Treatment of Severe FH Forms: PCSK9 Inhibitors
Prof. Raul Santos MD,PhDUniversity of Sao PauloHospital Albert Einstein
Sao Paulo, Brazil
Disclosure
• Honoraria received for consulting, speaker or researcher activities : Ache, Akcea, Astra Zeneca, Amgen, Esperion, Merck, MSD, Pfizer, PTC, Novo-Nordisk, Sanofi/Regeneron.2
3
Miname MH & Santos RD. Prog Cardiovasc Dis. 2019 Oct 25 e pub
Statins Reduce Mortality in FH
4
5
Blom et al J Clin Lipidol 2019; 13: 594–600
ESC/EAS 2019 Recommendations on FH
6
Mach F et al . EHJ (2019) doi:10.1093/eurheartj/ehz455
PCSK9 inhibition in FH
7
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)
FH I and FH II : Efficacy Endpoints Week 24
9
-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
What about Homozygous FH?
10
Santos RD et al Lancet Diab Endocrinol 2016;4: 850-61
Molecular Defect and LDL-C Phenotype
12Lancet Diabetes Endocrinol 2017; 5: 280–90
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.
What About Long-term Effects and Safety of PCSK9 Inhibition in FH?
14
15Santos RD et al presented at ACC 2019
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BaselineClinical
Characteristics
Santos RD et al presented at ACC 2019
Baseline LLT
17
Santos RD et al presented at ACC 2019
18
BaselineLaboratory
Santos RD et al presented at ACC 2019
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%
TAUSSIG: LDL-C Lowering With Evolocumab According to Apheresis Status
2
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
21
Taussig : Long-TermSafety
Santos RD et al presented at ACC 2019
22
Santos RD et al presented at ACC 2019
Taussig : Long-TermSafety
23
27
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
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