Inhibitors · 2020. 2. 13. · Conclusions: PCSK9 inhibitors in...
Transcript of Treatment of Severe FH Forms: PCSK9 Inhibitors · 2020. 2. 13. · Conclusions: PCSK9 inhibitors in...
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Treatment of Severe FH Forms: PCSK9 Inhibitors
Prof. Raul Santos MD,PhDUniversity of Sao PauloHospital Albert Einstein
Sao Paulo, Brazil
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Disclosure
• Honoraria received for consulting, speaker or researcher activities : Ache, Akcea, Astra Zeneca, Amgen, Esperion, Merck, MSD, Pfizer, PTC, Novo-Nordisk, Sanofi/Regeneron.2
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Miname MH & Santos RD. Prog Cardiovasc Dis. 2019 Oct 25 e pub
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Statins Reduce Mortality in FH
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Blom et al J Clin Lipidol 2019; 13: 594–600
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ESC/EAS 2019 Recommendations on FH
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Mach F et al . EHJ (2019) doi:10.1093/eurheartj/ehz455
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PCSK9 inhibition in FH
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Week 10 Week 8 Week 12
RUTHERFORD-2:Mean % Change in LDL-C from Baseline Over Time
• Raal FJ, et al. Lancet 2014; doi.org/10.1016/S0140-6736(14)61399-4.
% c
han
ge f
rom
Bas
elin
e in
LD
L-C
20%
0
-20%
-40%
-60%
-80%Baseline Week 2
Evolocumab Q2W
Evolocumab QM ....
.. ....
Placebo Q2W (N = 54)
Placebo QM (N = 55)
Evolocumab 140 mg Q2W (N = 110)
Evolocumab 420 mg QM (N = 110)
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FH I and FH II : Efficacy Endpoints Week 24
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-48,8 -49,3
-31,2
-42,8 -41,7
-26,9
-9,8
7,84,2
7,1 6,8 5,57,4
1,9
-8,5
4,30,2
-0,4
-60
-50
-40
-30
-20
-10
0
10
20LDL-C
LDL-C (ontreatment) Total-C Non-HDL-C Apo B Lp(a) TG HDL-C Apo A-1
Mean absolute Δ
-71.1 mg/dL
Mean baseline LDL-C was 141.3mg/dL in the PRALUENT group and 140.9mg/dL in the placebo group
(a) ITT analysis – intent-to-treat population, includes all lipid data throughout the duration of the study irrespective of adherence to the study treatment.
(b) On-treatment analysis – analysis restricted to the time period that patients actually received treatment.
Mean %
Change
From
Baseline
at
Week 24
Placebo
(on background maximally
tolerated dose of statin)
n=244
Alirocumab 75/150 mg
(on background maximally
tolerated dose of statin)
n=488
Kastelein JJP et al. European Heart Journal, 2015; doi:10.1093/eurheartj/ehv370
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What about Homozygous FH?
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Santos RD et al Lancet Diab Endocrinol 2016;4: 850-61
Molecular Defect and LDL-C Phenotype
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12Lancet Diabetes Endocrinol 2017; 5: 280–90
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Correlation of LDLRsurface expression with baseline and on treatment LDL-C withEvolocumabfor the same LDLR defects
Thedrez et al ATVB 2018;38:592-598. Thedrez et al ATVB 2018;38:592-598.
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What About Long-term Effects and Safety of PCSK9 Inhibition in FH?
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15Santos RD et al presented at ACC 2019
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BaselineClinical
Characteristics
Santos RD et al presented at ACC 2019
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Baseline LLT
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Santos RD et al presented at ACC 2019
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BaselineLaboratory
Santos RD et al presented at ACC 2019
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Long term Effects of Evolocumab in Homo and Heterozygous FH : TAUSSIG 4.1-Years
Santos RD et al presented at ACC 2019
-21%
-54.9%
Dose doubling LDL -19.6% to -29.7%
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TAUSSIG: LDL-C Lowering With Evolocumab According to Apheresis Status
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Online Table 2. LDL-C reduction stratified by apheresis at enrolment
Efficacy HoFH Severe HeFH
Apheresis at
enrolment
(N=34)
Non-apheresis at
enrolment
(N=72)
Apheresis at
enrolment
(N=27)
Non-apheresis
at enrolment
(N=167)
LDL-C (calculated)
Change at week 12, mean (SD)
% -18.1 (28.7) -22.7 (23.0) -64.7 (18.0) -53.4 (16.9)
Absolute, mg/dL -40.7 (70.4)
n=34
-69.0 (76.4)
n=70
-130.4 (37.1)
n=26
-100.3 (41.8)
n=165
Change at week 48, mean (SD)
% -18.7 (28.4) -27.6 (32.9) -57.3 (21.5) -56.8 (18.8)
Absolute, mg/dL -53.6 (81.9)
n=29
-91.5 (101.8)
n=64
-116.9 (53.2)
n=26
-106.9 (50.6)
n=161
Change at week 216, mean (SD)
% -25.9 (61.3) -23.4 (32.1) -44.1 (55.2) -47.3 (27.6)
Absolute, mg/dL -89.5 (142.0)
n=18
-69.7 (118.7)
n=50
-74.0 (89.8)
n=2
-91.0 (61.8)
n=94
Online Figure 1. Patient Disposition
EOS= end of study
Santos RD et al. Presented at ACC 2019
3% HoFH48% HeFHStopped
Apheresis
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Taussig : Long-TermSafety
Santos RD et al presented at ACC 2019
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Santos RD et al presented at ACC 2019
Taussig : Long-TermSafety
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Table 4. Annualized event rates for adjudicated cardiovascular events
HoFH Severe HeFH Overall
(N = 106) (N = 194) (N=300)
Positively adjudicated cardiovascular events 2.8% 2.6% 2.7%
Death 0.7% 0.8% 0.8%
Cardiovascular deaths 0.7% 0.3% 0.4%
Myocardial infarction 0.5% 0.7% 0.6%
Hospitalization for unstable angina 0.2% 0.3% 0.3%
Coronary revascularization 1.9% 1.9% 1.9%
Percutaneous coronary intervention 1.4% 1.6% 1.5%
Surgical 0.5% 0.3% 0.3%
Cerebrovascular event 0.7% 0.1% 0.3%
Transient ischemic attack 0.2% 0% 0.1%
Stroke 0.5% 0.1% 0.3%
Hospitalization for heart failure 0% 0.1% 0.1%
Patients may have had more than 1 event.
HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial
hypercholesterolemia.
ASCVDEvents
Santos RD et al presented at ACC 2019
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Conclusions: PCSK9 inhibitors in FH
• Very effective in HeFH
• TAUSSIG:• Evolocumab reasonable and variable effects in HoFH
• Response depends on molecular defect and LDLR expression
• However many individuals persist with still very high LDL-C
• Evolocumab sustained effects and safe in longer term