Η ΤΕΧΝΟΛΟΓΙΑ ΤΩΝ ΜΟΝΟΚΛΩΝΙΚΩΝ ΑΝΤΙΣΩΜΑΤΩΝ ΣΤΗ ΜΕΙΩΣΗ ΤΗΣ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ: ΑΝΑΣΤΟΛΗ ΤΗΣ PCSK9

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1 Η ΤΕΧΝΟΛΟΓΙΑ ΤΩΝ ΜΟΝΟΚΛΩΝΙΚΩΝ ΑΝΤΙΣΩΜΑΤΩΝ ΣΤΗ ΜΕΙΩΣΗ ΤΗΣ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ: ΑΝΑΣΤΟΛΗ ΤΗΣ PCSK9 Ευάγγελος Λυμπερόπουλος Επίκουρος Καθηγητής Παθολογίας Ιατρικής Σχολής Παν/μίου Ιωαννίνων

2 DISCLOSURES Συμμετοχή σε εκπαιδευτικές, ερευνητικές και συμβουλευτικές δραστηριότητες: ASTRA-ZENECA, PFIZER, ΒΙΑΝΕΞ, MSD, LILLY, WIN- MEDICA, ABBOTT, NOVARTIS, BAYER, AMGEN, SANDOZ

3 LDL ΧΟΛΗΣΤΕΡΟΛΗ ΚΑΙ ΚΑΡΔΙΑΓΓΕΙΑΚΟΣ ΚΙΝΔΥΝΟΣ

4 Epidemiologic Data Demonstrated a Strong Causal Link Between Elevated TC and CHD Multiple Risk Factor Intervention Trial (MRFIT) N=361,662 Framingham Heart Study (FHS) N=5209 Age-adjusted 6-year CHD mortality per 1000 men year CHD incidence per 1000 men < >295 TC (mg/dl) TC (mg/dl) TC=total cholesterol; CHD=coronary heart disease. Martin MJ et al. Lancet. 1986;2: ; Castelli WP. Am J Med. 1984;76:4-12.

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11 (70 mg/dl)

12 DYSIS-GREECE 2 στους 3 ασθενείς που παίρνουν στατίνες δεν επιτυγχάνουν ακόμη και τους παλαιότερουςστόχουςγια την LDL-χοληστερόλη!!! Liberopoulos E et al. Angiology 2011; Jun 15 Epub ahead of print

13 ΛΟΓΟΙ ΓΙΑ ΤΗ ΜΗ ΕΠΙΤΕΥΞΗ ΤΩΝ ΣΤΟΧΩΝ ΓΙΑ ΤΗΝ LDL ΧΟΛΗΣΤΕΡΟΛΗ 1. ΠΟΛY ΑΥΞΗΜΕΝΑ ΑΡΧΙΚΑ ΕΠΙΠΕΔΑ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ (FH) 2. ΔΟΣΟΕΞΑΡΤΩΜΕΝΕΣ ΑΝΕΠΙΘΥΜΗΤΕΣ ΕΝΕΡΓΕΙΕΣ ΣΤΑΤΙΝΩΝ 3. ΠΟΛΥ ΧΑΜΗΛΑ ΕΠΙΠΕΔΑ-ΣΤΟΧΟΙ ΓΙΑ ΤΗΝ LDL ΧΟΛΗΣΤΕΡΟΛΗ 4. ΠΤΩΧΗ ΣΥΜΜΟΡΦΩΣΗ ΣΤΗ ΘΕΡΑΠΕΙΑ

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15 Η ΣΥΝΑΡΠΑΣΤΙΚΗ ΙΣΤΟΡΙΑ ΤΗΣ ΑΝΑΚΑΛΥΨΗΣ ΤΗΣ PREPROTEIN CONVERTASE SUBTILISIN KEXIN 9 (PCSK9)

16 PCSK9: Rapid Progress From Discovery to Clinic Adenoviral expression in mice PCSK9 KO mouse LDL-C PCSK9 (NARC-1) discovered PCSK9 GOF mutations associated with ADH PCSK9 LOF mutations found with 28% LDL-C and 88% CHD risk Humans null for PCSK9 have LDL-C ~15 mg/dl Plasma PCSK9 binds to LDLr LDL-C in mice and nonhuman primates treated with anti-pcsk9 mab First subject treated with PCSK9 mab First patients with FH & nonfh treated with PCSK9 mab First publication POC in patients Seidah NG. Proc Natl Acad Sci USA 2003;100(3):928-33, Abifadel M. Nat Genet 2003;34(2):154-6, Maxwell KN. Proc Natl Acad Sci USA 2004;101(18):7100-5, Rashid S. Proc Natl Acad Sci USA 2005;102(15): , Lagace TA et al. JCI 2006;116: Cohen JC. N Engl J Med 2006;354(12): , Zhao Z. Am J Hum Genet 2006;79(3):514-23, Hooper AJ. Atherosclerosis 2007;193(2):445-8, Chan JC. Proc Natl Acad Sci USA 2009;106(24):9820-5; Stein et al N Engl J Med 2012;366:

17 LDL Receptor Function and Life Cycle 17 17

18 The Role of PCSK9 in the Regulation of LDL Receptor Expression 18 18

19 Genetic Variants of PCSK9 Demonstrate Its Importance in Regulating LDL Levels PCSK9 Gain of Function (GOF) = PCSK9 Loss of Function (LOF) = Less LDL-Rs 1,3,5 More LDL-Rs 2,4,5 Mutations in the human PCSK9 gene that lead to a loss of PCSK9 function are found in 1% to 3% of the population 6,7 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S Lakoski SG, et al. J Clin Endocrinol Metab. 2009;94: Abifadel M, et al. Hum Mutat. 2009;30: Cohen J, et al. Nat Genet. 2005;37: Steinberg D, et al. PNAS. 2009;106: Cohen JC, et al. N Engl J Med. 2006;354: Benn M, et al. J Am Coll Cardiol. 2010;55:

20 Clinical Outcomes Associated With PCSK9 GOF Mutations ADH caused by rare PCSK9 GOF mutations have a clinical phenotype resembling FH caused by LDL-R or apob gene mutations 1,2 ADH-associated physical abnormalities 1 Stroke 1 Coronary heart disease (CHD) 1,2 Premature myocardial infarction (MI) 1 1. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010: Benn M, et al. J Am College Cardiol. 2010;55:

21 Genetic Variants of PCSK9 Demonstrate Its Importance in Regulating LDL Levels PCSK9 Gain of Function (GOF) = PCSK9 Loss of Function (LOF) = Less LDL-Rs 1,3,5 More LDL-Rs 2,4,5 Mutations in the human PCSK9 gene that lead to a loss of PCSK9 function are found in 1% to 3% of the population 6,7 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S Lakoski SG, et al. J Clin Endocrinol Metab. 2009;94: Abifadel M, et al. Hum Mutat. 2009;30: Cohen J, et al. Nat Genet. 2005;37: Steinberg D, et al. PNAS. 2009;106: Cohen JC, et al. N Engl J Med. 2006;354: Benn M, et al. J Am Coll Cardiol. 2010;55:

22 Clinical Outcomes Associated With PCSK9 LOF Mutations Missense PCSK9 LOF mutations in families with hypocholesterolemia reported in global population studies 1,2 Reduced plasma levels of TC and LDL-C 1,3,4 Protection from CHD 1,3 Reduced risk of earlyonset MI 5 1. Abifadel M, et al. Hum Mutat. 2009;30: Abifadel M, et al. Hum Mutat. 2009;30: supplementary information. 3. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010: Benn M, et al. J Am Coll Cardiol. 2010;55:2833: Kathiresan S. N Engl J Med. 2008;358:

23 LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9 142X or PCSK9 679X Allele Frequency (%) No Nonsense Mutation 30 (n=3278) PCSK9 142X or PCSK9 679X (N=85) 50 th Percentile 28% Coronary Heart Disease (%) P= % 10 0 No Yes LDL Cholesterol in Black Subjects (mg/dl) PCSK9 142X or PCSK9 679X Cohen NEJM 2006; 354:

24 No health problem

25 Η ΕΠΑΝΑΣΤΑΣΗ ΤΗΣ ΔΗΜΙΟΥΡΓΙΑΣ ΜΟΝΟΚΛΩΝΙΚΩΝ ΑΝΤΙΣΩΜΑΤΩΝ ΕΝΑΝΤΙΟΝ ΤΗΣ PCSK9

26 Impact of an PCSK9 mab on LDL Receptor Expression For illustration purposes only mab 26 26

27 3 3

28 EVOLOCUMAB (AMGEN)

29 EVOLOCUMAB The PROFICIO Program Statinintolerant Monotherapy Phase 2 Phase 3 (N = 629) 1 (N = 1,700) Phase 2 Phase 3 (N = 406) 2 (N = 600) Combotherapy Phase 2 (N = 157) 3 Phase 3 (N = 300) Phase 3 (N = 500) HeFH HoFH Long-term safety and efficacy Open-label Extension Secondary Prevention Atheroma Phase 2 Phase 3 (N = 168) 4 (N = 300) Phase 2/3 Phase 2/3 (N 67) 5 (N = 125) Phase 2 (N = 1,400) 5 Phase 3 (N = 905) 5 Phase 3 (N 3,500) 5 Phase 3 (N = 22,500) 5 Phase 3 (N = 950) 5 1. Giugliano RP, et al. Lancet. 2012;380: Koren MJ, et al. Lancet. 2012:380: Sullivan D, et al. JAMA. 2012;308: Raal F, et al. Circulation. 2012;126: Clinical Trials.gov. Available at: Accessed June 4,

30 1. EVOLOCUMAB ΩΣ ΜΟΝΟΘΕΡΑΠΕΙΑ

31 MENDEL-1 Study: Primary Endpoint Percentage Change From Baseline in LDL-C at Week 12 Percent Change From Baseline in UC LDL-C at Week % vs placebo P < Placebo Q2W (n = 45) Placebo Q4W (n = 45) Ezetimibe 10 mg QD (n = 45) 52.5% vs placebo P < AMG mg Q2W (n = 45)* 420 mg Q4W (n = 45) *140 mg was the most effective biweekly dose of AMG mg was the most effective monthly dose of AMG 145 UC = ultracentrifugation Koren MJ, et al. Lancet. 2012;380:

32 2. EVOLOCUMAB ΜΑΖΙ ΜΕ ΣΤΑΤΙΝΗ (± ΕΖΕΤΙΜΙΜΠΗ)

33 LAPLACE-1 Study: Primary Endpoint Percentage Change From Baseline in LDL-C at Week 12 vs Placebo Percent Change From Baseline 66.1% vs placebo P < % vs placebo P < AMG mg Q2W (n = 78)* 420 mg Q4W (n = 80) *140 mg was the most effective biweekly dose of AMG mg was the most effective monthly dose of AMG 145 UC = ultracentrifugation Giugliano RP, et al. Lancet. 2012;380:

34 3. EVOLOCUMAB (± ΕΖΕΤΙΜΙΜΠΗ) ΣΕ ΑΣΘΕΝΕΙΣ ΠΟΥ ΔΕΝ ΑΝΕΧΟΝΤΑΙ ΜΙΑ ΣΤΑΤΙΝΗ

35 GAUSS-1 Study: Primary Endpoint Percentage Change From Baseline in LDL-C at Week 12 Percent Change From Baseline in UC LDL-C at Week % P < vs placebo + ezetimibe Placebo Q4W + Ezetimibe QD (n = 32) 420 mg AMG 145 Q4W (n = 32)* 420 mg AMG 145 Q4W + Ezetimibe QD (n = 30) *420 mg was the most effective monthly dose of AMG 145 UC = ultracentrifugation Sullivan D, et al. JAMA. 2012;308: % P < vs placebo + ezetimibe

36 4. EVOLOCUMAB ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ ΟΙΚΟΓΕΝΗ ΥΠΕΡΧΟΛΗΣΤΕΡΟΛΑΙΜΙΑ

37 RUTHERFORD-1 Study: Primary Endpoint Percentage Change From Baseline in LDL-C at Week 12 Percent Change From Baseline in UC LDL-C at Week % vs placebo P < Placebo Q4W (n = 56) 420 mg AMG 145 Q4W (n = 56)* *420 mg was the most effective monthly dose of AMG 145 UC = ultracentrifugation Raal F, et al. Circulation. 2012;126:

38 OSLER Study Design 12-week studies: MENDEL (monotherapy) LAPLACE-TIMI 57 (patients on statins) GAUSS (statin intolerance) RUTHERFORD (Familial hyper-cholesterolemia) Randomization 2:1 Standard of Care N = 368 Evolocumab + Standard of Care N = 736 Evolocumab + Standard of Care End of Study Blinded Stabilization Period Unblinded Lipid Treatment Visits* End of parent study / Day 1 Primary Objectives: Q4W 52 OSLER Week Effects on LDL-C over 1 year Safety and Tolerability Q4W, every 4 weeks. * Patients in the evolocumab + SOC group had in-person visits every 4 weeks. Patients in the SOC group had in-person visits at week 4, then every 3 months, with telephone visits every 4 weeks. Q4W 38

39 OSLER: Percentage Change in LDL-C, by UC, From Baseline to 1 Year UC LDL-C Percentage Change from Baseline to Week 52, Mean (SE) Baseline Parent Study Week OSLER Study Week -2% -3% -52% -52% Not Evolocumab / SOC Only (n = 96) Evolocumab / Evolocumab + SOC (n = 544) Not Evolocumab / Evolocumab + SOC (n = 192) Evolocumab / SOC Only (n = 272) SE, standard error; SOC, standard of care; UC, ultracentrifugation 39

40 OSLER: LDL-C Goal Achievement < 100 mg/dl < 70 mg/dl SOC Evolocumab + SOC Proportion of Patients, % Proportion of Patients, % LDL-C values by ultracentrifugation. SOC, standard of care 40

41 OSLER: Effect of Evolocumab on Other Lipid Parameters at 1 Year Error bars represent standard error. Data in parentheses represent interquartile ranges. Week 52 vs baseline: * P < ; P < 0.001; P < 0.01; P < 0.05 Evolocumab vs placebo: P< ; P<

42 OSLER: Safety and Tolerability Adverse events, % SOC N = 368 Evolocumab + SOC N = 736 Any adverse event Serious Possibly treatment-related (none serious) NA 5.6* Leading to discontinuation of evolocumab NA 3.7 Deaths Most common adverse events Nasopharyngitis Upper respiratory tract infection Arthralgia Back pain Muscle-related Injection-site reactions NA 5.2 NA, not applicable; SOC, standard of care. *Percentage of adverse events. Patients in the SOC group did not receive injections. 42

43 FOURIER N= patients with high-risk MI or Stroke + LDL-C>70 mg/dl on maximum statin ± ezetimibe Randomization to Evolocumab or Placebo Follow-up = 5 years Primary outcome: CVD events Συμμετοχή της Ελλάδας

44 ALIROCUMAB (SANOFI-REGENERON)

45 ALIROCUMAB

46 ALIROCUMAB

47 ALIROCUMAB

48 ΛΟΓΟΙ ΑΙΣΙΟΔΟΞΙΑΣ ΓΙΑ ΤΗN ΚΛΙΝΙΚΗ ΕΠΙΤΥΧΙΑ ΤΩΝ ΜΟΝΟΚΛΩΝΙΚΩΝ ΑΝΤΙΣΩΜΑΤΩΝ ΕΝΑΝΤΙ PCSK9 1. ΙΔΙΟ ΤΕΛΙΚΟ ΑΠΟΤΕΛΕΣΜΑ ΜΕ ΤΙΣ ΣΤΑΤΙΝΕΣ ( LDL ΥΠΟΔΟΧΕΩΝ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ) 2. ΑΝΑΛΟΓΟ ΣΤΗ ΦΥΣΗ ΤΑ ΑΤΟΜΑ ΜΕ LOF ΜΕΤΑΛΛΑΞΕΙΣ 3. ΑΣΦΑΛΕΙΑ

49 ΘΑ ΕΚΜΗΔΕΝΙΣΤΟΥΝ (ΣΧΕΔΟΝ) ΤΑ ΚΑΡΔΙΑΓΓΕΙΑΚΑ ΑΝ ΠΑΜΕ ΤΗΝ LDL ΧΟΛΗΣΤΕΡΟΛΗ ΚΟΝΤΑ ΣΤΟ 30 mg/dl ΚΑΙ ΠΟΣΟ ΑΣΦΑΛΕΣ ΕΙΝΑΙ ΑΥΤΟ?

50 Effect of Lowering LDL-C on CHD Events % Pateints with CHD Event? PROVE-IT A80 PROVE-IT P40 CARE-Rx ASCOT-Rx POSCH-Rx HPS-Rx 4S-Rx LIPID-Rx LIPID-PL AFCAPS-Rx HPS-PL WOSCOPS-Rx ASCOT-PL POSCH-PL CARE-PL 4S-PL WOSCOPS-PL LRC-Rx AFCAPS-PL LRC-PL Primary prevention trials Secondary prevention trials (mg/dl) (mmol/l) LDL cholesterol

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52 ΣΕ ΠΟΙΟΥΣ ΑΣΘΕΝΕΙΣ ΠΙΘΑΝΑ ΘΑ ΧΟΡΗΓΟΥΝΤΑΙ ΤΑ ΜΟΝΟΚΛΩΝΙΚΑ ΑΝΤΙΣΩΜΑΤΑ ΕΝΑΝΤΙ PCSK9?

53 1. ΠΟΛY ΑΥΞΗΜΕΝΑ ΕΠΙΠΕΔΑ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ ΠΑΡΑ ΤΗ ΧΟΡΗΓΗΣΗ ΣΤΑΤΙΝΗΣ (FH) 2. ΜΗ ΑΝΟΧΗ ΤΗΣ ΒΕΛΤΙΣΤΗΣ ΔΟΣΗΣ ΜΙΑΣ ΣΤΑΤΙΝΗΣ 3. ΑΣΘΕΝΕΙΣ ΜΕ ΣΤΕΦΑΝΙΑΙΑ ΝΟΣΟ Ή ΑΕΕ ΠΟΥ ΠΡΕΠΕΙ ΝΑ ΕΠΙΤΥΧΟΥΝ ΠΟΛΥ ΧΑΜΗΛΑ ΕΠΙΠΕΔΑ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ (ΟΙ ΠΕΡΙΣΣΟΤΕΡΟΙ???)

54 ΠΕΡΙΟΡΙΣΜΟΙ ΤΗΣ ΘΕΡΑΠΕΙΑΣ 1. ΑΝΑΓΚΗ ΥΠΟΔΟΡΙΑΣ ΧΟΡΗΓΗΣΗΣ ( 1 ΦΟΡΑ ΤΟΝ ΜΗΝΑ ΜΕ ΕΙΔΙΚΗ ΣΥΣΚΕΥΗ) ( ΣΥΜΜΟΡΦΩΣΗ) 2. ΚΟΣΤΟΣ ΘΕΡΑΠΕΙΑΣ

55 ΣΥΜΠΕΡΑΣΜΑ ΣΤΑ ΕΠΟΜΕΝΑ ΧΡΟΝΙΑ ΘΑ ΖΗΣΟΥΜΕ ΜΙΑ ΕΠΑΝΑΣΤΑΣΗ ΣΤΟΝ ΤΟΜΕΑ ΤΗΣ ΚΑΡΔΙΑΓΓΕΙΑΚΗΣ ΠΡΟΛΗΨΗΣ ΑΝΤΙΣΤΟΙΧΗ (ΑΝ ΟΧΙ ΜΕΓΑΛΥΤΕΡΗ) ΑΥΤΗΣ ΤΩΝ ΣΤΑΤΙΝΩΝ