Inibizione PCSK9, quale futuro nella pratica clinica P. Faggiano U.O. Cardiologia Spedali Civili, Brescia
Cosa sono? Come agiscono? Ma funzionano? Quando usarli?
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.
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.
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.
Phase III clinical trials of PCSK9 inhibitors
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 200 180 160 0-10 140-20 120-30 100 80-40 60 40 20 0 0 500 1000 1500 2000 2500 2 W 4 W Time (hours) Total REGN727/SAR236553 free PCSK9 LDL-c -50-60 -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
% patients La maggioranza di Pazienti ad Alto Rischio CV in Alirocumab a target per LDL-C alla 24 settimana Tutti i pazienti in terapia con dosi massime tollerate di statina Percentuale di pazienti a target per LDL-C< 70 mg/dl alla 24 settimana Percentuale di pazienti a target per LDL-C< 50 mg/dl alla 24 settimana Alirocumab Ezetimibe *P<0.0001 *P<0.0001
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
ODYSSEY COMBO II:Safety % (n) of patients All patients on background maximally tolerated statin Analysis Alirocumab (N=479) Ezetimibe (N=241) Including All Data Collected Until Last Patient Visit at Week 52 TEAEs 71.2% (341) 67.2% (162) Treatment-emergent SAEs 18.8% (90) 17.8% (43) TEAE leading to death* 0.4% (2) 1.7% (4) TEAEs leading to discontinuation 7.5% (36) 5.4% (35 Adverse Events of Interest Injection-site reactions 2,5% (12) 0,8% (2) Myalgia 4.4% (21) 5,0% (12) Neurocognitive disorders 0,8% (4) 1,2% (3) ALT >3 x ULN 1.7% (8/470) 0,8% (2/240) Creatine kinase >3 x ULN 2.8% (13/467) 2,5% (6/236) *The two deaths occurring during treatment with alirocumab were due to myocardial infarction and pulmonary embolism. Four deaths in the placebo group were due to sudden cardiac death, esophageal adenocarcinoma and dementia
ODISSEY LONG TERM Double Blind RCT ALIROCUMAB Durata 78 settimane 48 settimane Popolazione (numerosità) n= 2341 n= 4465 Tipo di analisi POST-HOC PRE-SPECIFICATO Pazienti Con CAD; Rischio CV elevato FH eterozigoti In Statina >99% 70% OSLER I e II Open Label Randomized EVOLOCUMAB Con CAD; Rischio CV elevato FH eterozigoti, Statin intolerant LDL-C 122 mg/dl 120 mg/dl (mediana) LDL-C Riduzione ~60% 48 mg/dl (24 settimane) ~60% 48 mg/dl (24 settimane) ODYSSEY LONG TERM and OSLER I e II were published on March 15, 2015, at NEJM.org.
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
HFhe Mona Lisa 1503-1506 dead at age 37
Criteri del Dutch Lipid Clinic Network per la diagnosi di Ipercolesterolemia Familiare
Familial Hypercholesterolemia (FH): Under-diagnosed and Undertreated Prevalence 1/200-300 (higher than 1/500): MORE PATIENTS! High CV risk: if untreated, men and women with heterozygous FH typically develop CHD before age 55 and 60 respectively Remarkably underdiagnosed (in Italy only 4-5% of FH) 1/5 FH achieve the recommended LDL-C targets Most FH need to decrease LDL-C by at least 60% Many FH receive statin doses insufficient to attain LDL-C targets Consensus Statement of the EAS, European Heart Journal e-pub August 15, 2013
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
Dutch Score (1) Improbabile 77.0% Possibile 19.5% Probabile 2.6% Certa 0.8% Improbabile/possibile 96.6% (1389 paz) Potenziale 3.4% (49 paz)
Dutch Score (2) N Classificazione FH improbabile possibile probabile certa potenziale Totale 1438 77.1 19.5 2.6 0.8 3.4 Maschi 1203 76.3 20.6 2.3 0.7 3.1 Femmine 235 80.9 14.0 4.3 0.9 5.1 M<55; F<60 250 51.8 36.4 5.6 3.2 8.8 M 55; F 60 1188 81.7 16.0 2.0 0.3 2.3
Colesterolo LDL al termine del percorso
A target: LDL<70 mg/dl Colesterolo LDL corretto : distanza % dal target Distanza %: Totale Rischio FH Improbabile Possibile Probabile Certo media ± d.s. 44.8 ± 19.6 38.8 ± 18.1 62.3 ± 10.7 70.6 ± 10.1 70.3 ± 12.1 mediana 49.0 43.3 64.3 71.4 75.4 min-max 0-83.4 0-63.3 24.5-76.8 24.5-83.4 44.4-82.6
UPDATE OPERATIVO: valutare presenza di SI utilizzando: 1) sintomi (approccio standardizzato) 2) livelli di CK 3) Drug re-challenge ( 2 statine)
Considerare gli eventi avversi muscoloscheletrici attribuibili alle statine in rapporto al Rischio CV del paziente (misurare livelli basali di CPK)! (debolezza muscolare sintomatica, crampi, astenia e/o dolore) Sintomi senza aumento o con CPK<5 x ULN Stop terapia almeno 2-4 settimane Miglioramento sintomi: Seconda Statina a dosi normali Sintomi persistono: Statin Re-challenge Non sintomi Ricomparsa dei sintomi 1) Basse dosi terza statina alta efficacia 2) Statina alta efficacia a dì alterni o 2-3 volte settimana Scopo: raggiungere il target di LDL con max dose tollerata di statina EZETIMIBE ( minime dosi statina se tollerata) 18 febbraio 2015 A) Resina B) Fenofibrato A + B Still Not at goal for LDL-C: Consider PCSK9 monoclonal Ab, CETP inhibitors
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, o intolleranti Sebbene gli studi siano stati di breve durata, non sono stati osservati AE di particolare rilievo associati all uso di Ab- anti PCSK9
HEREDITY SURVEY HEterozigous Familial hypercholesterolemia in coronary patients admitted to cardiac rehabilitation programs in ItalY Studio osservazionale sull epidemiologia dell ipercolesterolemia familiare eterozigote nei soggetti con malattia aterosclerotica afferenti a programmi di Cardiologia Riabilitativa e Preventiva RISULTATI
Casistica In ambito del presente studio sono stati presi in esame tutti i pazienti consecutivamente dimessi o valutati in ambulatorio al termine del programma riabilitativo nell ambito della finestra temporale di arruolamento. Febbraio Aprile 2015 27 strutture CRP aderenti al progetto 1438 soggetti arruolati
Rischio FH secondo nota 13 AIFA (2) SI 6.7% No 93.3% Prevalenza di FH: M < 55 ; F < 60 M 55 ; F 60
ODYSSEY COMBO II: Study Design Double-blind treatment period (104 weeks) Follow-up (8 weeks) High CV risk on maximally tolerated statin* I. LDL-C 70 mg/dl (manifest CVD) or II. LDL-C 100 mg/dl (No history of CVD) R Alirocumab 75 mg with potential to 150 mg Q2W SC + placebo ezetimibe PO (single 1 ml injection using prefilled pen for self-administration) N=479 N=241 Ezetimibe 10 mg/day PO + Placebo Q2W SC Assessments W0 W4 W8 W12 W16 W24 W36 W52 W64 W76 W88 W104 Clinicaltrials.gov identifier: NCT01644188 * Other LLT not allowed Dose if LDL-C 70 mg/dl at W8 Primary endpoint Pre-specified analysis Efficacy and Safety
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 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* Achieved LDL-C Over Time on Background of Maximally- Tolerated Statin ±Other LLT -60% -50-55% The Lancet, 385:331-340, 2015 * If LDL-C>70 mg/dl at 8 weeks Presented ESC 2014, Barcelona
Change from Baseline (%) Change from Baseline (%) Change from Baseline (%) Change from Baseline (%) Change from Baseline (%) Change from Baseline (%) Other Lipid Parameters 52% in Non-HDL-C 47% in ApoB 26% in Lp(a) 10 0-10 -20-30 -40-50 5.9 P<0.001-46.1 10 0-10 -20-30 -40-50 5.5 P<0.001-41.7 5 0-5 -10-15 -20-25 -30 0.0 P<0.001-25.5 13% in Triglycerides 10 3.5 5 0 P<0.001-5 -10-9.1-15 Standard of care alone Evolocumab plus standard of care 10 8 6 4 2 0 7% in HDL-C 4% in ApoA1 1.7 P<0.001 8.7 Week 12 data; values are means except for TG and Lp(a) which are medians. Error bars are 95% CI 8 7 6 5 4 3 2 1 0 2.6 P<0.001 6.8 Adapted from Sabatine et al. N Engl J Med. 2015 Apr 16;372(16):1500-9 (Suppl.):1-21
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!!!
Ann Intern Med. doi: 10.7326/M14-2957
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.
Statin Intolerance: Clinical Relevance Non-adherence: In up to 75% of former statin users, the prevailing reason for nonadherence or statin discontinuation is the onset of side effects [MUSCLE-RELATED] [Cohen 2012] Rate of reported statin-related events*: 2% to 5% in RCT, randomized, placebo controlled large statin trials. As high as 15-20% in observational studies [i.e. PRIMO, Bruckert 2005]. STOMP - Effect of STatins On Skeletal Muscle Performance [Parker et al Circulation 2013]: 9.4% on Atorva 80 mg for 6 months vs 4.5 placebo (p=0.05), net effect of about 5% HOWEVER: Cleveland Clinic: 63.2% patients with previous SI ( 2 statins) were able to tolerate daily statin therapy [Mampuya WM et al. 2013] Zhang et al [Ann Int Med 2013] showed that 90% of patients reporting muscle-related side effects to one statin were able to tolerate an alternative statin with continued use at 12 months.
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.
Summary of AE in the OSLER Trial modified from Circulation 2014;129:234