Η ΤΕΧΝΟΛΟΓΙΑ ΤΩΝ ΜΟΝΟΚΛΩΝΙΚΩΝ ΑΝΤΙΣΩΜΑΤΩΝ ΣΤΗ ΜΕΙΩΣΗ ΤΗΣ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ: ΑΝΑΣΤΟΛΗ ΤΗΣ PCSK9 Ευάγγελος Λυμπερόπουλος Επίκουρος Καθηγητής Παθολογίας Ιατρικής Σχολής Παν/μίου Ιωαννίνων
DISCLOSURES Συμμετοχή σε εκπαιδευτικές, ερευνητικές και συμβουλευτικές δραστηριότητες: ASTRA-ZENECA, PFIZER, ΒΙΑΝΕΞ, MSD, LILLY, WIN- MEDICA, ABBOTT, NOVARTIS, BAYER, AMGEN, SANDOZ
LDL ΧΟΛΗΣΤΕΡΟΛΗ ΚΑΙ ΚΑΡΔΙΑΓΓΕΙΑΚΟΣ ΚΙΝΔΥΝΟΣ
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 18 16 14 12 10 8 6 4 2 0 140 160 180 200 220 240 260 280 300 320 6-year CHD incidence per 1000 men 150 125 100 75 50 25 0 <204 205 234 235 264 265 294 >295 TC (mg/dl) TC (mg/dl) TC=total cholesterol; CHD=coronary heart disease. Martin MJ et al. Lancet. 1986;2:933-936; Castelli WP. Am J Med. 1984;76:4-12.
(70 mg/dl)
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
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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Η ΣΥΝΑΡΠΑΣΤΙΚΗ ΙΣΤΟΡΙΑ ΤΗΣ ΑΝΑΚΑΛΥΨΗΣ ΤΗΣ PREPROTEIN CONVERTASE SUBTILISIN KEXIN 9 (PCSK9)
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 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2012 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):5374-79, Lagace TA et al. JCI 2006;116:2995-3005 Cohen JC. N Engl J Med 2006;354(12):1264-72, 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;366:1108-18
LDL Receptor Function and Life Cycle 17 17
The Role of PCSK9 in the Regulation of LDL Receptor Expression 18 18
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-S177. 2. Lakoski SG, et al. J Clin Endocrinol Metab. 2009;94: 2537-2543. 3. Abifadel M, et al. Hum Mutat. 2009;30:520-529. 4. Cohen J, et al. Nat Genet. 2005;37:161-165. 5. Steinberg D, et al. PNAS. 2009;106:9546-9547. 6. Cohen JC, et al. N Engl J Med. 2006;354:1264-1272. 7. Benn M, et al. J Am Coll Cardiol. 2010;55:2833-2842.
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. 2010:3-23. 2. Benn M, et al. J Am College Cardiol. 2010;55:2833-2842.
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-S177. 2. Lakoski SG, et al. J Clin Endocrinol Metab. 2009;94: 2537-2543. 3. Abifadel M, et al. Hum Mutat. 2009;30:520-529. 4. Cohen J, et al. Nat Genet. 2005;37:161-165. 5. Steinberg D, et al. PNAS. 2009;106:9546-9547. 6. Cohen JC, et al. N Engl J Med. 2006;354:1264-1272. 7. Benn M, et al. J Am Coll Cardiol. 2010;55:2833-2842.
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;30:520-529. 2. 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. 2010:3-23. 4. Benn M, et al. J Am Coll Cardiol. 2010;55:2833:2842. 5. Kathiresan S. N Engl J Med. 2008;358:2299-2300.
LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9 142X or PCSK9 679X Allele Frequency (%) No Nonsense Mutation 30 (n=3278) 20 10 0 0 50 100 150 200 250 300 30 20 PCSK9 142X or PCSK9 679X (N=85) 50 th Percentile 28% Coronary Heart Disease (%) 12 8 4 P=0.008 88% 10 0 No Yes 0 0 50 100 150 200 250 300 LDL Cholesterol in Black Subjects (mg/dl) PCSK9 142X or PCSK9 679X Cohen NEJM 2006; 354:1264-72
No health problem
Η ΕΠΑΝΑΣΤΑΣΗ ΤΗΣ ΔΗΜΙΟΥΡΓΙΑΣ ΜΟΝΟΚΛΩΝΙΚΩΝ ΑΝΤΙΣΩΜΑΤΩΝ ΕΝΑΝΤΙΟΝ ΤΗΣ PCSK9
Impact of an PCSK9 mab on LDL Receptor Expression For illustration purposes only mab 26 26
3 3
EVOLOCUMAB (AMGEN)
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;380:2007-2017. 2. Koren MJ, et al. Lancet. 2012:380:1995-2006. 3. Sullivan D, et al. JAMA. 2012;308:2497-2506. 4. Raal F, et al. Circulation. 2012;126:2408-2417. 5. Clinical Trials.gov. Available at: http://www.clinicaltrials.gov. Accessed June 4, 2013. 29
1. EVOLOCUMAB ΩΣ ΜΟΝΟΘΕΡΑΠΕΙΑ
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 12 47.2% vs placebo P < 0.0001 Placebo Q2W (n = 45) Placebo Q4W (n = 45) Ezetimibe 10 mg QD (n = 45) 52.5% vs placebo P < 0.0001 AMG 145 140 mg Q2W (n = 45)* 420 mg Q4W (n = 45) *140 mg was the most effective biweekly dose of AMG 145 420 mg was the most effective monthly dose of AMG 145 UC = ultracentrifugation Koren MJ, et al. Lancet. 2012;380:1995-2006.
2. EVOLOCUMAB ΜΑΖΙ ΜΕ ΣΤΑΤΙΝΗ (± ΕΖΕΤΙΜΙΜΠΗ)
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 < 0.0001 50.3% vs placebo P < 0.0001 AMG 145 140 mg Q2W (n = 78)* 420 mg Q4W (n = 80) *140 mg was the most effective biweekly dose of AMG 145 420 mg was the most effective monthly dose of AMG 145 UC = ultracentrifugation Giugliano RP, et al. Lancet. 2012;380:2007-2017.
3. EVOLOCUMAB (± ΕΖΕΤΙΜΙΜΠΗ) ΣΕ ΑΣΘΕΝΕΙΣ ΠΟΥ ΔΕΝ ΑΝΕΧΟΝΤΑΙ ΜΙΑ ΣΤΑΤΙΝΗ
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 12 35.9% P < 0.001 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;308:2497-2506. 47.3% P < 0.001 vs placebo + ezetimibe
4. EVOLOCUMAB ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ ΟΙΚΟΓΕΝΗ ΥΠΕΡΧΟΛΗΣΤΕΡΟΛΑΙΜΙΑ
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 12 56.4% vs placebo P < 0.001 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;126:2408-2417.
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: 4 8 12 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
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) 10 0-10 -20-30 -40-50 -60 Baseline Parent Study Week 12 12 24 36 48 52 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
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
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 < 0.0001; P < 0.001; P < 0.01; P < 0.05 Evolocumab vs placebo: P< 0.0001; P< 0.001 41
OSLER: Safety and Tolerability Adverse events, % SOC N = 368 Evolocumab + SOC N = 736 Any adverse event 73.1 81.4 Serious 6.3 7.1 Possibly treatment-related (none serious) NA 5.6* Leading to discontinuation of evolocumab NA 3.7 Deaths 0.5 0.1 Most common adverse events Nasopharyngitis 9.8 12.2 Upper respiratory tract infection 7.6 7.7 Arthralgia 4.3 6.9 Back pain 5.4 6.5 Muscle-related 9.8 9.2 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
FOURIER N= 22.500 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
ALIROCUMAB (SANOFI-REGENERON)
ALIROCUMAB
ALIROCUMAB
ALIROCUMAB
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
ΘΑ ΕΚΜΗΔΕΝΙΣΤΟΥΝ (ΣΧΕΔΟΝ) ΤΑ ΚΑΡΔΙΑΓΓΕΙΑΚΑ ΑΝ ΠΑΜΕ ΤΗΝ LDL ΧΟΛΗΣΤΕΡΟΛΗ ΚΟΝΤΑ ΣΤΟ 30 mg/dl ΚΑΙ ΠΟΣΟ ΑΣΦΑΛΕΣ ΕΙΝΑΙ ΑΥΤΟ?
Effect of Lowering LDL-C on CHD Events % Pateints with CHD Event? 40 25 20 15 10 5 0 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 50 70 90 110 130 150 170 190 210 Primary prevention trials Secondary prevention trials (mg/dl) 1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/l) LDL cholesterol
ΣΕ ΠΟΙΟΥΣ ΑΣΘΕΝΕΙΣ ΠΙΘΑΝΑ ΘΑ ΧΟΡΗΓΟΥΝΤΑΙ ΤΑ ΜΟΝΟΚΛΩΝΙΚΑ ΑΝΤΙΣΩΜΑΤΑ ΕΝΑΝΤΙ PCSK9?
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???)
ΠΕΡΙΟΡΙΣΜΟΙ ΤΗΣ ΘΕΡΑΠΕΙΑΣ 1. ΑΝΑΓΚΗ ΥΠΟΔΟΡΙΑΣ ΧΟΡΗΓΗΣΗΣ ( 1 ΦΟΡΑ ΤΟΝ ΜΗΝΑ ΜΕ ΕΙΔΙΚΗ ΣΥΣΚΕΥΗ) ( ΣΥΜΜΟΡΦΩΣΗ) 2. ΚΟΣΤΟΣ ΘΕΡΑΠΕΙΑΣ
ΣΥΜΠΕΡΑΣΜΑ ΣΤΑ ΕΠΟΜΕΝΑ ΧΡΟΝΙΑ ΘΑ ΖΗΣΟΥΜΕ ΜΙΑ ΕΠΑΝΑΣΤΑΣΗ ΣΤΟΝ ΤΟΜΕΑ ΤΗΣ ΚΑΡΔΙΑΓΓΕΙΑΚΗΣ ΠΡΟΛΗΨΗΣ ΑΝΤΙΣΤΟΙΧΗ (ΑΝ ΟΧΙ ΜΕΓΑΛΥΤΕΡΗ) ΑΥΤΗΣ ΤΩΝ ΣΤΑΤΙΝΩΝ