ΔΟΡΥΦΟΡΙΚΗ ΔΙΑΛΕΞΗ. Αναστολή της PCSK9: νεότερα δεδοµένα στην αντιµετώπιση του κινδύνου της υψηλής LDL

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1 # ΔΟΡΥΦΟΡΙΚΗ ΔΙΑΛΕΞΗ Αναστολή της PCSK9: νεότερα δεδοµένα στην αντιµετώπιση του κινδύνου της υψηλής LDL

2 # ΑΜΟΙΒΕΣ ΑΠΟ ΠΟΛΥΚΕΝΤΡΙΚΕΣ ΜΕΛΕΤΕΣ, HONORARIA SERVIER, NOVARTIS, LILLY, ASTRA, SANOFI

3 ESC/EAS 2011: Κατευθυντήριες οδηγίες για την διαχείριση της δυσλιπιδαιµίας # Reiner Z., et al Eur Heart J Jul;32(14):

4 Θεραπευτικοί Στόχοι Συστάσεις Τάξη Επίπεδο Ασθενείς ΠΟΛΥ ΥΨΗΛΟΥ ΚΑ κινδύνου (εγκατεστηµένη ΚΑΝ, Διαβήτης Τύπου ΙΙ, Διαβήτης Τύπου Ι µε βλάβη σε όργανα στόχους, µέτρια/σοβαρή ΧΝΝ ή SCORE 10%) ο στόχος LDL-c είναι < 70 mg/dl και/ή 50% µείωση LDL-c σε περίπτωση που δεν επιτυγχάνεται ο στόχος I Α Ασθενείς ΥΨΗΛΟΥ ΚΑ κινδύνου (σηµαντικά αυξηµένοι µεµονωµένοι παράγοντες κινδύνου, 5 SCORE < 10%) o στόχος LDL-c είναι < 100 mg/dl IΙa A Ασθενείς ΜΕΤΡΙΟΥ ΚΑ κινδύνου (1 < SCORE 5%) o στόχος είναι LDL-c < 115 mg/dl IIa C 2011 ESC/EAS Guidelines for the management of dyslipidaemias #

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6 Τα πιο σηµαντικά σηµεία των συστάσεων ACC/AHA 2013: Πρωταρχική λιπιδαιµική παράµετρος η LDL-C και στόχος η ισχυρή ελάττωσή της Οι κατευθυντήριες οδηγίες συνιστούν ότι πρέπει να επιτευχθεί σηµαντική µείωση της LDL-C δια µέσου υγιεινοδιαιτητικών παρεµβάσεων και θεραπείας µε στατίνες. Μη συγκεκριµένα όρια-στόχοι για κάθε κατηγορία ασθενών. Συνιστούν τη χρήση κατάλληλης δυναµικότητας / δοσολογίας στατίνης για την επίτευξη της µείωσης της LDL-C δηλ. χρήση υψηλής ισχύος στατίνης σε υψηλού κινδύνου ασθενείς (>50% µείωση της LDL-C) ή µέτριας ισχύος στατίνη για τους ασθενείς µέτριου κινδύνου (επιθυµητή µείωση >30 50%) #

7 Σύγκριση κατευθυντήριων οδηγιών ACC/AHA & ESC/EAS διαφορετικά σηµεία ACC/AHA 2013 ESC/EAS 2011 τυχαιοποιηµένες ελεγχόµενες µε εικονικό φάρµακο µελέτες & µετα-αναλύσεις αυτών µελέτες παρατήρησης, τυχαιοποιηµένες (ή µη) ελεγχόµενες (ή µη) µε εικονικό φάρµακο, post-hoc αναλύσεις, µετααναλύσεις, απεικονιστικές µελέτες fire & forget στρατηγική treat-to-target στρατηγική - συστάσεις για χρόνια νεφροπαθείς όριο πρωτογενούς πρόληψης ASCVD score > 7.5%* όριο πρωτογενούς πρόληψης SCORE > 5% * ASCVD score 7.5% = SCORE 2.5% Ray K.K., et al Eur Heart J #

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10 Επιδηµιολογικά Δεδοµένα Tί γίνεται στη πράξη ; #

11 EUROASPIRE IV Ασθενείς σε υπολιπιδαιµική θεραπεία 98% #

12 EUROASPIRE IV Aσθενείς µε LDL-c > 100 mg/dl 100 mg/dl ~ ½ ασθενείς εκτός στόχων #

13 # (70 mg/dl) (70 mg/dl)

14 ΑΔΥΝΑΜΙΑ ΕΠΙΤΕΥΞΗΣ ΤΩΝ ΣΤΟΧΩΝ ΤΗΣ ΥΠΟΛΙΠΙΔΑΙΜΙΚΗΣ ΑΓΩΓΗΣ Μειωµένη συµµόρφωση των ασθενών Ανεπιθύµητες ενέργειες (δοσοεξαρτώµενες) Περιορισµένη αποτελεσµατικότητα της υπολιπιδαιµικής αγωγής («κανόνας του 6») Aνεπαρκής χορήγηση συνδυασµού υπολιπιδαιµικών φαρµάκων #

15 15 Μονοκλωνικά Αντισώµατα

16 History Of Discovery Paul Ehrlich proposes Side-Chain Theory for antibody & antigen (lock & key) interaction 3 Astrid Fagraeus discovered that B cells (plasma cells) were responsible for generating antibodies 5 First mab approved for clinical use in transplant rejection: Muromonab-CD3 a mouse antibody 1,2 Daclizumab first humanised mab (transplant rejection) 2 Discovery of tetanus and diphtheria antitoxins 2 Linus Pauling confirms lock & key theory 4 César Milstein and Georges Köhler develop method of producing "custom antibodies in vitro, by producing a hybridoma 1 Abciximab first chimeric antibody (fragment) 2 Adalimumab - 1 st fully human mab approved by FDA s Nobel Prize Emil Adolf von Behring Nobel Prize Paul Ehrlich, Ilya Mechnikov Nobel Prize Linus Pauling Nobel Prize César Milstein, Niels Jerne, Georges Köhler 6 1. Catapano AL, et al. (2013). Atherosclerosis, 228(1):18-28; 2. Foltz I, et al. Circulation 2013 Jun 4;127(22): ; 3. Prüll C Med Hist Jul;47(3):332-56; 4. Gormley M Endeavour Jun;31(2):71-7; 5. LeBien TW & Tedder TF Blood Sep 1;112(5): ; 6. Nobelprize.org (2014) All Nobel Laureates in Physiology or Medicine. Available at: medicine/laureates/ Accessed: July Nobelprize.org (2014). All Nobel Laureates in Chemistry. Available at: Accessed: July 2014.

17 Impact of Immunogenicity Usually no detectable adverse event Decrease efficacy Clear the drug from the body Neutralize drug by binding Adverse events Injection site reaction Systemic infusion reaction Acute hypersensitivity Severe adverse events Drug-induced immune response results in immunogenicity to the endogenous protein Y Y Y Y Y Y Y Y Y Monoclonal antibody drug Therapeutic protein Endogenous protein

18 Alirocumab Πλήρως ανθρώπινο µονοκλωνικό αντίσωµα PCSK9 Λιγότερο πιθανό να εµφανίσει παρενέργειες του ανοσοποιητικού: Ουδετεροπενία Θροµβοπενία Αιµολυτική αναιµία Αντιδράσεις υπερευαισθησίας 9

19 PCSK9 - Ταχεία εξέλιξη από το εργαστήριο στην κλινική σε λιγότερο από µια δεκαετία Απόδειξη της ύπαρξης του PCSK9 στα ζώα Επικύρωση της ύπαρξης του PCSK9 στον άνθρωπο Πρώτο άτοµο που θεραπεύεται µε PCSK9 mab (Alirocumab) Πρώτα διαθέσιµα δεδοµένα µελετών φάσης 3 (ODYSSEY MONO) Ανακάλυψη του PCSK9 mab που στοχεύει στο PCSK9 προκλινικά Δηµοσίευση µελετών φάσης Seidah NG. Proc Natl Acad Sci USA 2003;100: Abifadel M. Nat Genet 2003;34: Maxwell KN. Proc Natl Acad Sci USA 2004;101: Rashid S. Proc Natl Acad Sci USA 2005;102: Cohen JC. NEJM 2006;354: Zhao Z. Am J Hum Genet 2006;79: Hooper AJ. Atherosclerosis 2007;193: Chan JC. Proc Natl Acad Sci USA 2009;106: Stein et al. NEJM 2012;366: McKenney et al. JACC 2012;59: Stein et al. Lancet 2012;380: Roth et al. NEJM 2012;367: Giugliano et al. Lancet 2012;380: Koren et al. Lancet 2012;380: Raal et al. Circulation 2012;126: Sullivan et al. JAMA 2012:308: #

20 Λειτουργία του υποδοχέα του LDL και κύκλος ζωής Για λόγους απεικόνισης µόνο 620

21 Ο ρόλος του PCSK9 στην ρύθµιση της έκφρασης των υποδοχέων LDL Για λόγους απεικόνισης µόνο 21

22 Επιπτώσεις του Alirocumab στην έκφραση του υποδοχέα LDL Για λόγους απεικόνισης µόνο 822

23 23 LDL-C ως παράγοντας Καρδιαγγειακού κινδύνου δεδοµένα απο την µείωση

24 PROVE IT-TIMI 22: reduced risk of cardiovascular events with intensive therapy Hazard ratio (compared with LDL-cholesterol mg/dl) Wiviott SD et al. J Am Coll Cardiol 2005;46:1411 6

25 JUPITER: effects of lowering LDL-cholesterol to below 50 mg/dl In the JUPITER study in apparently healthy individuals, the risk of major cardiovascular events was reduced by 65%, compared with placebo, in patients in whom LDL-cholesterol was lowered to below 50 mg/dl The corresponding risk reduction in patients with LDLcholesterol >50 mg/dl was only 24% (P< for trend) Figure: time to occurrence of major cardiovascular events according to treatment group and achieved LDL-cholesterol concentrations Kaplan-Meier curves for the primary study endpoint, time to first occurrence of cardiovascular death, myocardial infarction, stroke, arterial revascularization, or hospitalized unstable angina for subjects allocated to placebo, rosuvastatin with no LDL-cholesterol <50 mg/dl, and rosuvastatin with LDL-cholesterol <50 mg/dl. P< for trend Hsia J et al. J Am Coll Cardiol 2011;57:

26 LDL-C: mg/dl!6.4%

27 Phase 3 clinical trial program extensive alirocumab patient exposure Double-Blinded Efficacy and Safety Evaluation Primary Endpoint Evaluation at Week 24 MONO (n=103) OPTIONS I (n=355) OPTIONS II (n=305) ALTERNATIVE (n=314) COMBO I (n=316) FH I (n=486) FH II (n= 249) HIGH FH (n=107) LONG TERM (n=2,341) 24 Weeks 52 Weeks 78 Weeks 4400 patient years at completion of studies COMBO II (n=720) 104 Weeks (1) Does not include ODYSSEY OUTCOMES (event-driven) and ODYSSEY OLE (open label safety study; up to 120 weeks), ODYSSEY ALTERNATIVE will have an indefinite open label extension

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30 Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated daily statin: results from the ODYSSEY COMBO II study Christopher P. Cannon, 1 Bertrand Cariou, 2 Dirk Blom, 3 James M. McKenney, 4 Christelle Lorenzato, 5 Robert Pordy, 6 Umesh Chaudhari, 7 Helen M. Colhoun 8 1 Harvard Clinical Research Institute, Boston, MA, USA; 2 L Institut du Thorax, CHU de Nantes, Nantes, France; 3 Division of Lipidology, Department of Medicine, University of Cape Town and MRC Cape Heart Group, Cape Town, South Africa; 4 Virginia Commonwealth University and National Clinical Research, Inc., Richmond, VA, USA; 5 Sanofi, Paris, France; 6 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 7 Sanofi, Bridgewater, NJ, USA; 8 University of Dundee, Dundee, Scotland, UK

31 ODYSSEY COMBO II Study Design High CV-risk patients on max-tolerated statin LDL-C 1.81 mmol/l [70 mg/dl] (history of CVD) or 2.59 mmol/l [100 mg/dl] (no history of CVD) R n=479 n=241 Double-blind treatment period (104 weeks) Alirocumab 75 mg with potential to 150 mg Q2W SC + placebo ezetimibe PO (single 1-mL injection using prefilled pen for self-administration) Per-protocol dose possible based on pre-specified LDL-C level Ezetimibe 10 mg/day PO + placebo Q2W SC Follow-up (8 weeks) Assessments W4 W0 W8 W12 W16 W24 W36 W52 W64 W76 W88 W104 Dose if LDL-C >70 mg/dl at W8 Primary endpoint Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W102 (all patients at least W52) 31 Other LLT not allowed. Clinicaltrials.gov identifier: NCT

32 Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Ezetimibe Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background of maximally-tolerated statin LS mean (SE) % change from baseline to Week n=467 n= % had dose increase at W Alirocumab Ezetimibe LS mean difference (SE) vs. ezetimibe: 29.8% (2.3); P< Intent-to-treat (ITT) analysis

33 Alirocumab Maintained Consistent LDL-C Reductions over 52 Weeks Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin LDL-C, LS mean (SE), mmol/l Ezetimibe Alirocumab 2.1 mmol/l 82.5 mg/dl 1.3 mmol/l 51.6 mg/dl Dose if LDL-C >70 mg/dl at W8 20.7% 50.6% Week 2.2 mmol/l 85.3 mg/dl 18.3% 1.4 mmol/l 53.3 mg/dl 49.5% mg /dl 33 Intent-to-treat (ITT) analysis

34 Most of These High CV-Risk Patients Receiving Alirocumab on Background Statin Achieved LDL-C Goal All patients on background of maximally-tolerated statin Proportion of Patients Reaching LDL-C <1.81 mmol/l (70 mg/dl) at Week 24 Proportion of Patients Reaching LDL-C <1.3 mmol/l (50 mg/dl) at Week Alirocumab Ezetimibe % patients % patients P< Post hoc 34 Intent-to-treat (ITT) analysis

35 Statistically Significant Reductions in Other Atherogenic Lipid Parameters at Week 24 Alirocumab + maximally-tolerated statin Ezetimibe + maximally-tolerated statin Non-HDL-C Apo B Lp(a) 0 LS mean (SE) % change from baseline to Week LS mean difference (SE) versus ezetimibe: 22.9 (2.0) % P< (1.8) % P< (2.4) % P< Intent-to-treat (ITT) analysis Adjusted mean (SE) shown for Lp(a)

36 Safety Analysis (Baseline-W102) Including All Data Collected Until Last Patient Visit at Week 52 % (n) of patients All patients on background max tolerated statin Alirocumab (n=479) Ezetimibe (n=241) 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% (13) Adverse Events of Interest Adjudicated CV events 4.8% (23) 3.7% (9) Injection-site reactions 2.5% (12) 0.8% (2) Neurocognitive disorders 0.8% (4) 1.2% (3) ALT >3 x ULN 1.7% (8/470) 0.4% (1/240) Creatine kinase >3 x ULN 2.8% (13/467) 2.5% (6/236) 36 Both deaths in the alirocumab arm were due to CV events (cardiac arrest and sudden cardiac death). Of the four deaths in the ezetimibe arm, two were due to CV events (malignant lung neoplasm, suicide, defect conduction intraventricular, sudden cardiac death and sudden death one patient was counted in two categories) Adjudicated CV events include all CV AEs positively adjudicated. The adjudication categories are the following: CHD death, non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalisation, congestive heart failure requiring hospitalisation, ischemia driven coronary revascularisation procedure [PCI, CABG]. Statistical analyses have not been performed.

37 Safety Analysis (Baseline-W102) TEAEs Occurring in 5% of Either Alirocumab or Ezetimibe Patients % (n) of patients Alirocumab Ezetimibe All patients on background max Upper respiratory tract infection (n=479) 6.5% (31) (n=241) 5.8% (14) Accidental overdose 6.3% (30) 6.6% (16) Dizziness 4.8% (23) 5.4% (13) Myalgia 4.4% (21) 5.0% (12) 37 Accidental overdose is an event suspected by the Investigator or spontaneously notified by the patient (not based on systematic injection/capsule counts) and defined as at least twice the intended dose within the intended therapeutic interval (i.e., 2 injections from the double-blind treatment kit administered in <7 calendar days or 2 capsules from the double-blind treatment kit are administered within 1 calendar day). Statistical analyses have not been performed.

38 Conclusions In this population of high CV-risk patients who had poorly controlled LDL-C on maximally-tolerated statin therapy: LDL-C from baseline maintained with alirocumab: significantly greater vs. ezetimibe at W24, 51% vs 21% (P<0.0001) Self-administered alirocumab had good compliance and was welltolerated This treat-to-target approach with alirocumab resulted in ~80% pts not requiring a dose to 150 mg at W12 77% of alirocumab pts achieved LDL-C <1.81 mmol/l (70 mg/dl) at W24 Mean achieved LDL-C levels of 1.4 mmol/l (53.3 mg/dl) at W52 with alirocumab TEAEs similar between alirocumab and ezetimibe arms 38

39 Long-term safety, tolerability and efficacy of alirocumab in high cardiovascular risk patients: ODYSSEY LONG TERM Efficacy by subgroup, and safety when LDL-C <25 mg/dl Jennifer G. Robinson, 1 Michel Farnier, 2 Michel Krempf, 3 Jean Bergeron, 4 Gérald Luc, 5 Maurizio Averna, 6 Erik Stroes, 7 Gisle Langslet, 8 Frederick J. Raal, 9 Mahfouz El Shahawy, 10 Michael J. Koren, 11 Norman Lepor, 12 Christelle Lorenzato, 13 Robert Pordy, 14 Umesh Chaudhari, 15 John J.P. Kastelein 7 1 University of Iowa, Iowa City, IA, USA; 2 Point Médical, Dijon, France; 3 CHU de Nantes - Hôpital Nord Laennec, Saint- Herblain, France; 4 Clinique des Maladies Lipidiques de Quebec Inc., Quebec, Canada; 5 University Hospital of Lille, Lille, France; 6 Università di Palermo Policlinico P.Giaccone, Palermo, Italy; 7 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; 8 Lipid Clinic, Oslo University Hospital, Oslo, Norway; 9 University of Witwatersrand, Johannesburg, South Africa; 10 Cardiovascular Center of Sarasota, Sarasota, FL, USA; 11 Jacksonville Center For Clinical Research, Jacksonville, FL, USA; 12 Westside Medical Associates of Los Angeles, Beverly Hills, CA, USA; 13 Sanofi, Chilly- Mazarin, France; 14 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 15 Sanofi, Bridgewater, NJ, USA This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.

40 ODYSSEY LONG TERM Study Design HeFH or High CV-risk patients On maximally tolerated statin ± other lipid-lowering therapy LDL-C 70 mg/dl R n=1553 n=788 Double-blind treatment (18 months) Alirocumab 150 mg Q2W SC (single 1 ml injection using prefilled syringe for self-administration) Placebo Q2W SC Follow-up (8 weeks) Assessments W0 W4 W8 W12 W16 W24 W36 W52 W64 W78 Primary efficacy endpoint Pre-specified analysis Efficacy: All patients up to W52 (ITT) Safety: All patients randomized and treated 85.8% (2009/2341) completed 52 weeks (both treatment arms) 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) had completed 78 weeks by time of this analysis Mean treatment duration: 65 weeks (both treatment arms) 40 ClinicalTrials.gov identifier: NCT

41 Baseline Characteristics All pts on background of maximally tolerated Alirocumab Placebo statin ± other lipid-lowering therapy (n=1553) (n=788) Age, years, mean (SD) 60.4 (10.4) 60.6 (10.4) Male, % (n) 63.3% (983) 60.2% (474) Race, White 92.8% (1441) 92.6% (730) BMI, kg/m 2, mean (SD) 30.2 (5.7) 30.5 (5.5) HeFH, % (n) 17.8% (276) 17.6% (139) CHD history, % (n) 67.9% (1055) 70.1% (552) Type 2 diabetes, % (n) 34.9% (542) 33.9% (267) Any statin, % (n) 99.9% (1552) 99.9% (787) High dose statin, % (n) 46.8% (727) 46.8% (369) Any LLT other than statins, % (n) 28.1% (437) 27.9% (220) Ezetimibe, % (n) 13.9% (216) 15.0% (118) LDL-C, calculated (42.6) (41.4) Patients should receive either rosuvastatin mg, atorvastatin mg daily, or simvastatin 80 mg daily unless not tolerated and/or appropriate other dose given according to the judgement of the investigator 41 High dose statin: atorvastatin mg, rosuvastatin mg, or simvastatin 80 mg daily.

42 Alirocumab Maintained Consistent LDL-C Reductions Over 52 Weeks Achieved LDL-C Over Time All patients on background of maximally tolerated statin ± other lipid-lowering therapy Calculated LDL-C, LS mean (SE), mg/dl Alirocumab Placebo mg/dl (+0.8%) 48.3 mg/dl ( 61.0%) Week Difference 61.9% mg/dl (+4.4%) 53.1 mg/dl ( 56.8%) Difference 61.3% 42 Intent-to-treat (ITT) analysis

43 Effects on LDL-C Consistent Regardless of HeFH Status All patients on background of maximally tolerated statin ± other lipid-lowering therapy Alirocumab Placebo Interaction p-value HeFH population Non-HeFH population LS mean (SE) % change from baseline to Week n=271 n=145 n=1259 n= LS mean difference 63.2% 61.5% vs placebo: LS mean absolute LDL-C reduction, mg/dl:

44 Consistent Effects on LDL-C Across a Range of Baseline LDL-C Values All patients on background of maximally tolerated statin ±other lipid-lowering therapy Alirocumab Placebo Interaction p-value < LS mean (SE) % change from baseline to Week <100 mg/dl 100 to 130 to <130 mg/dl <160 mg/dl mg/dl n=470 n=241 n=562 n=285 n=271 n=143 n=227 n= LS mean difference 75.0% 62.5% 54.6% 41.3% vs placebo: LS mean absolute LDL-C reduction, mg/dl:

45 Efficacy Observed Across Baseline PCSK9 Levels All patients on background of maximally tolerated statin ± other lipid-lowering therapy Alirocumab Placebo Interaction p-value < Below median At or above median LS mean (SE) % change from baseline to Week n=736 n=376 n=740 n= LS mean difference vs placebo: 57.3% 67.3%

46 Efficacy Observed in Both Genders All patients on background of maximally tolerated statin ± other lipid-lowering therapy Alirocumab Placebo Interaction p-value Male Female LS mean (SE) % change from baseline to Week n=967 n=471 n=563 n= LS mean difference vs placebo: 64.7% 56.6%

47 Efficacy Comparable Across Various Subgroups Difference (alirocumab vs. placebo) in LDL-C % Change from Baseline to W24 Subgroup Alirocumab Placebo Interaction n LS mean n LS mean p-value Overall Race White Black/African American Age < to < BMI < Moderate CKD Yes No Diabetes Yes No Baseline fasting TGs, mg/dl < All patients on background of maximally tolerated statin ±other lipid-lowering therapy LS -80 mean difference -60 vs. -40 placebo (95% -20 CI) 0

48 Treatment-Emergent Adverse Events % (n) of patients All pts on background of maximal statin Alirocumab (n=1550) Alirocumab with 2 consecutive LDL cholesterol Placebo (n=788) TEAEs 78.6% (1218) 71.9% (404) 80.6% (635) Treatment-emergent SAEs 16.5% (255) 14.6% (82) 17.6% (139) TEAE leading to death TEAEs leading to treatment discontinuation 0.5% (7) 0.5% (3) 1.0% (8) 6.2% (96) 3.6% (20) 5.5% (43) Mean exposure: 65 weeks (both treatment arms) % (405/1553 alirocumab) and 25.6% (202/788 placebo) completed the 18-month double-blind treatment period TEAEs, treatment-emergent adverse events. Completed = 76 weeks exposure and W78 visit performed.

49 TEAEs ( 2%) in any Group Comparable in Patients With 2 Consecutive LDL-C <25 mg/dl % (n) of patients Alirocumab Alirocumab with 2 Placebo All pts on background of maximal statin therapy ± other lipid- (n=1550) consecutive (n=788) Infections + infestations 45.5% (705) 39.0% (219) 46.1% (363) Musculoskeletal + connective tissue disorders 27.2% (422) 22.6% (127) 28.6% (225) Gastrointestinal disorders 18.6% (288) 13.7% (77 ) 18.8% (148) Nervous system disorders 17.0% (262) 11.2% (63 ) 17.8% (140) General disorders + administration site conditions 15.4% (238) 11.0% (62) 17.0% (134) Injury, poisoning, + procedural complications 13.4% (207) 10.5% (59) 14.2% (112) Respiratory, thoracic, + mediastinal disorders 11.0% (171) 7.7% (43) 10.9% (86) Cardiac disorders 9.1% (141) 7.5% (42 ) 11.8% (93) Skin + subcutaneous tissue disorders 9.1% (141) 6.9% (39 ) 8.5% (67) Metabolism + nutrition disorders 9.1% (141) 8.0% (45) 8.4% (66) Vascular disorders 7.9% (122) 5.0% (28) 8.9% (70) Eye disorders 6.5% (100) 6.4% (36) 6.1% (48) Laboratory investigations 6.1% (95) 3.7% (21 ) 5.2% (41) Psychiatric disorders 5.9% (91) 4.3% (24) 8.0% (63) Renal + urinary disorders 4.6% (72) 3.6% (20) 6.0% (47) Neoplasms, benign, malignant (incl cysts/polyps) 2.5% (38) 3.0% (17 ) 3.4% (27) Reproductive system + breast disorders 2.5% (38) 2.0% (11) 3.2% (25) Blood + lymphatic system disorders 2.4% (37) 1.6 % (9) 3.0% (24) Ear + labyrinth disorders 2.0% (31) 1.2% (7) 2.9% (23) 49

50 TEAEs ( 2%) in any Group Comparable in Patients With 2 Consecutive LDL-C <25 mg/dl % (n) of patients All pts on background of maximally tolerated statin ± other lipid- Alirocumab (n=1550) Alirocumab with 2 consecutive LDL-C Placebo (n=788) Nasopharyngitis 12.6% (196) 10.0% (56) 12.7% (100) % (n) of patients All pts on background of maximally tolerated statin ± other lipid- Alirocumab (n=1550) Alirocumab with 2 consecutive LDL-C Placebo (n=788) Cough 3.2% (49) 2.0% (11) 2.2% (17) URTI 7.0% (109) 5.7% (32) 8.0% (63) LRTI 3.0% (46) 2.8% (16) 2.9% (23) Injection site reaction c 5.7% (89) 3.6% (20) 4.3% (34) Fall 2.8% (43) 1.6% (9) 4.1% (32) Influenza 5.4% (84) 4.1% (23) 5.5% (43) Diarrhea 5.3% (82) 3.9% (22) 5.1% (40) Sinusitis 2.6% (40) 3.0% (17) 2.4% (19) Dizziness 2.5% (38) 1.4% (8) 3.7% (29) Urinary tract infection 5.2% (81) 5.5% (31) 6.2% (49) Gastroenteritis 2.4% (37) 0.7% (4) 2.8% (22) Bronchitis 5.2% (80) 5.2% (29) 4.7% (37) Nausea 2.4% (37) 0.9% (5) 2.5% (20) Myalgia 4.9% (76) 3.0% (17) 3.0% (24) Musculoskeletal pain 2.3% (36) 1.4% (8) 1.9% (15) Headache 4.8% (74) 1.8% (10) 5.6% (44) Osteoarthritis 2.3% (35) 2.1% (12) 3.0% (24) Back pain 4.7% (73) 5.0% (28) 6.0% (47) Contusion 2.3% (35) 1.2% (7) 0.8% (6) Arthralgia 4.5% (70) 3.2% (18) 6.0% (47) Angina pectoris 2.1% (32) 1.8% (10) 2.9% (23) Muscle spasms 3.7% (58) 2.8% (16) 3.2% (25) Depression 1.8% (28) 1.4% (8) 3.2% (25) Fatigue 3.0% (47) 3.0% (17) 3.8% (30) Pain in extremity 3.0% (46) 2.1% (12) 4.4% (35) Hypertension 3.5% (54) 2.0% (11) 3.4% (27) Non-cardiac chest pain 1.8% (28) 2.0% (11) 1.9% (15) Type 2 diabetes mellitus 1.7% (27) 2.5% (14) 1.3% (10) Rhinitis 1.4% (22) 1.2% (7) 2.2% (17) Atrial fibrillation 1.4% (22) 1.6% (9) 2.2% (17) 50

51 TEAEs of Interest Comparable in Patients With 2 Consecutive LDL-C <25 mg/dl % (n) of patients Alirocumab Alirocumab with Placebo All pts on background of maximally tolerated statin ± (n=1550) 2 consecutive (n=788) General allergic reaction events* 9.0% (140) 6.0% (34) 9.0% (71) Treatment-emergent local injection site reactions 5.8% (90) 3.7% (21) 4.3% (34) Neurological events 4.2% (65) 1.8% (10) 3.9% (31) All cardiovascular events 4.0% (62) 3.2% (18) 4.4% (35) Ophthalmological events 2.5% (38) 1.8% (10) 1.9% (15) Neurocognitive disorders 1.2% (18) 0.5% (3) 0.5% (4) Haemolytic anaemia Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients overall who completed W78 visit) * 1 alirocumab-treated patient diagnosed with Miller Fisher Syndrome at week 27 after typical prodromal gastroenteritis, he had a complete recovery following treatment discontinuation; at week 24 the patient had low LDL-C, reaching 1.5 mg/dl. Confirmed by adjudication. Adjudicated CV events include all CV AEs positively adjudicated. The adjudication categories are the following: CHD death, non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization, ischemia driven coronary revascularization procedure [PCI, CABG]. Company MedDRA Queries (CMQ).

52 Robinson JG et al. NEJM 2015; Mar 15

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54 Conclusions: ODYSSEY LONG TERM Consisted of 80% high CV risk patients and 20% of HeFH patients receiving max tolerated dose of statins (68% with previous CHD) 61% LDL C reduction vs. baseline (61.9% vs. placebo) starting from week 4 and maintained over time 80% of patients reached LDL-C<70mg/dL Reduction in LDL-C was seen across age, gender, body mass index (BMI), race, baseline LDL-C levels, patients with HeFH and non-hefh, and patients with mixed dyslipidemia, including diabetic patients TEAEs were generally comparable in both treatment arms and in 562 pts with confirmed low LDL-C (LDL-C < 25 mg/dl) vs. patients with LDL-C > 25 mg In a post-hoc analysis of a subgroup of adjudicated major adverse CV events, a lower rate of MACE was observed in the ALI arm compared to the PBO arm, HR=0.52 (95% CI 0.31 to 0.90, nominal P = 0.02)) 54

55 55 Ανεπιθύµητες ενέργειες στο ODYSSEY program

56 Safety Analysis (Pool of 4x Phase x Phase 3 trials*) % (n) of patients All pts on background statin Ezetimibe-controlled pool (N=1482) Alirocumab n=864 Ezetimibe n=618 Placebo-controlled pool (N=3752) Alirocumab n=2476 Placebo n=1276 TEAEs 70.3% (607) 68.1% (421) 75.8% (1876) 76.4% (975) Treatment-emergent SAEs 13.1% (113) 11.2% (69) 13.7% (340) 14.3% (182) TEAEs leading to death 0.2% (2) 1.1% (7) 0.5% (13) 0.9% (11) TEAEs leading to discontinuation 8.8% (76) 9.7% (60) 5.3% (131) 5.1% (65) Safety terms of interest Adjudicated CV events 3.1% (27) 1.9% (12) 3.6% (83) 3.5% (41) HLT: Injection site reactions 3.0% (26) 2.1% (13) 7.3% (180) 5.2% (66) CMQ: Neurocognitive disorders 0.9% (8) 1.0% (6) 0.8% (21) 0.7% (9) PCSA: ALT >3 x ULN 1.1% (9/850) 0.2% (1/612) 1.7% (41/2455) 1.4% (18/1266) 56 *Placebo-controlled studies: phase 3 (LTS11717, FH I, FH II, HIGH FH, COMBO I), phase 2 (DFI11565, DFI11566, CL-1003, DFI12361) Ezetimibe-controlled studies: phase 3 (COMBO II, MONO, OPTIONS I, OPTIONS II, ALTERNATIVE). Includes all data collected to last patient visit at 52 wks for COMBO, FH, HIGH FH and LONG TERM studies. Includes CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalization, Congestive heart failure requiring hospitalization, Ischemia driven coronary revascularization procedure. CMQ, Custom MedDRA Query; HLT, High-Level Term, PCSA, Potentially Clinically Significant Abnormalities.

57 TEAEs Occurring in 5% Patients in Any Group (Pool of 4x Phase x Phase 3 trials*) % (n) of patients All pts on background statin Ezetimibe-controlled pool (N=1482) Placebo-controlled pool (N=3752) TEAEs by preferred term in 5% patients Alirocumab n=864 Ezetimibe n=618 Alirocumab n=2476 Placebo n=1276 Nasopharyngitis 5.4% (37) 5.7% (35) 11.3% (279) 11.1% (141) Myalgia 6.7% (58) 7.6% (47) 4.2% (104) 3.4% (44) Upper respiratory tract infection 5.9% (51) 6.0% (37) 6.1% (152) 7.0% (89) Injection site reaction 2.9% (25) 1.9% (12) 6.7% (166) 4.8% (61) Influenza 3.7% (32) 2.3% (14) 5.7% (141) 4.6% (59) Headache 3.9% (34) 3.4% (21) 4.8% (119) 5.2% (66) 57 *Placebo-controlled studies: phase 3 (LTS11717, FH I, FH II, HIGH FH, COMBO I), phase 2 (DFI11565, DFI11566, CL-1003, DFI12361) Ezetimibe-controlled studies: phase 3 (COMBO II, MONO, OPTIONS I, OPTIONS II, ALTERNATIVE). Includes all data collected to last patient visit at 52 wks for COMBO, FH, HIGH FH and LONG TERM studies.

58 58