Terapia ipocolesterolemizzante: linee guida e nuovi ... Marcello.pdf · Bisogni insoddisfatti nella...

Marcello Arca

Dipartimento di Medicina Interna e

Specialità Mediche

UOS Centro Arteriosclerosi

Sapienza Università di Roma

Terapia ipocolesterolemizzante:

linee guida e nuovi approcci

terapeutici.

Il ruolo degli inibitori della

PCSK9

Presenter Disclosure Information

I have the following potential conflicts of interest to report:

☑ Consulting: Kowa, Regeneron, ISIS, Aegerion

☑ Speakers honoraria: AstraZeneca, MSD, Pfizer, Roche, Genzyme, Abbott, Sanofi, SigmaTau

☑ Research grants: MSD, Pfizer, Regeneron, Sanofi, Genzyme, Boheringer, Aegerion

Bisogni insoddisfatti nella terapia delle dislipidemie

• Parziale risposta nei pazienti condislipidemie genetiche (FH)

• Difficoltà a raggiungere il target neipazienti ad alto/altissimo rischio

• Presenza di pazienti che mostranouna intolleranza (muscolare) allestatine

Emerging lipid-lowering therapies

CETP, cholesteryl ester transfer protein; MTP, microsomal triglyceride transfer protein; PCSK9, proprotein convertase subtilisin/kexin type 9; SI, statin intolerant

1. Sullivan D et al. J Am Coll Cardiol. 2012;308;2497–2508; 2. Stroes E et al. J Am Coll Cardiol. 2014;63;2541–2548; 3. Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant

Subjects -3 (GAUSS-3), available at: http://clinicaltrials.gov/ct2/show/NCT01984424?term=NCT01984424%26rank=1, accessed October 2014;

4. Moriarty PM et al. Late-breaker abstract at AHA, Chicago, 15–19 November 2014; 5. ClinicalTrials.gov. The Evaluation Of PF-04950615 (RN316) In Reducing The Occurrence Of Major Cardiovascular

Events In High Risk Subjects (SPIRE-2) available at: http://clinicaltrials.gov/ct2/show/NCT01975389?term=SPIRE-2andrank=1, accessed October 2014

PCSK9 inhibitorsFarmaci Biologici

PCSK9 inhibitors

Evolocumab

Alirocumab

Bococizumab

CURRENT LIPID LOWERING STRATEGIES (Statins±Ezetimibe) Targeting LDL-C

UNMET CLINICAL NEEDS

Emerging therapies

CETP inhibitors MTP inhibitors

Anacetrapib

EvacetrapibLomitapideMipomersen

Anti-senseoligonucleotides

http://clinicaltrials.gov/ct2/show/NCT01984424?term=NCT01984424&rank=1

http://clinicaltrials.gov/ct2/show/NCT01975389?term=SPIRE-2andrank=1

Plasma LDL-C is controlled by hepatic low-density lipoprotein receptor (LDLR) levels

Brown et al. Proc Natl Acad Sci USA 1979;76:3330–3337.

Recycling of LDLR

Increased LDLR surface concentration

LDL particles

LDLR

PCSK9 reduces LDLR recycling, thereby increasing plasma LDL-C

Horton et al. J Lipid Res 2009;50:S172–S177.

LDL particles

LDLR

PCSK9 secretion

PCSK9 routes LDLR for lysosomal degradation

LDLR recycling blocked

Impact of PCSK9 inhibition on LDL receptor

expression

11

For illustration purposes only

13

Alirocumab : relationship between mAb levels, PCSK9 and LDL-C

-70

-60

-50

-40

-30

-20

-10

0

0

20

40

60

80

100

120

140

160

180

200

0 500 1000 1500 2000 2500

LDL-

-C m

ean

% c

han

ge

Fre

e/T

ota

l PC

SK9

Co

nc.

(n

g/m

L)To

tal R

EGN

72

7 (

ng/

mL)

X 0

.01

Time (hours)

Free PCSK9, Total REGN727/SAR236553 Concentration and Mean % Change LDL-C vs Time

Total REGN727/SAR236553 free PCSK9 LDL-c2 W 4 W

Alirocumab is available in a pre-filled autoinjector pen

• 1mL solution in a single-use pre-filled

pen containing a syringe made from

type I glass with a stainless steel

27-gauge needle

• The needle cover of the pre-filled

pen is made from dry natural rubber

(a derivative of latex)

• The solution should be clear to

opalescent, colourless to yellowish,

and practically free from particles

• Pack sizes of one, two, three or

multipack of six (3 × 2) pre-filled

pens*

Yellow

(injection

complete)

Yellow

safety

guard

Orange

cap off

Grey start

button

Window

Medicine

Orange

cap on

Before

use

After

use

?Hypercholesterolemia in high

CV-risk population (NOT

controlled with max tolerated

dose of statins±Eze)

PCSK9 Inhibitors as Add-on to

max tolerated statin

(± other LLT)

PCSK9 inhibitorsFarmaci Biologici: PCSK9 inhibitors

Evolocumab, Alirocumab, Bococizumab

?????

?BASELINE LDL-C TO HIGH

TO REACH TARGETS!

I MONOCLONALI ANTI-PCSK9 NEI PAZIENTI

IPERCOLESTEROLEMICI SEVERI E/O INTOLLERANTI

ALLE STATINE

Lipidi, Malattia Cardiovascolare

ed Ipercolesterolemia Familiare (FH)

LDL-C

FH Target #1

in tutte le

Linee Guida

Terapia di scelta

Statine (ad elevata efficacia) al massimo dosaggio tollerato (± ezetimibe)

Livelli Target di LDL-C

FH senza CVD: rischio CV elevato: LDL-C<100 mg/dl (<2.5 mmol/L)

FH con CVD: rischio CV molto elevato: LDL-C< 70 mg/dl (<1.8 mmol/L)

ESC/EAS Guidelines - European Heart Journal (2011,32:1769-1818)

Pazienti con FH: rischio di eventi CV elevato anche in assenza di CVD

NON vanno utilizzate le carte del rischio CV (es. SCORE)

Colesterolo

Plasmatico

Ipercolesterolemia

Familiare Eterozigote*300-580 mg/dl

480-1000 mg/dl

Forme

PRIMITIVE

Ipercolesterolemia

Familiare Omozigote*

*Ipercolesterolemia Familiare (FH) monogenica

The Lancet, 385:331-340, 2015

Efficacy and safety of alirocumab in patients

with heterozygous familial

hypercholesterolaemia (heFH) not adequately

controlled with current lipid-lowering therapy:

Results of ODYSSEY FH I and FH II studies

J.J.P. Kastelein, HN.Ginsberg, G Langslet, G.K Hovingh, R. Ceska,

R. Dufour, D. Blom, F. Civeira, M. Krempf, M.Farnier

Presented ESC 2014, Barcelona

• 329 patients with heterozygous

familial hypercholesterolaemia

• LDL-C≥ 100 mg/dl

• Evolocumab 140 mg every 2 weeks

• Evolocumab 420 mg monthly

Mean % change from baseline in LDL-C

• 486 (FH I) e 249 (FH II) patients with

heterozygous familial hypercholesterolaemia

• LDL-C≥ 100 mg/dl o ≥ 70 mg/dl se CVD

• Alirocumab 75 mg every 2 weeks

• Alirocumab 150 mg every two weeks*

* If LDL-C>70 mg/dl at 8 weeks

Achieved LDL-C Over Time on Background of Maximally-

Tolerated Statin ±Other LLT

-50-55%-60%

The Lancet, 385:331-340, 2015

Efficacy and safety of alirocumab in patients

with heterozygous familial

hypercholesterolaemia (heFH) not adequately

controlled with current lipid-lowering therapy:

Results of ODYSSEY FH I and FH II studies

J.J.P. Kastelein, HN.Ginsberg, G Langslet, G.K Hovingh, R. Ceska,

R. Dufour, D. Blom, F. Civeira, M. Krempf, M.Farnier

Presented ESC 2014, Barcelona* If LDL-C>70 mg/dl at 8 weeks

LDL-C Goal Achievement < 70 mg/dL Weeks 10 and 12

2%

67%

2%

80%

78%*

65%*

Placebo Q2W (N = 54)

Placebo QM (N = 55)

Evolocumab 140 mg Q2W (N = 110)

Evolocumab 420 mg QM (N = 110)

*P<0.0001 evolocumab treatment difference vs placebo

Proportion of patients reaching LDL-C

goal† at Week 24

RUTHERFORD-2: Evolocumab in HeFHSafety and Tolerability: Events of Interest

*Reported using high-level term grouping, which includes injection site (IS) rash, IS inflammation, IS

pruritus, IS reaction, and IS urticaria.

Adapted from Raal FJ, et al. Lancet 2014; doi.org/10.1016/S0140-6736(14)61399-4.

Adverse Events (AEs), % (n)Placebo Q2W

(N = 54)

Evolocumab 140 mg Q2W

(N = 110)

Placebo QM (N = 55)

Evolocumab 420 mg QM

(N = 110)

4% (2) 5% (5) 4% (2) 7% (8)

Neurocognitive AEs 0 0 0 0

Muscle-related AEs 0 7% (8) 2% (1) 2% (2)

ALT or AST > 3x ULN (any post-baseline

value)0 0

0Potential

injection-site reactions*

0

Creatine kinase > 5x ULN (any post-

baseline value)0 0 4% (2) 0

Anti-evolocumab antibodies, %

Binding antibodies NA 0 NA 0

Neutralising antibodies NA 0 NA 0

Hypercholesterolemia in high

CV-risk population (not





Patients with Familial

Hypercholesterolemia

(i.e HeFH)



(± other LLT)

55-60% greater LDL-C reduction on top of max statin!

65-80% of pts with HeFH with LDL-C <70 mg/dL!!!



ALLE STATINE

PCSK9 inhibition in high risk patients

24

March 15, 2015

NEJM, March 15, 2015

N=1553

N=788

2341 patients at high CV risk for cardiovascular with events who had LDL-C > 70 mg/dl while receiving statins at the maximum tolerated dose

Baseline Characteristics

of 4465 patients

Characteristic Value

Age, years, mean (SD) 58 (11)

Male sex (%) 51

Cardiovascular risk factor (%) 80

Hypertension 52

Diabetes mellitus 13

Metabolic syndrome 34

Current cigarette use 15

Family hx of premature CAD 24

Known familial hyperchol. 10

Known vascular disease (%) 25

Coronary 20

Cerebrovascular or Peripheral 9

LDL Cholesterol Goals

P<0.001

P<0.001

Standard of care alone (n=1489)

Evolocumab plus standard of care (n=2976)










(i.e HeFH)



(± other LLT)

?

55-60% greater LDL-C reduction on top of max statin!

65-80% of pts with HeFH with LDL-C <70 mg/dL!!!



ALLE STATINE

Patients with

Statin Intolerance

PCSK9 Inhibitors MONOTHERAPY

(or Add-on other LLT?)



(± other LLT)

Double-Blind Treatment Period (24 Weeks)

Alirocumab 75/150 mg SC Q2W + placebo PO QDadministered via single 1 mL injection using prefilled pen for self-administration

Per-protocol dose ↑ possible depending on W8 LDL-C

N=100

Ezetimibe 10 mg PO QD + placebo SC Q2W

N=100

W8 W16

Primary endpoint (LDL-C % change from baseline,

ALI and EZE only) Safety analysis (all groups)

W4 W12 W24

Per-protocol dose increase if Week 8 LDL-C ≥70 or ≥100 mg/dL

(depending on CV risk)

*Unable to tolerate at least two different statins, including one at the lowest dose, due to muscle-related symptoms*Unable to tolerate at least two different statins, including one at the lowest dose, due to muscle-related symptoms

ODYSSEY ALTERNATIVE Study Design

Statin

intolerant

patients*

(by medical

history)

with LDL-C

≥70 mg/dL

(very-high

CV risk) or

≥100 mg/dL

(moderate/

high risk)

†4-week single-blind placebo run-in follows 2-week washout of statins, ezetimibe and red yeast rice.

OLTP: Alirocumab open-label treatment period; W, Week.

Assessments

W0W -4

Patients discontinued if muscle-related AEs reported with placebos during run-in

R

Placebo PO QD

+ Placebo

SC Q2W†

Atorvastatin 20 mg PO QD + placebo SC Q2W

N=50

OLT

P/8

we

ek

FU

21/24

Alirocumab Maintained

LDL-C Reductions Week 4–24

Week

156 mg/dL

97 mg/dL

157 mg/dL

92 mg/dL

EzetimibeAlirocumab

LD

L-C

, m

ean

(S

E),

mg

/dL

Achieved calculated LDL-C over time – on-treatment analysis

(modified ITT – observed data only)

49.5% received 150 mg Q2W at W12

Δ 59 mg/dLΔ 65 mg/dL

-52.2%

-17.1%

22/24

Fewer Skeletal Muscle AEs with Alirocumab

than with Atorvastatin

0.50

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00

Cu

mu

lati

ve

pro

ba

bil

ity o

f e

ve

nt

Week

Atorvastatin

Alirocumab

0 4 8 12 16 20 24 28 32 36

Kaplan-Meier estimates for time to first skeletal muscle event†

†Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue.

ALI, alirocumab; ATV, atorvastatin, EZE, ezetimibe.

Cox model analysis:

HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042

Ezetimibe

HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P=0.096

I MONOCLONALI ANTI-PCSK9 NEL CONTROLLO DEL

COLESTEROLO LDL


UNMET CLINICAL NEED WITH CURRENT THERAPY

REMARKABLE LDL-C REDUCTION BY 50-65% AS ADD-ON TO MAX LLT OR MONOTHERAPY

EXCELLENT SAFETY PROFILE, POTENTIALLY RELEVANT CLINICAL BENEFITS

POPULATION AT TOP COST/BENEFIT RATIO

1)Heterozygotes Familial Hypercholesterolemia2) Statin intolerant at very high CV risk







(i.e HeFH)

Patients with

Statin Intolerance

COST ($) CV BENEFITS

Ann Intern Med. doi:10.7326/M14-2957

Effects of PCSK9 Antibodies in adults with hypercholesterolemiaA systematic review and meta-analysis

Serious adverse events

Neurocognitive adverse event in the ODISSEY LONG TERM


Anti-PCSK9 antibody treatment reduces atherosclerosis in APOE*3Leiden.CETP mice

J Lipid Res 2014. 55: 2370–2379.

ODISSEY LONG TERMDouble Blind RCT

ALIROCUMAB

OSLER I e IIOpen Label Randomized

EVOLOCUMAB

Duration 78 week 48 weeks

Population (size) n= 2341 n= 4465

Patients With CADHigk CV RiskHeFH

With CADHigk CV RiskHeFH

On Statins >99% 70%

Calculated LDL-C 122 mg/dl 120 mg/dl (median)

LDL-C Reduction ~60%48 mg/dl (week 24)58 mg/dl (week 78)

~60%48 mg/dl (week 24)51 mg/dl (week 48)

CV Event Reduction ~50% ~50%

Safety AE not significant vs Placebo AE not significant vs Standard Therapy Group

This article was published onMarch 15, 2015, at NEJM.org

This article was published onMarch 15, 2015, at NEJM.org.

Conclusioni

La inibizione del PCSK9 attraverso l’uso dianticorpi monoclinali rappresenta una strategiamolto promettente per raggiungere il valoretarget di LDL-C nei pazienti a rischio CV

La somministrazione di Ab-anti-PCSK9 puòconsentire di ottenere una riduzione del LDL-Cdel 50-60%, in diverse tipologie di pazienti giàin trattamento con statine

Sebbene gli studi sono stati di breve durata,non sono stati osservati AE di particolare rilievoassociati all’uso di Ab- anti PCSK9

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