Gli inibitori della proteina PCSK9:

l’arma finale nella lotta alle dislipidemie?

P. Faggiano

U.O. Cardiologia - Spedali Civili, Brescia

Utilizzo di statine nel lungo termine:

problemi aperti

Mancato raggiungimento dei target di col-LDL

nonostante l’impiego di statine ad alta efficacia

Ipercolesterolemia familiare

Intolleranza alle statine

3

Mona Lisa 1503-1506 dead at age 37

Baseline LDL-CReduction to reach an

LDL-C Target 50% >50%

180-200 45-50% >50%

160-180 40-45% >50%

Modified from ESC/EAS Guidelines for the Management of Dyslipidaemias: Addenda, European Heart Journal 2011

LDL-C>50%

LDL-C50%-60% Necessaria nei Pazienti HeFH

Solo 1 su 5 pazienti FH raggiungeI target di LDL-C raccomandati!

LDL Cholesterol Reduction with Current Available

Pharmacological Approaches

UPDATE OPERATIVO: valutare presenza di SI utilizzando:1) sintomi2) livelli di CK3) Drug re-challenge (≥2 statine)

Proprotein Convertase Subtilisin/Kexin 9 inhibitors

LDL

Elaborated from 1. Brown MS, et al. Proc Natl Acad Sci 1979;76:3330-3337.Elaborated from 2. Qian YW, et al. J Lipid Res. 2007;48:1488-1498.Elaborated from 3. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547.

Hepatic LDLRs Play a Central Role in Cholesterol Homeostasis

Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles

Elaborated from 1. Brown MS, et al. Proc Natl Acad Sci U S A. 1979;76:3330-3337.Elaborated from 2. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547.Elaborated from 3. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438.

PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation

Elaborated from 1. Qian YW, et al. J Lipid Res. 2007;48:1488-1498.Elaborated from 2. Horton JD, et al. J Lipid Res. 2009;50:S172-S177.Elaborated from 3. Zhang DW, et al. J Biol Chem. 2007;282:18602-18612.

Genetic Variants of PCSK9 Demonstrate Its Importance in Regulating LDL Levels

PCSK9 Gain of Function = Less LDLRs PCSK9 Loss of Function = More LDLRs

Heterozygous LOF mutations found in 1% to 3% of population1

Associated with

Lower serum LDL-C1

Lower incidence of coronary heart disease1

PCSK9 null individual identified (compound heterozygote for two inactivating mutations)

No detectable circulating PCSK9 with strikingly low LDL-C (14 mg/dL)4

Healthy and fertile college graduate in apparent good health4

Inhibiting LDLR/PCSK9 interaction may lower plasma LDL-C levels5

Loss-of-Function Mutations in PCSK9 Are

Associated With Decreased LDL-C and CHD Risk

LOF = loss of function.

Adapted from 1. Cohen JC, et al. N Engl J Med. 2006;354:1264-1272.

Adapted from 2. Cohen J, et al. Nat Genet. 2005;37:161-165.

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

Adapted from 4. Zhao et al. Am Journal of Hum Gen. 2006;79:514-534.

Adapted from 5. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547.

PCSK9 Variant Population LDL-C CHD Risk

R46L ARIC, DHS ↓ 15%1 ↓ 47%1

Y142X or C679X ARIC, DHS ↓ 28%-40%1,2 ↓ 88%1

R46L CGPS ↓ 11%3 ↓ 46%3

LDLR and PCSK9 Expression Are Both Upregulated When Intracellular Cholesterol Levels Are Low

*[SREBP] = sterol regulatory element-binding protein.

Elaborated from 1. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438.Elaborated from 2. Dubuc G, et al. Arterioscler Thromb Vasc Biol. 2004;24:1454-1459.

Blockade of PCSK9/LDLR Interaction May Lower LDL Levels

Elaborated from 1. Chan JC, et al. Proc Natl Acad Sci U S A. 2009;106:9820-9825.

Fully Human Antibodies Have Reduced Immunogenicity

Mouse(0% human)

Fully Human(100% human)

Humanized (> 90% human)

Chimeric (65% human)

Elaborated from:1. Weiner LM. J Immunother. 2006;29:1-9. 2. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23. 3. Lonberg N. Nat Biotechnol. 2005;23:1117-1125.4. Gerber DE. Am Fam Physician. 2008;77:311-319.

-umab-zumab-ximab-omabGeneric suffix

LowHigh Potential for immunogenicity

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

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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

Dose finding study with evolocumab

Adapted from Dias CS, et al. J Am Coll Cardiol 2012; 60(19): 1888-98

Cohorts 1-5:

SC Cohorts

Phase 1b: Multiple Doses,

Subjects with Hypercholesterolemia

Y.J. Shimada and C.P. Cannon . Eur Heart J 2015

Y.J. Shimada and C.P. Cannon . Eur Heart J 2015

3% 5% 6%11%

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Placebo Evolocumab

Diet Alone Diet + Atorvastatin

10 mg

Diet + Atorvastatin

80 mg

Diet + Atorvastatin80 mg +

Ezetimibe 10 mg

DESCARTES: UC LDL-C Goal Achievement

LDL-C < 70 mg/dL at Week 52

Total

MENDEL-2: Other Lipids at Week 12

26Error bars represent standard error for mean treatment difference and 95% CI for median treatment difference. No notable difference in results for average at weeks 10 and 12. P values are multiplicity adjusted.

Treatment difference (biweekly and monthly)vs placebo P < 0.001vs ezetimibe P < 0.001

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Biweekly

Biweekly

Monthly

Monthly

Placebo

Ezetimibe

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

0

50

100

150

200

250

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Week

156 mg/dL

97 mg/dL

157 mg/dL

92 mg/dL

EzetimibeAlirocumab

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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

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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

Summary of AE in the OSLER Trial

modified from Circulation 2014;129:234

Hypercholesterolemia in high CV-risk population (not controlled

with max tolerated dose of statins±Eze)

PCSK9 inhibitorsFarmaci Biologici: PCSK9 inhibitors

Evolocumab, Alirocumab, Bococizumab

Patients with Familial Hypercholesterolemia

(i.e HeFH)

PCSK9 Inhibitors as Add-on to max tolerated statin (± other LLT)

?

55-60% greater LDL-C reduction on top of max statin! 65-80% of pts with HeFH with LDL-C

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

These articles were published on March 15, 2015, at NEJM.org

Ann Intern Med. doi: 10.7326/M14-2957

Ann Intern Med. doi: 10.7326/M14-2957

Ann Intern Med. doi: 10.7326/M14-2957

Conclusioni

La inibizione del PCSK9 attraverso l ’ uso dianticorpi monoclonali 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-C del50-60%, in diverse tipologie di pazienti già intrattamento con statine

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

AIFA Pillole dal Mondo n. 785 01/06/2015Primo anticorpo monoclonale per abbassare il colesterolo

L'Agenzia Europea dei Medicinali (EMA) ha raccomandato l’autorizzazione di Repatha

(evolocumab) come trattamento per ridurre i livelli elevati di colesterolo nel sangue in

soggetti che non riescono a controllare il colesterolo nonostante l’assunzione di dosi

ottimali di statine o che non possono assumere statine.

L'efficacia di Repatha come agente ipolipemizzante è stata valutata in circa 5.500

persone con ipercolesterolemia e dislipidemia mista, e in pazienti con

ipercolesterolemia familiare omozigote. Repatha ha ridotto il colesterolo LDL in

entrambi i gruppi di pazienti. Le evidenze disponibili non consentono ancora di

determinare i benefici a lungo termine di Repatha nel ridurre le malattie cardiache o la

morte per malattia cardiaca.

Il CHMP ha valutato anche le informazioni sulla sicurezza relative ai pazienti con

ipercolesterolemia e dislipidemia mista .Il Comitato ha ritenuto che il profilo di

sicurezza di Repatha sia accettabile, con pochi pazienti che hanno interrotto il

trattamento o che hanno evidenziato eventi avversi gravi. Ulteriori dati saranno raccolti

per valutare le implicazioni di livelli di colesterolo molto bassi.