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PCSK9 inibitori: Basi fisiopatologiche ed

impiego clinico

Alirocumab

Paolo Calabrò Cattedra Cardiologia

Seconda Università Napoli

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Atherosclerotic CVD is a major cause of hospitalisation and mortality in Europe

• Each year, over 22.5 million in-patients with diseases of the circulatory system are discharged from hospitals across Europe1

1. http://data.euro.who.int/hfadb. Accessed 25 Feb 2016. 2. http://ec.europa.eu/eurostat/statistics-explained/index.php/Cardiovascular_diseases_statistics. Accessed 22 Jan 16. 3. http://ec.europa.eu/eurostat/statistics-explained/index.php/Causes_of_death_statistics. Accessed 22 Jan 16.

Hospital discharge rates for in-patients with CVD, per 100,000 population2

Standardised death rate for CVD per 100,000 population3

Epidemiology shows that higher LDL-C levels are associated with greater CV morbidity and mortality

In epidemiological studies, including the Framingham Heart Study1 and MRFIT2, high levels of cholesterol or LDL-C resulted in more CV events

1. Kannel et al. Ann Intern Med 1971;74:1–12. 2. MRFIT Research Group. Prev Med 1986;15:254–273.

MRFIT

Pharmacological evidence shows lower LDL-C

levels are associated with lower CV event rates

Besseling et al. Drugs 2013;73:293–301.

Even

ts %

LDL-C (mg/dL)

Treatment group

Control group Secondary prevention

Primary

prevention

LINEE GUIDA ESC/EAS 2011 LINEE GUIDA ESC/EAS 2016

Catapano A. EHJ 2016

CHECK STUDY:

A Survey of the Italian Population

area dei soggetti “non a target”

Poli A et al Giorn Ital Arterioscler 2015;6:1-12

5367 individuals, age 40-79 yrs

42.3% with an LDL-C

higher that their

individual target

35% at very high CV (19,9%)

or high (15,1%) CV risk

LDL target YES LDL target NO

Subjects at very high CV risk : 2,6% 97,4%

Subjects at high CV risk : 14,7% 85,3%

Very High Risk

40-55%

High Risk

10-25%

Complex combination therapy is needed to reach recommended LDL-C levels

Nordestgaard et al. Eur Heart J 2013;34:3478–3490.

Weisweiler et al. Metabolism 1989;38:271–274.

LD

L-C

(m

mol/L)

8.0

~4.0 (↓50%)

~3.4 (↓15%)

~3.1 (↓10%) ~2.8 (↓10%)

2.6mmol/L

1.8mmol/L

~1.4 (↓50%)

% -60 -55 -50 -45 -40

-

35 -30 -25 -20 -15 -10 -5 0

Rosuvastatin

10mg

40mg 20mg

20mg Atorvastatin 80mg 40mg

Simvastatin 10mg 20mg 40mg 80mg

Pravastatin 10mg 20mg 40mg

Pitavastatin 1mg/d 2mg 4mg

10mg

Doubling statin dose achieves ~6% additional LDL-C reduction

www.fda.gov/drugs/drugsafety/ucm256581.htm#relative. Accessed 10 Jan 2016.

Change in LDL-C (%)

ALIROCUMAB

• Alirocumab: cosa è e come agisce

• Efficacia su LDL-C (in associazione a statine)

• Quando impiegarlo (popolazioni Target)

• Potenziali benefici su eventi CV

*Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9)

Imm

unogenic

ità

Fully Mouse 1st generazione

Chimeric 2nd generazione

Humanised 3rd generazione

“Fully” Human 4th generazione

Highly immunogenic 100% Mouse

Still immunogenic ~30% Mouse

rituximab abciximab

Still immunogenic ~5-10% Mouse

trastuzumab bococizumab

Least immunogenic

Evolocumab Alirocumab

ibritumomab

Mouse variable

Mouse constant

Human variable

Human constant

1.1. Foltz I et al. Circulation 2013 Jun 4;127(22):2222-30;

L’evoluzione degli anticorpi monoclonali

BLA 125559 Animal Toxicology Summary – C. Lee Elmore, PhD

Figure 3: Alirocumab inhibits PCSK9, increases LDLR, and decreases LDL-C

Alirocumab bound to PCSK9 (represented here by mAb, monoclonal antibody) prevents the association

between PCSK9 and the LDLR. The LDLR binds the LDL particle and is internalized. The LDL particle is

degraded in the lysosome, but the LDLR is recycled back to the plasma membrane. SREBP, sterol

regulatory element binding protein. ASO, antisense oligonucleotides and siRNA, small interfering RNAs

are alternate mechanisms for targeting PCSK9 at the transcriptional level.

(Adapted from Lambert G, et al.3)

PCSK9 and LDLR pharmacology:

Transcription of PCSK9 and LDLR genes share a common regulatory mechanism mediated by

sterol regulatory element-binding protein 2 (SREBP2). SREBP2 interacts with another

membrane protein, SREBP cleavage-activating protein (SCAP), which functions as a sterol

sensor. Intracellular sterols inhibit LDLR and PCSK9 gene transcription by suppressing the

processing and release of SREBP2. In the presence of sterols, inactive SREBP2 remains bound

to the endoplasmic reticulum after synthesis.4

In the sterol-depleted state, SCAP escorts the SREBP2 to the Golgi where it is proteolytically

cleaved, which releases the mature SREBP2 capable of transcriptional activation. Mature

SREBP2 enters the nucleus and binds to the sterol regulatory element 1 (SRE-1) site of LDLR and PCSK9 promoters, leading to increased transcription and translation of both proteins.

3 Lambert G, et al. “The PCSK9 decade” J Lipid Res 2012; 53:2515-2524.

4 Dong B, et al. “CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo

through a SREBP2 dependent mechanism” Atherosclerosis 2014; 235:449-462.

3

Inhibition of PCSK9 increases LDLR and decreases LDLc

Lambert G et al. J Lipid Res 2012; 53: 2515

ODYSSEY versus PROFICIO Caratteristiche e profilo di rischio

1Praluent EPAR, EMA/CHMP/392430/2015 Committee for Medicinal Products for Human Use 2Repatha EPAR, EMA/CHMP/222019/2015 Committee for Medicinal Products for Human Use

ODYSSEY PROGRAMME1

alirocumab PROFICIO PROGRAMME2

evolocumab

N° pazienti inclusi 24.300 33.400

Esposizione anno /paziente > 5000 > 1000

Disegno degli studi Maggior durata di trattamento in doppia cecità

Maggior utilizzo di OLE Esclusione dei pazienti che non tolleravano l’iniezione di placebo nella fase di run-in

Dosaggio Farmaco

Sperimentale

75 mg Q2W ( 150 mg); 150 mg Q2W 300 mg Q4W

140 mg Q2W 420 mg Q4W

Statina ad alta intensità 56% 30%

Endpoint primario % riduzione LDL-C alla settimana 24 Media della % riduzione LDL-C fra la settimana 10 e la settimana 12

%°pazienti con storia di CHD 38-91 0-63

Popolazioni 97% rischio CV alto/ molto alto > 30% diabete mellito 1250 HeFH 632 SI

34% rischio CV alto/molto alto 13% diabete mellito 329 pazienti HeFH 307 SI

Overview of ODYSSEY Phase 3 Clinical Trial Program

15 global phase 3 trials including >23,500 patients across >2,000 study centers

ODYSSEY OUTCOMES (NCT01663402; EFC11570)

LDL-C ≥70 mg/dL

N=18,000; 64 months

HC in high CV risk population

ODYSSEY COMBO I (NCT01644175; EFC11568)

LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL

N=316; 12 months

Add-on to max-tolerated statin (± other LMT)

*ODYSSEY COMBO II (NCT01644188; EFC11569)


N=720; 24 months

Additional populations

ODYSSEY ALTERNATIVE (NCT01709513; CL1119)

Patients with defined statin intolerance


N=250; 6 months

ODYSSEY OPTIONS II (NCT01730053; CL1118)

Patients not at goal on moderate dose rosuvastatin


N=305; 6 months

ODYSSEY MONO (NCT01644474; EFC11716)

Patients on no background LMTs

LDL-C ≥100 mg/dL

N=100; 6 months

ODYSSEY OPTIONS I (NCT01730040; CL1110)

Patients not at goal on moderate dose atorvastatin


N=355; 6 months

ODYSSEY CHOICE I (NCT01926782; CL1308)


N=803; 12 months

ODYSSEY CHOICE II (NCT02023879; EFC13786)

Patients not treated with a statin


N=233; 6 months

ODYSSEY FH II (NCT01709500; CL1112)


N=249; 18 months

HeFH population

ODYSSEY HIGH FH (NCT01617655; EFC12732)

LDL-C ≥160 mg/dL

N=107; 18 months

ODYSSEY FH I (NCT01623115; EFC12492)

LDL-C ≥ 70 mg/dL OR LDL-C ≥100 mg/dL

N=486; 18 months

ODYSSEY LONG TERM (NCT01507831; LTS11717)

LDL-C ≥70 mg/dL

N=2,100; 18 months

Add-on to max-tolerated statin (± other LMT)

ODYSSEY OLE (NCT01954394; LTS 13463)

Open-label study for FH from EFC 12492,

CL 1112, EFC 12732 or LTS 11717

N≥1000; 30 months

ClinicalTrials.gov. ODYSSEY Phase 3 Trials. http://clinicaltrials.gov. Accessed February 12, 2014.

ODYSSEY ESCAPE (NCT02326220)

LDL apheresis every week or Q2W

N=62; 18 weeks

Anticorpo monoclonale Anti PCSK9*: ALIROCUMAB

• Alirocumab: cos è e come agisce

• Efficacia su LDL-C (in associazione a statine e/o altre LLT)




ClinicalTrials.gov. ODYSSEY Phase 3 Trials. http://clinicaltrials.gov. Accessed February 12, 2014.

14 global phase 3 trials including >23,500 patients across >2,000 study centers

Overview of ODYSSEY Phase 3 Clinical Trial Program

Ipercolesterolemia in pazienti a rischio CV molto alto (non controllati con dosi massime

tollerate di statine±Eze)

Inibitori di PCSK9 utilizzati in

ASSOCIAZIONE a dose massima

tollerata di statina (± altre LLT)




Pazienti con

Ipercolesterolemia

Familiare (i.e HeFH)

PCSK9 inibitori nei pazienti ad alto rischio CV: UNMET NEEDS

Farmaci Biologici: Inibitori di PCSK9

Evolocumab, Alirocumab, Bococizumab

Inibitori di PCSK9 in

MONOTERAPIA

(o Associazione con altre LLT)

Pazienti con

Intolleranza a Statine

79% with HeFH not at goal

(<100 mg/dL [2.6 mmol/L])

20% at high risk not at goal (<100 mg/dL [2.6 mol/L])

59% at very high CV risk not at goal (<70 mg/dL [1.8 mmol/L])

Nearly all patients who need

considerable LDL-C reductions

will not reach goal

P ijlman et al. Atherosclerosis 2010;209:189-94; Jones PH, et al. J Am Heart Assoc. 2012;1:e001800






I monoclonali Anti-PCSK9 nei pazienti ad alto rischio CV: UNMET NEEDS






ODYSSEY COMBO II Study Design

Double-blind treatment period (104 weeks)

High CV-risk patients on max-tolerated statin

LDL-C ≥1.81 mmol/L [70 mg/dL]

(history of CVD)

or

≥2.59 mmol/L [100 mg/dL]

(no history of CVD)

R

n=479

n=241

Assessments W0

W4 W8

W12

W16

W24 W36 W52

Primary endpoint

W64 W76 W104

Dose ↑ if LDL-C >70 mg/dL

at W8

W88

Follo

w-u

p

(8 w

eeks

)

Alirocumab 75 mg SC + placebo ezetimibe PO

Ezetimibe 10 mg/day PO + placebo Q2W SC

Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W102 (all patients at least W52)

Cannon CP, et al. EHJ 2015,

LD

L-C

, L

S m

ean

(S

E),

mm

ol/

L

Ezetimibe (n=240)

Week

2.1 mmol/L

82.5 mg/dL

1.3 mmol/L

51.6 mg/dL

Alirocumab (n=467)

2.2 mmol/L

85.3 mg/dL

1.4 mmol/L

53.3 mg/dL

mg/

dL

Intent-to-treat (ITT) analysis Dose ↑if LDL-C >70 mg/dL at W8

−20.7%

−50.6%

−18.3%

−49.5%


LS mean difference (SE) vs. ezetimibe: −29.8% (2.3);

P<0.0001 18.4% had dose increase

at W12

ODYSSEY COMBO II End-point

ODYSSEY COMBO II Significantly More High CV-Risk Patients Achieved Target

Proportion of Patients Reaching LDL-C <1.81 mmol/L (70 mg/dL) at Week 24

% p

atie

nts

P<0.0001 Intent-to-treat (ITT) analysis

60.3%

14.2%

0

10

20

30

40

50

60

70

80

90

Proportion of Patients Reaching LDL-C <1.3 mmol/L (50 mg/dL) at Week 24

% p

atie

nts

Ezetimibe

Alirocumab

Post hoc













Pazienti con

Ipercolesterolemia



(<100 mg/dL [2.6 mmol/L])




ODYSSEY FH I e FH II Study Design

Placebo Q2W SC

HeFH patients on max tolerated statin

± other lipid-lowering

therapy

OLE

/8 w

eek

FU

Alirocumab 75 mg Q2W SC with potential ↑ to 150 mg Q2W SC

Assessments W0 W8 W16 W36

W52 W78

Double-Blind Treatment Period (78 Weeks)

Primary efficacy endpoint

W64

W4 W12 W24

Dose ↑ if LDL-C >70 mg/dL

at W8

Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W78

R LDL-C ≥1.81 mmol/L [70 mg/dL] (history of CVD)

or ≥ 2.59 mmol/L [100 mg/dL]

(no history of CVD)

Kastelein et al. - European Heart Journal 2015; doi:10.1093/eurheartj/ehv370

n=323 (FH I); n=167 (FH II)

n=163 (FH I); n=82 (FH II)

LS m

ean

(SE

) %

ch

ange

fro

m b

ase

line

t

o W

eek

24

N=163

Alirocumab

N=81

FH I

Placebo

FH II

43.4% had dose increase

at W12 38.6%

had dose increase at W12

Intent-to-treat (ITT) Analysis


FH I FH II

Alirocumab (N=323) Placebo (N=163) Alirocumab (N=167) Placebo (N=82)

LDL-C mg/dL, mean (SD) 144.7 (51.2) 144.4 (46.8) 134.6 (41.3) 134.0 (41.6)

ODYSSEY FH I e FH II End-point

P<0.0001

% p

atie

nts

Placebo

Proportion of patients reaching LDL-C goal at Week 24

FH I FH II

Alirocumab

Intent-to-treat (ITT) Analysis

ODYSSEY FH I e FH II End-point


Background

Patients with HeFH were on stable background treatment (statins, ezetimibe, etc.) and had undergone consistent lipoprotein apheresis QW for ≥4 weeks or Q2W for

≥8 weeks (14 study sites in US & Germany)

ODYSSEY ESCAPE_P. Moriarty_EHJ 2016

1. Ito MK et al. J Clin Lipidol. 2011;5:S38–S45; 2. Huijgen et al. PLoS One. 2010;5:e9220; CHD, coronary heart disease; FH, familial hypercholesterolemia; He, heterozygous; LDL-C, low-density lipoprotein cholesterol; LLT; lipid-lowering therapies; PCSK9, proprotein convertase subtilisin kexin type 9; Q2W, every 2 weeks; 3. Jacobson TA et al. J Clin Lipidol. 2015;9:129–169; 4. Reiner Z et al. Eur Heart J. 2011; 32:1769–1818

• Untreated heterozygous familial hypercholesterolemia (HeFH) is associated with severely elevated LDL-C levels and a high risk for premature CHD1

• Despite LDL-C-lowering therapy, many patients with FH do not reach their target LDL-C levels2

• Apheresis = Greek for ‘taking away’; lipoprotein apheresis is removal of LDL-C3,4

• This trial was designed to clarify whether adding alirocumab could reduce or eliminate apheresis therapy

Apheresis only performed if LDL-C <30% lower than baseline LDL-C (pre-apheresis LDL-C

during regular apheresis)

FU 8 weeks/OLE Screening (2 weeks)

W12

Alirocumab 150 mg Q2W (s.c.)

W-2

Placebo Q2W (s.c.)

W9†

W6 W4 W18 W16 W26

Fixed apheresis frequency‡

ESCAPE: Study Design Double-blind treatment period (18 weeks)

Alirocumab 150 mg Q2W (s.c.)

W0

Randomization

W1† W13†

W2

W5† W7†

W8 W10

W11† W3†

W14

W15† W17†

Male and female patients ≥18 years of age with

HeFH undergoing QW/Q2W lipoprotein

apheresis therapy

Standardized Apheresis Treatment Rates from Week 7–18

An apheresis rate of 0 indicates that the patient skipped all planned apheresis treatments An apheresis rate of 1 indicates that the patient received all planned apheresis treatments between Week 7 and Week 18 (apheresis rate of 0.75:, the patient received 75% of planned apheresis treatments)

Standardised apheresis treatment rate in the period:

Hodges-Lehmann estimate of median treatment difference (95% CI):

p-value versus placebo:

Weeks 7–18

0.75 (0.67 to 0.83)

p<0.0001

Weeks 15–18

0.50 (0.50 to

1.00) p<0.0001

93% vs. 14%


Time-Averaged Cholesterol Concentrations

0 8–10 10–12 12–14 14–16

Interval (weeks) Data labels are expressed in both measurements; 1Kroon Formula; Kroon AA et al. Atherosclerosis. 2000;152:519–526. LS, least squares

LDL-C % change from baseline (%), LS mean (SE): Week 6 Week 18

Alirocumab -53.7 (2.3) -42.5 (4.7)

Placebo 1.6 (3.1) 3.9 (6.3)

p-value versus placebo <0.0001 <0.0001

0

50

100

150

200

250

0

1

2

3

4

5

6

7

16–18

mg

/dL

Ave

rage

LD

L-C

val

ue

, me

an, m

mo

l/L

Alirocumab 150 mg Q2W (n=41) Placebo (n=21)

4.3/166.0 4.5/174.7 4.3/165.0 4.5/172.6 4.5/175.2

2.4/92.1 2.5/98.1 2.4/93.6 2.5/95.2 2.4/94.3

4.5/175.1

5.0/191.6










Pazienti con

Ipercolesterolemia






(<100 mg/dL [2.6 mmol/L])



Inibitori di PCSK9 in

MONOTERAPIA

(o Associazione con altre LLT)

Pazienti con

Intolleranza a Statine

Nearly all patients who need

considerable LDL-C reductions

will not reach goal


• STATO ATTUALE: Diagnosi difficile perché non vi è consenso unanime e la segnalazione di mialgia è soggettiva e influenzata da comorbidità

• UPDATE OPERATIVO: valutare presenza di SI utilizzando: 1. sintomi 2. livelli di CK 3. Drug re-challenge (≥2 statine)

• SCOPO: Massimizzare la probabilità di identificare pazienti con reale SI attraverso combinazione di symptom score (standardizzato), livelli di CK e risposta a “repetitive statin rechallenge»

Efficacy and safety of alirocumab versus ezetimibe,

in patients with statin intolerance defined by

placebo run-in and statin rechallenge arm

Patrick M. Moriarty1, Paul D. Thompson2, Christopher P. Cannon3, John R. Guyton4, Jean Bergeron5, Franklin J. Zieve6, Eric Bruckert7, Terry A. Jacobson8, Marie T. Baccara-Dinet9, Jian Zhao10, Yunling Du10,

Robert Pordy11, Daniel Gipe11

Double-Blind Treatment Period (24 Weeks)

Alirocumab 75/150 mg SC Q2W + placebo PO QD

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)

ODYSSEY ALTERNATIVE Study Design

SI patients with LDL-C

≥70 mg/dL (very-high CV risk)

Or

≥100 mg/dL (moderate/

high risk)

Assessments

W0 W -4

Patients discontinued if muscle-related AEs reported with

placebos during run-in

Atorvastatin 20 mg PO QD + placebo SC Q2W

N=50 OLT

P/8

we

ek

FU

Moriarty PM, et al. Journal of Clinical Lipidology 2015

R

ODYSSEY ALTERNATIVE Alirocumab Maintained LDL-C Reductions Week 4–24

Week

156 mg/dL

97 mg/dL

157 mg/dL

92 mg/dL

Ezetimibe

Alirocumab

LD

L-C

, m

ea

n (

SE

), m

g/d

L

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

49.5% received 150 mg Q2W at W12

Δ 59 mg/dL Δ 65 mg/dL


-52.2%

-17.1%

Goals: Very high-risk: LDL-C <70 mg/dL, High/moderate-risk: <100 mg/dL

P<0.0001

% p

atie

nts

reac

hin

g LD

L-C

go

al a

t W

eek

24

Ezetimibe

Alirocumab

51%

6%

0

10

20

30

40

50

60

P<0.0001

ITT On-treatment

ODYSSEY ALTERNATIVE Significantly More SI Patients Achieved Target


Riduzione dell’incidenza degli eventi cardiovascolari maggiori e riduzione media del LDL-C

Adapted from CTT Collaborators. Baigent C., et al.; Lancet. 2005; 366:1267-78

1) Riduzione ulteriore LDL-C 70-100 mg/dl

-10

0

40

50

30

20

10

20 40 60 80

Riduzione del LDL-C (mg/dL)

Rid

uzi

on

e d

eg

li e

ve

nti (

%)

-21% ogni 40 mg/dl LDL-C

?

Anti PCSK9

(Meta-analisi di 14 trials, n=90.056, pubblicati dal 1994 al2004)

2) ULTERIORE possibile RIDUZIONE EVENTI CHD/CVD di circa il 40-45%

Robinson JG et al. NEJM 2015; 372:1489-99.

Adults with HeFH or at high CV-risk

On maximally tolerated statin

other LLT

LDL-C ≥70 mg/dL (1.81 mmol/L)

Double-blind treatment (18 months)

N=1553

N=788

R

Follow-up (8 weeks)

Alirocumab 150 mg Q2W SC

Placebo Q2W SC

Assessments W0

W4

W8

W12

W16

W24

W36

W52

Primary efficacy endpoint

W64 W78


ODYSSEY LONG TERM Study Design

Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W78

Efficacy endpoint

% change in calculated LDL-C level from baseline to week 24 using an ITT approach

ODYSSEY LONG TERM Alirocumab Maintained LDL-C Reductions 78 week

Placebo

Alirocumab

Least-

Sq

uare

s M

ean

Calc

ula

ted

LD

L-C

Level

(mg

/dL

)

118.9 mg/dL

[3.08 mmol/L]

48.3 mg/dL

[1.25 mmol/L]

122.6 mg/dL

[3.17 mmol/L]

57.9 mg/dL

[1.50 mmol/L]

0.8% 3.6%

–52.4%

mm

ol/L

Week 0 4 8 12 16 24 36 52 64 78


Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C

Intent-to-treat (ITT) analysis

-61.0%

Proportion of patients reaching LDL-C < 70 mg/dl at Week 24 regardless of risk -79.3%

*Based on primary endpoint for the ODYSSEY OUTCOMES trial, including CHD death, non-fatal MI, fatal and non-fatal ischemic stroke, and unstable angina requiring hospitalization.Unstable angina requiring hospitalization was considered based on strict criteria / clear progression of ischemia.

Placebo + maximally

tolerated statin ± other LLT

Alirocumab + maximally

tolerated statin ± other LLT

Cu

mu

lati

ve

p r o

ba

bil

ity o

f e

ve

nt

Time (weeks)

Cox model analysis

HR = 0.52 (95% CI 0.31 to 0.90)

Nominal p-value = 0.02

No. at risk: Placebo

Alirocumab

788 776 731 700 670 653 644 597

1550 1533 1445 1392 1342 1306 1266 1170

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 52 64 78 86

0.06

0.04

0.02

0.00

0 12 24 36 52 64 78 86

ODYSSEY LONG TERM Post hoc Analysis of Adjudicated MACE


Double-blind treatment period (2-5 years)

N=9000

N=9000

R

Follow-up (2 weeks) after end treatment

Alirocumab Q2W SC

Placebo Q2W SC

Until Month 2

ODYSSEY OUTCOMES Study Design

Primary endpoint

Composite of:

CHD death, non-fatal MI, Ischemic Stroke, Unstable Angina Requiring Hospitalization

Schwartz_et al., EAH 2014

*At least one of the following: LDL-C ≥70 mg/dL; non-HDL ≥100 mg/dl; apo B ≥80 mg/dl

75 mg every two wks

After Month 2

75 or 150 mg every two wks

adusted in blinded fashion to achieve 15 ≤ LDL < 50 mg/dl

18,000 patients, age > 40 years, with recent

ACS (4-52 weeks)

Inadequate control of atherogenic

lipoproteins* despite optimal statin

treatment (ato 40/80 or rosu 20/40 or MTD of

one these statin) other LLT

Alirocumab Pooled Safety Overall

EAS 2015

M. Farnier, D. Gaudet, V. Valcheva, P. Minimi, K. Miller, B. Cariou

Safety Pooled Analysis of 4 phase 2 and 10 phase 3 trials*

% (n) of patients All pts on background statin

Ezetimibe-controlled pool

(N=1482) Placebo-controlled pool

(N=3752)

Alirocumb n=864 Ezetimibe n=618 Alirocumab n=2476 Placebo n=1276

TEAEs 70,3% (607) 68,1% (421) 78,8% (1876) 76,4% (975)

Treatment-emergent SAEs 13,1% (113) 11,2% (69) 13.7% (340) 14.3% (182)

TEAEs leading to daeth 0.2% (2) 1.1% (7) 0.5% (13) 0.9% (11)

TEAEs leading to discontinuation 8.8% (76) 9.7% (60) 5.3% (131) 5.1% (65)

Safety terms of interest

Adjudicated CV events 3.1% 827) 1.9% (12) 3.6% (83) 3.5% (41)

HLT: injection site reaction 3.0% (26) 2.1% (13) 7.3% (180) 5.2% (66)

CMQ: Neurocognitive disorders 0.9% (8) 1.0% (6) 0.8% (21) 0.7% (9)

PCSA: ALT>3 X ULN 1.1% (9/850) 0.2% (1/612) 1.7% (41/2455) 1.4% (18/1266)

TEAEs by preferred term in >5% pts

Nasopharymgitis 5.4% (37) 5.7% (35) 11.3% (279) 11.1% (141)

Myalgia 6.7% (58) 7.6% (47) 4.2% (104) 3.4% (44)

Upper respiratory tract infection 5.9% (51) 6.0% (37) 6.1% (152) 7.0% (89)

*Placebo controlled studies: phase 3 (LTS11717, FHI, FHII, HIGH FH,COMBO I), phase 2 (DFI11565,DFI11566, CL-1003, DFI12361) Ezetimibe controlled studies: phase 3(COMBO II, MONO, OPTION I, OPTION II, ALTERNATIVE).

CMQ, Custom MedDRA Query; HLT, High-level Term;

PCSA, Potentinally Clinically Significant Abnormalities

Reazioni avverse nei pazienti che presentavano LDL-C <25 o 15 mg/dL nei 14 trial di Alirocumab

TEAE : Treatment Emergent Adverse Event

Pooled controlli (n=1894)

Pooled Alirocumab

(n=3340)

Pooled Alirocumab LDL-C < 25 mg/dL

(n=796)

Pooled Alirocumab LDL-C < 15 mg/dL

(n=288)

Infezioni 36.3 38.5 34.0 35.4

Alterazioni muscoloscheletriche

25.2 24.2 21.1 20.1

Reazioni in sede di iniezione

3.9 5.7 3.0 3.5

Alterazioni Sitema nervoso Centrale

14.9 14.9 10.3 9.0

Diabete 1.3 1.2 1.5 2.4

Cancro 2.5 2.5 2.8 2.4

Poster presented at: 64th Annual Scientific Sessions of the American College of Cardiology; March 14-16, 2015; San Diego, CA. Abstract 1164M-05.

Alirocumab personalizzazione della terapia

La dose può essere personalizzata in base alle caratteristiche del paziente,

quali il livello basale di LDL-C, l’obiettivo della terapia e la risposta.

PRALUENT 75 mg è

la dose iniziale per i pazienti che

necessitano di riduzioni di LDL-C

< 60% per raggiungere il target

PRALUENT 150 mg è

la dose iniziale per i pazienti che

necessitano di riduzioni di LDL-C

> 60% per raggiungere il target

Alirocumab Final clinical considerations

Sarah L. Greig Am J Cardiovasc Drugs: DOI 10.1007/s40256-016-0166-3

• Fully human monoclonal antibody against PCSK9

• Administered as a subcutaneous injection of 75 or 150 mg once every 2

weeks

• Significantly reduces LDL-C levels in patients with heFH or nonFH

(including those with statin intolerance), whether used as monotherapy

or added to statin or non-statin LLT

• Has favorable effects on other lipid parameters,including non-HDL-C

and Lp(a)

• Efficacy maintained in the longer-term

• Generally well tolerated

GRAZIE DELL’ATTENZIONE

[email protected]

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