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

16

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