La Nuova Terapia...LDLR PCSK9 1. Catalytic domain 2. Prodomain 3. C-terminus PCSK9 is a Regulator of LDL Metabolism • Proprotein convertase subtilisin/kexin type 9 • A serine proprotein

La Nuova Terapia dell’Ipercolesterolemia

Susanna Morano“Sapienza” Università di Roma

Dipartimento di Medicina Sperimentale

Plasma LDL-c is Controlled by Hepatic Low-density Lipoprotein Receptor (LDLR) Levels

Recycling of LDLR

Increased LDLR

surface concentration

LDL

particles

LDLR

1. Brown MS, et al. Proc Natl Acad Sci USA. 1979;76:3330-3337. 2. Steinberg D, et al. Proc Natl Acad Sci USA. 2009;106:9546-9547.

3. Brown MS, et al. Science. 1986;232:34-47.

LDLR

PCSK9

3. C-terminus2. Prodomain1. Catalytic domain

PCSK9 is a Regulator of LDL Metabolism

• Proprotein convertase subtilisin/kexin type 9

• A serine proprotein convertase1

• Expressed in hepatocytes, kidney mesenchymal cells, intestinal ileum and colon epithelia, CNS2

• Regulates hepatic LDLRs, which bind and internalize LDL particles3

1

2

3

CNS = central nervous system

1. Abifadel M, et al. Hum Mutat. 2009;30:520-529. 2. Seidah NG, et al. Proc Natl Acad Sci U S A. 2003;100:928-933.

3. Horton JD, et al. J Lipid Res. 2009;50 Suppl:S172-S177.

PCSK9 Promotes the Degradation of LDLRs, Increasing Plasma LDL-c Levels

LDL

particles

LDL-R

PCSK9 secretion

PCSK9 routes LDLR for lysosomal degradation

LDL-R

recycling

inhibited

1. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. 2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177.3. Brown MS, et al. Proc Natl Acad Sci.

1979;76:3330-3337. 4. Steinberg D, et al. Proc Natl Acad Sci. 2009;106:9546-9547. 5. Goldstein JL, et al. Arterioscler Thromb Vasc Biol.

2009;29:431-438. 6. Zhang DW, et al. J Biol Chem. 2007;282:18602-18612.

Genetic Variants of PCSK9 and LDL Levels

ARIC = Atherosclerosis Risk in Communities; CGPS = Copenhagen General Population Survey; CHD = coronary heart disease;

CVD = cardiovascular disease; DHS = Dallas Heart Study; LDL = low density lipoprotein; MI = myocardial infarction

1. Abifadel M, et al. Hum Mutat. 2009;30:520–529. 2. Dadu RT, et al. Nat Rev Cardiol. 2014;11:563–575.

3. Benn M, et al. J Am Coll Cardiol. 2010;55:2833–2842.

PCSK9 gain of function (GOF) = Fewer LDLRs1 (rare2)

GOF variant Population Characteristics

D374Y British, Norwegian families, 1 Utah familyPremature CHD, tendon xanthomas, severehypercholesterolaemia

S127R French, South African, Norwegian patients Tendon xanthomas; CHD, early MI, stroke

D129G New Zealand familyBrother died at 31 from MI; strong family history of CVD

PCSK9 loss of function (LOF) = More LDLRs3 (more 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 InhibitorsMechanism of Action

PCSK9 Inhibitors Lower LDL-c Levels by Decreasing LDLR Degradation

• Monoclonal antibodies, inhibiting PCSK9, reduce LDL receptor degradation, increasing LDL receptor number and reducing levels of circulating LDL-c1-3

• Lowering LDL-c by targeting PCSK9 via a variety of mechanisms may reduce CV risk1-3

ASO = antisense oligonucleotides; CV = cardiovascular; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol;

LDLR = low-density lipoprotein receptor; mAb = monoclonal antibody; PCSK9 = proprotein convertase subtilisin/kexin type 9;

siRNA = small interfering RNA; SREBP = sterol regulatory element-binding protein.

1. Lambert G, et al. J Lipid Res. 2012;53:2515-2524. Use of illustration ©2016 The American Society for Biochemistry and Molecular Biology.

2. Dadu RT, et al. Nat Rev Cardiol. 2014;11:563-575. 3. Giugliano RP, et al. J Am Coll Cardiol. 2015;65:2638-2651.

LDLR LDL particle

Endocytosis

Endosome

Lysosome

siRNAor ASO

Recyclingof LDLR

Endoplasmicreticulum

Nucleus↑SREBP

Golgi apparatus

PCSK9processing/export

Hepatocyte

mAb

Clathrin-coated

vesicle

LDLR synthesis

Monoclonal Antibodies

1. Ecker DM, et al. mAbs. 2015;7:9–14. 2. Silberstein S, et al. Headache Currents. 2015;1171–1183.

3. Foltz IN, et al. Circulation. 2013;127:2222–2230.

Antibody-Based Therapeutics Research and Development of mAbs is Rapidly Evolving

The first monoclonal antibody (mAb) was produced in 1975; since then:

> 45antibody-based therapeutics have been approved for common (e.g.,

cancer, autoimmune) and rare diseases

> 10fully human mAbs (i.e., those with no mouse sequence)

are now approved

> 20different antigens are targeted by currently approved mAbs,

including growth factors and cell signaling receptors

> 500 mAbs are in clinical development

Ig Class Diagram Distribution

IgA External secretions

IgD B-cell surface receptor

IgEPlays an important role in

hypersensitivity or allergic reactions

IgGMain antibody in serum

Most stable

IgMFirst antibody produced in a primary

response to antigen

Immunoglobulin Classes and Subclasses

1. Foltz IN, et al. Circulation. 2013;127:2222–2230. 2. Silberstein S, et al. Headache Currents. 2015;1171–1183

An

tib

od

y S

ub

cla

ss

es

IgG1

IgG2

IgG3

IgG4

or

IgG is used as the structural basis for therapeutic mAbs

IgG2 and IgG4 subtypes are frequently used to generate

therapeutic mAbs with little to no effector function

Therapeutic Monoclonal AntibodiesNomenclature and Evolution

Mouse

(0% human)

Human

(100% human)

Humanized

(> 90% human)

Chimeric

(65% human)

1. Foltz IN, et al. Circulation. 2013;127:2222–2230. 2. Beck A, et al. Nat Rev Immunol. 2010;10:345–352.

-umab-zumab-ximab-omabGeneric Suffix

Potential for

ImmunogenicityLowerHigher

Longer

Time(First Produced)

1975 1984 1986 1994

PCSK9 Inhibitors

Alirocumab ed Evolocumab

Pharmacokinetics/Pharmacodynamics and Overall Efficacy

Pharmacokinetics and Pharmacodynamics

Adapted from Stein AE, et al, Drugs of the Future. 2013;38(7):451-459.

The administration of Evolocumab results in the binding of PCSK9 and neutralization of its effect on

decreasing LDLR recycling and the net number of LDLRs on the cell surface, leading to LDL-C reduction

PCSK9

Evolocumab

One Single Dose 420 mg

0 14 28 42 56 70 84

0

100

200

300

400

50

75

100

125

150

175

Study Day

LD

L-C

(mg

/dL

)F

ree

PC

SK

9 C

on

ce

ntr

ati

on

(n

g/m

L)

Fre

e E

vo

loc

um

ab

Co

nc

en

tra

tio

n (

ng

/mL

x 0

.01

)

LDL-C

Approximately 75% ofmonths of active

treatment were at the 75 mg dose

LDL-c: On-Treatment Analysis

0 4 8 12 16 20 24 28 32 36 40

Months Since Randomization

37.642.3

53.3

93.3

∆ 55.7mg/dL

96.4101.4

∆ 48.1mg/dL

105

90

75

60

45

30

15

044 48

Me

an

LD

L-C

(mg

/dL

)

–62.7%

∆ 54.1mg/dL

–61.0%–54.7%

Placebo

Alirocumab

Therapy, n (%) Alirocumab (N=9462)

Placebo (N=9462)

High-dose atorvastatin/rosuvastatin 8380 (88.6) 8431 (89.1)

Low-/moderate-dose atorvastatin/rosuvastatin 830 (8.8) 777 (8.2)

Other statin 19 (0.2) 27 (0.3)

Ezetimibe, with or without statin 269 (2.8) 285 (3.0)

No lipid-lowering therapy 87 (0.9) 91 (1.0)

Schwartz GG, et al. N Engl J Med 2018 - Odissey outcomes

LDL-c Reduction

LDL-C was significantly reduced in the Evolocumab group (median: 30 mg/dL)

including 42% who achieved levels ≤ 25 mg/dL vs < 0.1% in the placebo group

Placebo

Median 92 mg/dL

Evolocumab

Median 30 mg/dL

13,251 13,151 12,954 12,596 12,311 10,812 6,926 3,352 79013,779Placebo13,288 13,144 12,964 12,645 12,359 10,902 6,958 3,323 76813,784Evolocumab

No. at risk

40

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Weeks

59% mean reduction (95%CI 58-60), P < 0.001

Absolute reduction: 56 mg/dL (95% CI 55-57)

LD

L C

ho

leste

rol

(mg

/dL

)

Data shown are median values with 95% confidence intervals in the two arms

Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722 – Fourier Study

Effect on Other Lipid Parameters by Baseline Diabetic Status

Without Diabetes With Diabetes

Evolocumab Placebo

No

n-H

DL

-CC

ha

ng

e f

rom

Bas

eli

ne

(%

)

-60

-50

-30

-10

10

-40

-20

00.3

-52.5

Ap

oB

Ch

an

ge f

rom

Bas

eli

ne

(%

)

-60

-50

-30

-10

10

-40

-20

0

2.6

-47.0

No

n-H

DL

-CC

ha

ng

e f

rom

Bas

eli

ne

(%

)

-60

-50

-30

-10

10

-40

-20

00.3

-49.5

P<0.0001

Ap

oB

Ch

an

ge f

rom

Bas

eli

ne

(%

)

-60

-50

-30

-10

10

-40

-20

0

2.7

-44.8

P<0.0001 P<0.0001 P<0.0001

Tri

gly

ceri

des

Ch

an

ge f

rom

Bas

eli

ne

(%

)

-20

-15

-5

5

-10

0-0.5

-15.9

P<0.0001

Lp

(a)

Ch

an

ge f

rom

Bas

eli

ne

(%

)

-30

-25

-15

-5

5

-20

-10

00.0

-26.9

Tri

gly

ce

rid

es

C

ha

ng

e f

rom

Bas

eli

ne

(%

)

-20

-15

-5

5

-10

0-1.0

-16.4

P<0.0001

Lp

(a)

Ch

an

ge f

rom

Bas

eli

ne

(%

)

-30

-25

-15

-5

5

-20

-10

00.0

-26.9

P<0.0001 P<0.0001

Sabatine MS, et al. Lancet Diab Endocrinol. 2017. Sep 14 – Fourier Study

PCSK9 InhibitorsCV Event Reduction

Schwartz GG, et al. Am Heart J 2014;168:682-689.e1.

Main Inclusion CriteriaAge ≥40 years

ACS• 1 to 12 months prior to randomization

• Acute myocardial infarction (MI) or unstable angina

High-intensity statin therapy*• Atorvastatin 40 to 80 mg daily or

• Rosuvastatin 20 to 40 mg daily or

• Maximum tolerated dose of one of these agents for ≥2 weeks

Inadequate control of lipids• LDL-C ≥70 mg/dL (1.8 mmol/L) or

• Non-HDL-C ≥100 mg/dL (2.6 mmol/L) or

• Apolipoprotein B ≥80 mg/dL

*Patients not on statins were authorized to participate if tolerability issues were present and documented

The ODYSSEY OUTCOMES TrialAlirocumab in Patients After Acute Coronary Syndrome

The ODYSSEY OUTCOMES Trial

*Ascertainment was complete for 99.1% and 99.8% of potential patient-years of follow-up for the primary endpoint and all-cause death, respectively

• Premature treatment discontinuation

• Blinded switch to placebo (2 consecutive LDL-C values <15 mg/dL)

• Patients lost to follow-up (vital status)

Randomized 18,924 patients

1955 patients experienced a primary endpoint726 patients died

Follow-up*: median 2.8 (Q1–Q3 2.3–3.4) years8242 (44%) patients with potential follow-up ≥3 years

Alirocumab(N=9462)

Placebo (N=9462)

1343 (14.2%) 1496 (15.8%)

730 (7.7%) Not applicable

14 9


The ODYSSEY OUTCOMES Trial:Target Range for LDL-c

(Alirocumab)


Undesirably high baseline range

50 70

LDL-C (mg/dL)

Targetrange

Alirocumab

Be

low

targ

et

15 250

Acc

epta

ble

ran

ge

75 mg -> 150 mg

The ODYSSEY OUTCOMES TrialBaseline Demographics and Lipid Characteristics

Characteristic Alirocumab (N=9462)

Placebo (N=9462)

Age, years, median (Q1−Q3) 58 (52−65) 58 (52−65)

Female, n (%) 2390 (25.3) 2372 (25.1)

Medical history, n (%)

Hypertension 6205 (65.6) 6044 (63.9)

Diabetes mellitus 2693 (28.5) 2751 (29.1)

Current tobacco smoker 2282 (24.1) 2278 (24.1)

Prior MI 1790 (18.9) 1843 (19.5)

Characteristic, mg/dL, median (Q1–Q3)

Alirocumab (N=9462)

Placebo (N=9462)

LDL-C 87 (73–104) 87 (73–104)

Non-HDL-C 115 (99−136) 115 (99−137)

Apolipoprotein B 79 (69−93) 80 (69−93)

HDL-C 43 (37−50) 42 (36−50)

Triglycerides 129 (94−181) 129 (95−183)

Lipoprotein(a) 21 (7−59) 22 (7−60)


The ODYSSEY OUTCOMES TrialPrimary Efficacy Endpoint: MACE

MACE:CHD death, non-

fatal MI, ischemic

stroke, or

unstable angina

requiring

hospitalization


HR 0.85(95% CI 0.78, 0.93)

P=0.0003

ARR* 1.6%

*Based on cumulativeincidenxe

The ODYSSEY OUTCOMES TrialPrimary Efficacy and Components

Endpoint, n (%) Alirocumab (N=9462)

Placebo (N=9462)

HR (95% CI) Log-rank P-value

MACE 903 (9.5) 1052 (11.1) 0.85 (0.78, 0.93) 0.0003

CHD death 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38

Non-fatal MI 626 (6.6) 722 (7.6) 0.86 (0.77, 0.96) 0.006

Ischemic stroke 111 (1.2) 152 (1.6) 0.73 (0.57, 0.93) 0.01

Unstable angina 37 (0.4) 60 (0.6) 0.61 (0.41, 0.92) 0.02


The ODYSSEY OUTCOMES TrialPrimary Efficacy in LDL-c Subgroups

*P-value for interaction

Incidence (%)Alirocumab PlaceboSubgroup Patients HR (95% CI) p-value*

<80 mg/dL 80 to <100 mg/dL ≥100 mg/dL


- 24%- 14%

Basal

The ODYSSEY OUTCOMES TrialAll-Cause Death

HR 0.85(95% CI 0.73, 0.98)

P=0.026*


ARR† 0.6%

*Nominal P-value†Based on cumulative incidence

- 15%


NNT: number needed to treat



Treatment-emergentadverse events, n (%)

Alirocumab (N=9451)

Placebo (N=9443)

Any 7165 (75.8) 7282 (77.1)Serious 2202 (23.3) 2350 (24.9)

Laboratory value Alirocumab Placebo

ALT >3 × ULN, n/N (%) 212/9369 (2.3) 228/9341 (2.4)Creatine kinase >10 × ULN, n/N (%)

46/9369 (0.5) 48/9338 (0.5)

*HR vs. placebo 1.82 (95% CI 1.54, 2.17)

Event Alirocumab (N=9451)

Placebo (N=9443)

Diabetes worsening or diabetic complications: pts w/DM at baseline, n/N (%)

506/2688 (18.8) 583/2747 (21.2)

New onset diabetes; pts w/o DM at baseline, n/N (%) 648/6763 (9.6) 676/6696 (10.1)

General allergic reaction, n (%) 748 (7.9) 736 (7.8)

Hepatic disorder, n (%) 500 (5.3) 534 (5.7)

Local injection site reaction, n (%)* 360 (3.8) +1.7 % 203 (2.1)

Neurocognitive disorder, n (%) 143 (1.5) 167 (1.8)

Cataracts, n (%) 120 (1.3) 134 (1.4)

Hemorrhagic stroke, n (%) 9 (<0.1) 16 (0.2)


Safety

FOURIER Trial (Evolocumab): Study Design Overview

Screening

• Age 40–85 years

• MI, stroke, or PAD

• Additional risk factors (one

major or two minor)

• Optimal background lipid

therapy (including effective

dose of statin ± ezetimibe)

• LDL-C ≥ 70 mg/dL or

non–HDL-C ≥ 100 mg/dL

Evolocumab SC 140 mg Q2W or 420 mg QM

(per subject preference)

n ~ 13,750

Placebo SCQ2W or QM

(per subject preference)

n ~ 13,750R

an

do

miz

ati

on

1:1

En

d o

f S

tud

y (

EO

S)

Maximum approximately 15 weeks D1 W4 W12 W24 Q24W Number of

key 20

endpoints

achieved

D = day; Q2W = every 2 weeks; Q24W = every 24 weeks; QM = every month; SC = subcutaneous; W = week.

Sabatine MS, et al. Am Heart J. 2016;173:94-101.

FOURIER (Evolocumab):Key Inclusion Criteria

• Men or women aged 40–85 years

• History of clinically evident CVD (MI, nonhemorrhagic stroke, or symptomatic PAD*) plus additional risk factors (see table)

• Fasting LDL-C ≥ 70 mg/dL or non–HDL-C ≥ 100 mg/dL after ≥ 2 weeks of optimized stable lipid-lowering therapy**; fasting triglycerides ≤ 400 mg/dL

Major Risk Factors (One Required) Minor Risk Factors (Two Required)

Diabetes (type 1 or 2) History of non-MI–related coronary revascularization

Age ≥ 65 years at randomization (≤85 years at time of informed consent)

Residual CAD with ≥ 40% stenosis in ≥ 2 large vessels

MI or non-hemorrhagic stroke at ≤ 6 months of screening HDL-C < 40 mg/dL for men and < 50 mg/dL for women

Additional diagnosis of MI or non-hemorrhagic stroke excluding qualifying MI

LDL-C ≥ 130 mg/dL or non–HDL-C ≥ 160 mg/dL after ≥ 2 weeks of stable lipid-lowering therapy

Current daily smoking hsCRP > 2.0 mg/L

History of symptomatic PAD* if eligible by MI or stroke history

Metabolic syndrome

*Symptomatic PAD, as evidenced by either intermittent claudication with ABI (ankle-branchial index) <0.85, or peripheral arterial

revascularization procedure, or amputation due to atherosclerotic disease.

**Moderate to high intensity statin +/-ezetimibe

1. Sabatine MS, et al. Am Heart J. 2016;173:94-101. 2. Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722.

OR

FOURIER Baseline Demographics and CV Risk Factors

CharacteristicsEvolocumab(N = 13,784)

Placebo(N = 13,780)

Demographics

Age – y (SD) 62.5 (9.1) 62.5 (8.9)

Male sex – n (%) 10,397 (75.4) 10,398 (75.5)

White race – n (%) 11,748 (85.2) 11,710 (85.0)

Weight – kg (SD) 85.0 (17.3) 85.5 (17.4)

*There were no nominally statistically significant differences in baseline

characteristics between the two arms except for weight (P=0.014).


Placebo(N = 13,780)

Type of atherosclerosis – n (%)

Myocardial infarction 11,145 (80.9) 11,206 (81.3)

Time from most recent prior MI – yr (IQR) 3.4 (1.0-7.4) 3.3 (0.9-7.7)

Non-hemorrhagic stroke 2,686 (19.5) 2,651 (19.2)

Time from most recent prior stroke – yr (IQR) 3.2 (1.1-7.1) 3.3 (1.1-7.3)

Peripheral artery disease – n (%) 1,858 (13.5) 1,784 (12.9)

Cardiovascular risk factors

Hypertension – n/total n (%) 11,045/13,784 (80.1) 11,039/13,779 (80.1)

Diabetes mellitus – n (%) 5,054 (36.7) 5,027 (36.5)

Current cigarette use – n/total n (%) 3,854/13,783 (28.0) 3,923/13,779 (28.5)

Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722

FOURIERBaseline Lipid-Lowering Therapies and Lipid Parameters

*Statin intensity was categorized per the ACC/AHA Guidelines. Note, that in some countries where FOURIER was conducted, higher statin doses are not

approved.

ACC = American College of Cardiology; ACE = angiotensin converting enzyme; AHA = American Heart Association;

ARB = angiotensin receptor blockers; HDL = high-density lipoprotein; IQR = interquartile range; LDL = low-density lipoprotein; Lp(a) = Lipoprotein(a).

1. Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722. 2. Malinowski HJ, et all. J Clin Pharmacol. 2008;48:900-908.


Placebo(N = 13,780)

Statin use* – n (%)

High intensity 9,585 (69.5) 9,518 (69.1)

Moderate intensity 4,161 (30.2) 4,231 (30.7)

Low intensity, unknown intensity, or no data 38 (0.3) 31 (0.2)

Ezetimibe – n (%) 726 (5.3) 714 (5.2)

Other cardiovascular medications – n/total n (%)

Aspirin and/or P2Y12 inhibitor 12,766/13,772 (92.7) 12,666/13,767 (92.0)

Beta-blocker 10,441/13,772 (75.8) 10,374/13,767 (75.4)

ACE inhibitor or ARB and/or aldosterone antagonist 10,803/13,772 (78.4) 10,730/13,767 (77.9)

Lipid measures - Median (IQR) – mg/dL

LDL cholesterol – mg/dL 92 (80, 109) 92 (80, 109)

Total cholesterol – mg/dL 168 (151, 188) 168 (151, 189)

HDL cholesterol – mg/dL 44 (37, 53) 44 (37, 53)

Triglycerides – mg/dL 134 (101, 183) 133 (99, 181)

Lp(a) - nmol/L 37 (13, 166) 37 (13, 164)

FOURIER Primary and Key Secondary Endpoints

Key Secondary Composite

Endpoint

No. at RiskPlacebo

Evolocumab

Months13780 13449 13142 12288 7944 3893 73113784 13501 13241 12456 8094 3935 724

3.7

6.8

9.9

Cu

mu

lati

ve I

ncid

en

ce (

%)

Placebo

Evolocumab

0

2

4

6

8

9

10

11

0 6 1812 24 3630

1

3

5

7

3.1

5.5

7.9

HR 0.80 (95% CI 0.73 to 0.88);

P < 0.001

Primary Endpoint

6.0

10.7

14.6

5.3

9.1

12.6

No. at Risk

Placebo 13780 13278 12825 11871 7610 3690 686Evolocumab 13784 13351 12939 12070 7771 3746 689

Cu

mu

lati

ve I

ncid

en

ce (

%)

Placebo

Evolocumab

0

2

4

6

8

10

12

14

16

0 6 1812 24 3630

Months

HR 0.85 (95% CI 0.79 to 0.92);

P < 0.001

MI = myocardial infarction; UA = unstable angina.

Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722.

Composite of CV Death, MI, Stroke,

Hospitalization for UA, or Coronary

Revascularization

Composite of CV Death, MI,

or Stroke

Statistically significant reduction of LDL-C by 59% from a median of 92 to 30 mg/dL, including 42% who achieved LDL-C ≤ 25 mg/dL

FOURIERPrimary, Key Secondary, and Other Endpoints

Outcome

Evolocumab(n = 13,784)

n (%)

Placebo (n = 13,780)

n (%)HR

(95% CI) P-value

Primary endpoint* 1,344 (9.8) 1,563 (11.3) 0.85 (0.79-0.92) <0.001

Key secondary endpoint† 816 (5.9) 1,013 (7.4) 0.80 (0.73-0.88) <0.001

Other endpoints

CV death 251 (1.8) 240 (1.7) 1.05 (0.88-1.25) 0.62

Death from any cause 444 (3.2) 426 (3.1) 1.04 (0.91-1.19) 0.54

MI 468 (3.4) 639 (4.6) 0.73 (0.65-0.82) <0.001

Hospitalization for UA 236 (1.7) 239 (1.7) 0.99 (0.82-1.18) 0.89

Stroke 207 (1.5) 262 (1.9) 0.79 (0.66-0.95) 0.01

Coronary revascularization 759 (5.5) 965 (7.0) 0.78 (0.71-0.86) <0.001

CV Death or Hospitalization for Worsening Heart Failure

402 (2.9) 408 (3.0) 0.98 (0.86-1.13) 0.82

Ischemic stroke or TIA 229 (1.7) 295 (2.1) 0.77 (0.65-0.92) 0.003

*Time to CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first †CV death, myocardial infarction, or stroke, whichever occurs first

CV = cardiovascular; MI = myocardial infarction; TIA = transient ischemic attack; UA = unstable angina.

Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722.

The primary endpoint was driven by reductions in MI,

stroke, coronary revascularization and ischemic stroke or TIA

FOURIER Primary Endpoint by Baseline Diabetic Status

Data are the cumulative event rates for the primary efficacy endpoint (composite of cardiovascular death, myocardial infarction, stroke,

hospital admission for unstable angina, or coronary revascularization).

ARR over 3 years. ARR = absolute risk reduction

Sabatine MS, et al. Lancet Diab Endocrinol. 2017. Sep 14. doi: 10.1016/S2213-8587(17)30313-3

Cu

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lati

ve

In

cid

en

ce

(%

)

0

2

6

10

14

16

18

4

8

12

0 180 360 540 720 900 1080

Days

EvolocumabPlacebo

HR 0.83 (95% CI 0.75–0.93);

p = 0.0008

ARR 2.7% (95% CI 0.7–4.8%)

With Diabetes

0 180 360 540 720 900 1080

Days

0

2

6

10

14

16

18

4

8

12

HR 0.87 (95% CI 0.79–0.96);

p = 0.0052

ARR 1.6% (95% CI 0.1–3.2%)

Without Diabetes

Patients with diabetes treated with evolocumab showed a greater ARR because of their heightened baseline risk than those without diabetes (2.7% vs 1.6%);

driven by a larger ARR in coronary revascularization (2.7% vs 1.8%)

Composite of CV Death, MI, Stroke, Hospitalization for UA, or Coronary Revascularization

FOURIER Incidence of new-onset DM

*Data are the cumulative incidence of NODM as adjudicated by a centralized clinical events committee at the end of 1, 2,and 3 years of follow-up, among

patients without diabetes at baseline. Error bars are 95% CIs. Note: Post-hoc analyses of patients with pre-diabetes at baseline similarly showed no difference

between treatment groups in the incidence of NODM (HR 1.00 [95% CI 0.89 – 1.13]).

NODM = new-onset diabetes mellitus.

Sabatine MS, et al. Lancet Diab Endocrinol. 2017. Sep 14. doi: 10.1016/S2213-8587(17)30313-3.

End of Year 1 End of Year 2 End of Year 3

Kap

lan

-Meie

r R

ate

(%

)

EvolocumabPlacebo

0

2

6

10

14

16

20

4

8

12

18

p = 0.43

3.8%4.0%

p = 0.64

7.0%7.3%

p = 0.32

10.9%11.6%

In patients without diabetes at baseline, there was no difference in the incidence of NODM* over time between the evolocumab and placebo groups (HR 1.05 [95% CI 0.94 - 1.17]).

PCSK9 Inibitori

nella Pratica Clinica

Risk Categories and LDL-C Treatment Goals

Risk category Risk factors/10-year riskTreatment goals

LDL-C

(mg/dL)

Non-HDL-C

(mg/dL)

Apo B

(mg/dL)

Extreme risk

– Progressive ASCVD including unstable angina in individuals after achieving an LDL-C <70 mg/dL

– Established clinical cardiovascular disease in individuals with DM, stage 3 or 4 CKD, or HeFH

– History of premature ASCVD (<55 male, <65 female)

<55 <80 <70

Very high

risk

– Established or recent hospitalization for ACS, coronary, carotid or peripheral vascular disease, 10-year risk >20%

– DM or stage 3 or 4 CKD with 1 or more risk factor(s)

– HeFH

<70 <100 <80

High risk– ≥2 risk factors and 10-year risk 10%-20% – DM or stage 3 or 4 CKD with no other risk factors <100 <130 <90

Moderate

risk

≤2 risk factors and 10-year risk <10%

<100 <130 <90

Low risk 0 risk factors <130 <160 NR

American Association of Clinical Endocrinologists and American College of Endocrinology

Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease

ENDOCRINE PRACTICE Vol 23 (Suppl 2) April 2017

HeFH, Heterozygous Familial Hypercholesterolaemia

Maximal Therapeutic Responses for Statins Is Generally Observed Within 6 Weeks

2013 ACC/AHA guidelines recommend evaluating LDL-c levels 4-12 weeks after initiating statin therapy to determine patient’s response and adherence to treatment

Select non-PCSK9i agents

Time to Maximal or Near Maximal Effect

Effect

Atorvastatin Generally within 4 weeks and maintained during chronic therapy

Reduces TC, LDL-C, VLDL-C, ApoB, and TG, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia1

Simvastatin Generally within 4-6 weeks and maintained during chronic therapy

Reduces TC, LDL-C, ApoB, TG and increases HDL-C in HeFH and non-familial forms of hyperlipidemia and in mixed hyperlipidemia

Simvastatin / Ezetimibe

Generally within 2 weeks and maintained during chronic therapy

Reduces TC, LDL-C, ApoB, TG, and non-HDL-C and increases HDL-C in patients with hyperlipidemia

Ezetimibe Generally within 2 weeks and maintained during chronic therapy

Reduces TC, LDL-C, ApoB, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia

Rosuvastatin Generally within 2-4 weeks and maintained during chronic therapy

Reduces elevated TC, LDL-C, ApoB, non-HDL-C, and TG levels, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia

ACC = American College of Cardiology; AHA = American Heart Association; HeFH = heterozygous familial hypercholesterolemia;

Stone NJ, et al. J Am Coll Cardiol. 2014;63:2889-2934.

Statin Therapy Increases Circulating PCSK9 Levels

Sahebkar A, et al. Diabetes Obes Metab. 2015;17:1042-1055.

The Impact of Statin Therapy on Plasma PCSK9 Concentrations

Study Difference in Means (95% CI) P Value

Awan et al. 2012a 26.000 (25.373-26.627) 0.000

Awan et al. 2012b 20.000 (19.312-20.688) 0.000

Careskey et al. 2008 15.000 (6.029-23.971) 0.001

Guo et al. 2013a 38.000 (-1.742-77.742) 0.061

Guo et al. 2013b 90.000 (41.037-138.963) 0.000

Guo et al. 2014 101.000 (48.005-153.995) 0.000

Costet et al. 2010 42.200 (-85.198-169.598) 0.516

Kawashiri et al. 2012 245.700 (191.168-300.232) 0.000

Mayne et al. 2008 44.000 (-19.820-107.820) 0.177

Nozue et al. 2013a 57.000 (36.061-77.939) 0.000

Nozue et al. 2013b 57.000 (36.215-77.785) 0.000

Raal et al. 2013a 59.000 (-25.919-143.919) 0.173

Raal et al 2013b 76.000 (41.176-110.824) 0.000

Theusch et al. 2014 59.040 (53.863-64.217) 0.000

Welder et al. 2010 45.000 (35.268-54.732) 0.000

Berthold et al. 2013 32.000 (-46.810-110.810) 0.426

Overall 40.716 (34.786-46.647) 0.000

-300,0 -200,0 -100,0 0,0 100,0 200,0 300,0

Statins Upregulatethe Expression of the LDLR and PCSK9

SREBP-2 = sterol regulatory element-binding protein-2

Urban D, et al. J Am Coll Cardiol. 2013;62:1401-1408.

SREBP-2 (sterol regulatoryelement-binding protein-2)

Intracellular cholesterol

PCSK9 LDLR

LDL-C

Statin Therapy

This self-regulatorymechanism contributes to maintain cholesterolhomeostasis preventingexcessive cholesterol uptake, but it may limit the therapeutic effect of statins

Prescrivibilità

Ipercolesterolemia primaria (familiare eterozigote e non familiare) o dislipidemia mista in aggiunta alla dieta nei pazienti adulti:

In associazione alla statina o alla statina con altre terapie ipolipemizzanti, in pazienti che non raggiungono livelli di LDL-C target con la dose massima tollerata di statina, oppure

In monoterapia o in associazione ad altre terapie ipolipemizzanti, in pazienti intolleranti alle statine o per i quali l’uso di statine e controindicato

Ipercolesterolemia familiare omozigote (solo per Evolocumab)

Negli adulti e negli adolescenti di almeno 12 anni di eta , in associazione ad altre terapie ipolipemizzanti

Anticorpi monoclonali anti-PCSK9

Farmaco Dosaggio iniziale raccomandato Range dosaggio Somministrazione

Alirocumab 75 mg ogni 2 settimane 75-150 mg ogni 2 settimane sc

Evolocumab 140 mg ogni 2 settimane o

420 mg una volta al mese*NA sc

Considerazioni:

Refrigerazione generalmente necessaria Reazioni avverse e interruzione del trattamento poco

frequenti Reazioni avverse più comunemente riportate:

reazioni nel sito di iniezione

Altre reazioni avverse: Alirocumab: infezioni delle vie aeree superiori(dolore orofaringeo, nasofaringite), prurito, ipersensibilita, vasculite da ipersensibilita (raro)

Evolocumab: influenza, nasofaringite, mal di schiena, rash cutaneo, nausea, artralgia

*Non disponibile in Italia

Praluent® (Alirocumab) Repatha® (Evolocumab)

Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497; Praluent (alirocumab) [PI] 2015; Repatha (evolocumab) [PI]; 2016.

Indicazioni autorizzate e rimborsate SSN


In prevenzione primaria in pazienti di eta ≤80 aa con ipercolesterolemia familiare eterozigote e livelli di LDL-C ≥130 mg/dl, nonostante terapia da almeno 6 mesi con statina ad alta potenza alla massima dose tollerata + ezetimibe oppure con dimostrata intolleranza alle statine

In prevenzione secondaria in pazienti di eta ≤80 aa con ipercolesterolemia familiare eterozigote o ipercolesterolemia non familiare o dislipidemia mista con livelli di LDL-C ≥100 mg/dl nonostante terapia da almeno 6 mesi con statina ad alta potenza alla massima dose tollerata + ezetimibe oppure terapia da almeno 6 mesi con ezetimibe in pazienti con dimostrata intolleranza alle statine

Ipercolesterolemia familiare omozigote in pazienti di eta ≤80 aa (solo per Evolocumab)

Alta Intensità Moderata Intensità Bassa Intensità

Riduzione di LDL-c ≥50% 30-49% <30%

Statine Atorvastatina 40-80 mgRosuvastatina 20-40 mg

Atorvastatina 10-20 mgRosuvastatina 5-10 mgSimvastatina 20-40 mg

Simvastatina 10 mgPravastatina 10-20 mgLovastatina 20 mgFluvastatina 20-40 mg

Potenza delle Statine

Grundy SM, et al. 2018 Cholesterol Clinical Practice Guidelines2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol

Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel Arch Med Sci 2015; 11, 1: 1–23

1. Impossibilità a tollerare almeno 2 statine, di cui una alla dose iniziale ed una seconda statina ad una qualsiasi dose

2. Associazione con uno o più eventi avversi correlati all’uso di statine, confermati e non tollerabili, oppure associazione con significative alterazioni dei biomarker (CPK >10xULN, eseguito in assenza di sforzi muscolari)

3. Risoluzione o netto miglioramento della sintomatologia, normalizzazione o netta riduzione dei biomarker alla sospensione/riduzione della dose di statina

4. Sintomatologia/innalzamento dei biomarker non attribuibile ad altre cause (interazioni farmacologiche o condizioni cliniche che possono aumentare il rischio di intolleranza alle statine es. ipotiroidismo, patologie muscolari, importante aumento dell’attività fisica)

Definizione unificata di intolleranza alle statine

Criteri di eleggibilita in regime di prevenzione secondaria


Età ≤ di 80 anni

Cardiopatia ischemica (Pregresso IMA, malattia coronarica documentata, pregressa angioplastica o by-pass aorto-coronarico) e/o Malattia Cerebrovascolare (pregresso ictus ischemico, TIA o rivascolarizzazione carotidea) e/o Arteriopatia Periferica e/oDiabete Mellito con complicazioni (insufficienza renale, retinopatia)

Terapia con statina ad alta potenza alla massima dose tollerata (atrovastatina 40-80 mg o rosuvastatina 20-40 mg) in associazione con ezetimibe da almeno 6 mesi (terapia regolare e continuativa)

LDL-C > 100 mg/dL in tre controlli effettuati nell’arco di 6 mesi in corso di terapia con statina ad alta efficacia ed ezetimibe

Devono essere presenti tutte le seguenti condizioni:

Età > 80 anni

Malattia renale cronica di grado severo (eGFR < 30 ml/min/1.73 m2)

Cirrosi epatica (classe Child-Pugh B o C)

Paziente non eleggibile per la terapia


Una delle seguenti condizioni:

Piano Terapeutico AIFA online

https://servizionline.aifa.gov.it

• Piano terapeutico semestrale/trimestrale• Centri prescrittori• Specialisti individuati da AIFA alla prescrizione: cardiologo, internista ed endocrinologo

Take home messages

• Gli anticorpi monoclonali anti-PCSK9, Alirocumab ed Evolocumab, riducono

significativamente i livelli di LDL-c e il rischio di eventi cardiovascolari in

pazienti con malattia cardiovascolare, in associazione al trattamento con

statine o ad altre terapie ipolipemizzanti

• La terapia con anticorpi monoclonali anti-PCSK9 è risultata sicura e ben

tollerata nei principali trial clinici effettuati

• L’utilizzo di anticorpi monoclonali anti-PCSK9 può essere considerato dopo

aver attentamente valutato i criteri di prescrivibilità e rimborsabilità

Documents

La Nuova Terapia...LDLR PCSK9 1. Catalytic domain 2. Prodomain 3. C-terminus PCSK9 is a Regulator of LDL Metabolism • Proprotein convertase subtilisin/kexin type 9 • A serine proprotein