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

Mona Lisa 1503-1506 dead at age 37

LDL Cholesterol Reduction with Current Available Pharmacological Approaches Baseline LDL-C Reduction to reach an LDL-C Target <100 mg/dl Reduction to reach an LDL-C Target <70 mg/dl >200 >50% >50% Solo 1 su 5 pazienti FH raggiunge 180-200 45-50% >50% HeFH Riduzione LDL-C >50%-60% I Necessaria target di LDL-C nei Pazienti raccomandati! HeFH 160-180 40-45% >50% LDL-C>50% LDL-C<50% Medium High Statin dose* Statins Ezetimibe *High Efficacy Statins Modified from ESC/EAS Guidelines for the Management of Dyslipidaemias: Addenda, European Heart Journal 2011

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

Proprotein Convertase Subtilisin/Kexin 9 inhibitors

Hepatic LDLRs Play a Central Role in Cholesterol Homeostasis 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.

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

Loss-of-Function Mutations in PCSK9 Are Associated With Decreased LDL-C and CHD Risk 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 Heterozygous LOF mutations found in 1% to 3% of population 1 Associated with Lower serum LDL-C 1 Lower incidence of coronary heart disease 1 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 health 4 Inhibiting LDLR/PCSK9 interaction may lower plasma LDL-C levels 5 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.

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) Chimeric (65% human) Humanized (> 90% human) Fully Human (100% human) Generic suffix -omab -ximab -zumab -umab High Potential for immunogenicity Low 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.

Free/Total PCSK9 Conc. (ng/ml) Total REGN727 (ng/ml) X 0.01 LDL--C mean % change Alirocumab : relationship between mab levels, PCSK9 and LDL-C Free PCSK9, Total REGN727/SAR236553 Concentration and Mean % Change LDL-C vs Time 200 0 180 160 140-10 -20 120 100 80-30 -40 60 40 20-50 -60 0 0 500 1000 1500 2000 2500 2 W 4 W Time (hours) Total REGN727/SAR236553 free PCSK9 LDL-c -70

Dose finding study with evolocumab Phase 1b: Multiple Doses, Subjects with Hypercholesterolemia Cohorts 1-5: SC Cohorts Adapted from Dias CS, et al. J Am Coll Cardiol 2012; 60(19): 1888-98

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

Proportion of Patients, % DESCARTES: UC LDL-C Goal Achievement 100 90 80 70 60 50 40 30 20 10 0 84% 90% 3% 5% 6% Diet Alone Diet + Atorvastatin 10 mg LDL-C < 70 mg/dl at Week 52 81% Diet + Atorvastatin 80 mg 11% 67% Diet + Atorvastatin 80 mg + Ezetimibe 10 mg 6% 82% Total Placebo Evolocumab

Treatment Difference, Median (%) Treatment Difference, Mean (%) MENDEL-2: Other Lipids at Week 12 ApoB 0-10 -20 Biweekly Monthly Treatment difference (biweekly and monthly) vs placebo P < 0.001 vs ezetimibe P < 0.001 Lp(a) -30-40 -50-60 0-5 -10-15 -20-25 -30 48% Biweekly 34% 20% 20% 48% Monthly 33% 18% 16% Error 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 < 0.001 vs ezetimibe P < 0.001 Placebo Ezetimibe 26

OLTP/8 week FU 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) Placebo PO QD + Placebo SC Q2W R N=100 Double-Blind Treatment Period (24 Weeks) Alirocumab 75/150 mg SC Q2W + placebo PO QD administered via single 1 ml injection using prefilled pen for self-administration N=100 N=50 Per-protocol dose possible depending on W8 LDL-C Ezetimibe 10 mg PO QD + placebo SC Q2W Atorvastatin 20 mg PO QD + placebo SC Q2W Assessments W -4 W0 W4 W8 W12 W16 W24 Patients discontinued if muscle-related AEs reported with placebos during run-in Per-protocol dose increase if Week 8 LDL-C 70 or 100 mg/dl (depending on CV risk) Primary endpoint (LDL-C % change from baseline, ALI and EZE only) Safety analysis (all groups) *Unable to *Unable tolerate at to least tolerate two at different least two statins, different including statins, one including at the lowest one at dose, the lowest due to dose, muscle-related due to muscle-related symptoms symptoms 21/24 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.

LDL-C, mean (SE), mg/dl Alirocumab Maintained LDL-C Reductions Week 4 24 250 Achieved calculated LDL-C over time on-treatment analysis (modified ITT observed data only) Alirocumab Ezetimibe 200 150 100 50 156 mg/dl 97 mg/dl Δ 59 mg/dl 157 mg/dl 92 mg/dl -17.1% Δ 65 mg/dl -52.2% 22/24 0 49.5% received 150 mg Q2W at W12 0 4 8 12 16 20 24 Week

Cumulative probability of event Fewer Skeletal Muscle AEs with Alirocumab than with Atorvastatin Kaplan-Meier estimates for time to first skeletal muscle event 0.50 0.45 Atorvastatin Ezetimibe Alirocumab 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 Cox model analysis: HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042 HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P=0.096 0.00 0 4 8 12 16 20 24 28 32 36 Week Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue. ALI, alirocumab; ATV, atorvastatin, EZE, ezetimibe.

Summary of AE in the OSLER Trial modified from Circulation 2014;129:234

I MONOCLONALI ANTI-PCSK9 NEI PAZIENTI IPERCOLESTEROLEMICI SEVERI E/O INTOLLERANTI ALLE STATINE Farmaci Biologici: PCSK9 inhibitors PCSK9 inhibitors Evolocumab, Alirocumab, Bococizumab Patients with Familial Hypercholesterolemia (i.e HeFH) Hypercholesterolemia in high CVrisk population (not controlled with max tolerated dose of statins±eze)? Patients with Statin Intolerance PCSK9 Inhibitors as Add-on to max tolerated statin (± other LLT) PCSK9 Inhibitors MONOTHERAPY (or Add-on 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!!!

ODISSEY LONG TERM Double Blind RCT ALIROCUMAB OSLER I e II Open Label Randomized EVOLOCUMAB Duration 78 week 48 weeks Population (size) n= 2341 n= 4465 Patients With CAD Higk CV Risk HeFH On Statins >99% 70% With CAD Higk CV Risk HeFH Calculated LDL-C 122 mg/dl 120 mg/dl (median) LDL-C Reduction ~60% 48 mg/dl (week 24) 58 mg/dl (week 78) CV Event Reduction ~50% ~50% ~60% 48 mg/dl (week 24) 51 mg/dl (week 48) 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

Conclusioni La inibizione del PCSK9 attraverso l uso di anticorpi monoclonali rappresenta una strategia molto promettente per raggiungere il valore target di LDL-C nei pazienti a rischio CV La somministrazione di Ab-anti-PCSK9 può consentire di ottenere una riduzione del LDL-C del 50-60%, in diverse tipologie di pazienti già in trattamento con statine Sebbene gli studi siano stati di breve durata, non sono stati osservati AE di particolare rilievo associati all uso di Ab- anti PCSK9

AIFA Pillole dal Mondo n. 785 01/06/2015 Primo 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.