ΝΕΑ ΦΑΡΜΑΚΑ ΓΙΑ ΤΗΝ ΑΝΤΙΜΕΤΩΠΙΣΗ ΤΩΝ ΔΥΣΛΙΠΙΔΑΙΜΙΩΝ

ΝΕΑ ΦΑΡΜΑΚΑ ΓΙΑ ΤΗΝ ΑΝΤΙΜΕΤΩΠΙΣΗ ΤΩΝ ΔΥΣΛΙΠΙΔΑΙΜΙΩΝ Ευάγγελος Λυμπερόπουλος Επίκουρος Καθηγητής Παθολογίας Ιατρικής Σχολής Παν/μίου Ιωαννίνων www.bpath.gr www.atherosclerosis.gr

LDL Receptor Function and Life Cycle 3 3

The Role of PCSK9 in the Regulation of LDL Receptor Expression 4 4

I. APOB ANTISENSE OLIGONUCLEOTIDE THERAPY

Mipomersen A 2 nd Generation Antisense Drug Gapmer design (to activate RNase H) 5 -wing G C C T C gap A G T C T G C T T C 3 -wing G C A C C MOE modification at ends DNA in middle Phosphorothioate throughout MOE DNA MOE 20 bases for high specificity and affinity Molecular model of mipomersen Phosphorothioate linkage MOE side chain 10

Raal FJ, et al. Lancet. 2010:375(9719):998-1006. HoFH

Raal FJ, et al. Lancet. 2010:375(9719):998-1006.

Mipomersen Significantly Reduced Apo B in HoFH Patients; absolute by 0.7 mmol/l (2.8 to 2.1 mmol/l) Reduction in Apo B over 28 weeks (full analysis set) PET 3% 27% 16 Raal FJ, et al. Lancet. 2010:375(9719):998-1006. CI, confidence interval; PET, primary efficacy time point, 2 weeks after final dose.

CS5 Mipomersen Significantly Reduced Lp(a) in HoFH Patients; Absolute by 0.2 g/l (0.6 to 0.4 g/l) Reduction in Lp(a) over 28 weeks (full analysis set) PET 8% 31% 17 Raal FJ, et al. Lancet. 2010:375(9719):998-1006. CI, confidence interval; PET, primary efficacy time point, 2 weeks after final dose.

Mipomersen significantly reduced LDL-C in statin-intolerant patients (approx. half were FH) 45%

ΑΝΕΠΙΘΥΜΗΤΕΣ ΕΝΕΡΓΕΙΕΣ 1) Αντιδράσεις στο σημείο της ένεσης (~100%, <5% διακοπή) 2) Γριππώδης συνδρομή (~33%, ~3% διακοπή) 3) Αύξηση τρανσαμινασών (10-20%)/ηπατική στεάτωση

ΕΓΚΡΙΣΕΙΣ FDA: Approved for homozygous FH with a warning for the possible clinical consequences of liver fat accumulation (January 2013) EMA: Not approved (March 2013)

II. MICROSOMAL TRANSFER PROTEIN (MTP) INHIBITORS

VLDL and Chylomicron Synthesis TG Liver Cell LIVER Apo B100 MTP Nascent VLDL VLDL Cytoplasm ER Lumen Blood Vessel LDL Intestinal Epithelial GUT Cell Hussain M, et al. J Lipid Res. 2003:44;22-32. 31 Apo B48 MTP Nascent Chylomicron Chylomicron TG Cytoplasm ER Lumen Chylomicron Remnant

MTP Inhibition Predicted to Reduce Production of Both Chylomicrons and VLDL Diet Source triglyceride cholesterol Liver Source triglyceride cholesterol Intestinal Cell MTP Apo B-48 Liver Cell MTP Apo B-100 Chylomicron Lomitapide Decreases Secretion into the Blood VLDL

Lomitapide, an MTP Inhibitor Once-a-day, orally-administered, small molecule drug Being developed as a potential treatment for homozygous familial hypercholesterolaemia (HoFH) Clinical development/experience Clinical experience with lomitapide: >900 patients Clinical trials were initially conducted in patients with mild-to-moderate hypercholesterolaemia Early studies at fixed doses led to a high rate of discontinuations due to gastrointestinal side effects Development was subsequently focused on HoFH 36

Phase 3 study in patients with HoFH: study design Run-in Period 5 mg Lomitapide Dose Escalation Concomitant LLTs Fixed 10 mg 20 mg 40 mg Efficacy Phase 60 mg Maintenance Dose of Lomitapide Alteration in Concomitant LLTs allowed Continue Maximum Tolerated Dose Safety Phase -6 0 2 6 10 14 26 56 78 Weeks Open label 78 week study in 29 patients with a clinical diagnosis of HoFH 6-week run-in phase to stabilize diet and background lipid-lowering therapy Dose escalated from 5 mg to maximum tolerated dose (MTD) during efficacy phase (26 weeks) Primary endpoint: change from baseline in LDL-C at week 26 Safety phase: weeks 26 78, to evaluate longer-term safety at MTD Low-fat diet (<20% energy as fat) throughout study; concomitant therapy fixed through week 26, with ability to change background therapy weeks 26 78 Cuchel et al. Lancet. 2012 online Nov 2. doi 10.1016/S0140-6736(12)61731 40

Mean % Change in TC, LDL-C, and Apo B Through the Efficacy Phase (ITT, LOCF) Mean Change from Baseline (%) Efficacy Phase 40% Study Week Rader DJ. J Clin Lipid. 2012:6(3): 282-3; Data on File, Aegerion Pharmaceuticals 41

Secondary Lipid Parameters Declined Through Week 56 (Completer Population, N=23) Mean % Change from Baseline (95% CI) Efficacy Phase Safety Phase Study Week CE-052

Attainment of LDL-C goals Patients achieving LDL-C goals of <100 mg/dl or 2.4mmol/L and <70 mg/dl or 1.8mmol/L Time Point <100 mg/dl <2.4mmol/L LDL-C <70 mg/dl <1.8mmol/L Baseline (N=29) 0 (0%) 0 (0%) At any time on treatment with lomitapide (N=29) 16 (55%) 9 (31%) Changes in apheresis 13 patients were receiving apheresis at the beginning of safety phase 6 patients (46%) had permanent changes to apheresis regimen 3 patients (23%) stopped apheresis permanently 3 patients (23%) permanently increased the interval between apheresis Rader DJ. J Clin Lipid. 2012:6:282 3; Data on File, Aegerion Pharmaceuticals 44

Phase 3 - Gastrointestinal Adverse Events (Safety Population, N=29) Efficacy Phase Safety Phase Data on File, Aegerion Pharmaceuticals Cuchel, M. et al. Lancet 2013; 381: 40-46. (published online: 02 November 2012) 2013 Aegerion Pharmaceuticals, Inc.

Peak aminotransferase levels in Phase 3 (safety population N=29) ALT and/or AST Levels Anytime During Lomitapide Treatment N=29 Efficacy Phase 0-26 Weeks N=29 Safety Phase From 26-56 Weeks N=23 Safety Phase From 56-78 Weeks N=23 2x ULN 15 (52%) 17 (59%) 16 (70%) 16 (70%) >2x ULN - 3 x ULN 4 (14%) 4 (14%) 3 (13%) 5 (22%) >3x ULN - 5 x ULN 6 (21%) 4 (14%) 2 (9%) 2 (9%) >5x ULN - 10 x ULN 3 (10%) 3 (10%) 2 (9%) 0 * ULN for ALT: 33 U/L (females); 40 U/L (males); ULN for AST: 36 U/L (females); 43 U/L (males) >10x ULN - 20 x ULN 1 (3%) 1 (3%) 0 0 ULN for ALT: 33 U/L (females); 40 U/L (males); ULN for AST: 36 U/L (females); 43 U/L (males). ALT/AST elevations >5 x ULN managed with dose interruptions/down titrations No discontinuations due to ALT/AST elevations No concomitant changes in bilirubin (No Hy s Law cases) or alkaline phosphatase Data on File, Aegerion Pharmaceuticals 47

Hepatic fat content as measured by NMRS: Lomitapide Phase 3 study N: Mean (%): Range (%): 22 0.97 0 to 3.8 21 8.32 0.8 to 33.6 20 6.97 0.4 to 37.7 20 7.80 0.6 to 19.0 48

LOJUXTA, Aegerion Pharmaceuticals Caps 5, 10, 20 mg APPROVED, 3 AUG 2013 50

III. PREPROTEIN CONVERTASE SUBTILISIN KEXIN-9 (PCSK-9) INHIBITORS

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.

Η ΕΠΑΝΑΣΤΑΣΗ ΤΗΣ ΔΗΜΙΟΥΡΓΙΑΣ ΜΟΝΟΚΛΩΝΙΚΩΝ ΑΝΤΙΣΩΜΑΤΩΝ ΕΝΑΝΤΙΟΝ ΤΗΣ PCSK9

Impact of an PCSK9 mab on LDL Receptor Expression For illustration purposes only mab 65 65

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 Stein modified from Swergold, Regeneron

EVOLOCUMAB (Repatha, AMGEN) Πλήρως ανθρώπινο μονοκλωνικό αντίσωμα που χορηγείται υποδόρια κάθε 2 ή 4 εβδομάδες με συσκευή έγχυσης μιας χρήσης (autoinjector)

PROFICIO Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations Combotherapy Monotherapy Statinintolerant HeFH HoFH Long-term safety and efficacy Open-label Extension Secondary Prevention Athero Phase 2 Phase 3 (N = 629) (N = 1,700) Phase 2 (N = 406) Phase 2 (N = 157) Phase 2 (N = 168) Phase 2/3 (N 67) Phase 2 (N = 1,400) Phase 3 (N = 905) Phase 3 (N = 300) Phase 3 (N = 600) Phase 3 (N = 300) Phase 2/3 (N = 125) Phase 3 (N 3,500) Phase 3 (N = 27,500) Phase 3 (N = 950) Phase 3 (N = 500)

MENDEL-2: Efficacy and Safety of Evolocumab (AMG 145) Monotherapy Compared With Ezetimibe and Placebo in Hypercholesterolemic Subjects: A Phase 3 Randomized Clinical Trial Michael J Koren, Pernille Lundqvist, Michael Bolognese, Joel M Neutel, Maria Laura Monsalvo, Jingyuan Yang, Jae B Kim, Rob Scott, Scott M Wasserman, Harold Bays for the MENDEL-2 Investigators Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy For Easing Lipid Levels-2 (NCT01763827) 29 Mar 2014, Featured Clinical Research Session 400, American College of Cardiology and J Am Coll Cardiol 2014;63:2531 40

Randomization End of study MENDEL-2: Study Design 140 mg evolocumab Q2W / placebo PO QD N = 153 Screening period with placebo injection 2:2:1:1:1:1 420 mg evolocumab QM / placebo PO QD N = 153 Placebo SC Q2W / 10 mg ezetimibe PO QD N = 77 Placebo SC QM / 10 mg ezetimibe PO QD N = 77 Placebo SC Q2W / placebo PO QD N = 76 Placebo SC QM / placebo PO QD N = 78* Biweekly SC administration: Monthly SC administration: Co-primary endpoints Percent change from baseline in LDL-C at Week 12 and mean of Weeks 10 and 12 *One patient was randomized but not dosed. Phone call for AEs, SAEs. AEs, adverse events; EOS, end of study; QD, daily; Q2W, biweekly; QM, monthly Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 Secondary endpoints At mean of Weeks 10 and 12 and at Week 12: Percent change from baseline in ApoB, ApoA-I, lipoprotein(a), TG, and HDL-C Percent of patients with LDL-C <70 mg/dl QM EOS Key safety endpoints Treatment-emergent and serious adverse events Muscle and hepatic enzyme elevations Anti-evolocumab antibodies Q2W EOS 73

Mean percent change in LDL-C from baseline MENDEL-2: Evolocumab Primary Endpoint Biweekly and Monthly Doses 10 0 10 20 30 40 50 60 Biweekly SC Monthly SC BL Day 1 Week 2 Week 4 Week 6 Week 8 Study Week Placebo (N = 76) Ezetimibe (N = 77) Evolocumab biweekly (N = 153) Placebo (N = 78) Ezetimibe (N = 77) Evolocumab monthly (N = 153) Evolocumab resulted in significant LDL-C reductions compared with ezetimibe* Biweekly: 39% and 39%, respectively Monthly: 40% and 38%, respectively Biweekly and monthly dosing regimens were clinically equivalent Week 10 Week 12 0.1% 1% 18% 19% 56% 57% Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. p values are multiplicity adjusted. *Average at Weeks 10 and 12 and Week 12; p<0.001 for both. BL, baseline 75

MENDEL-2: Safety and Tolerability Adverse events (AEs), n (%) Placebo (N = 154) Ezetimibe (N = 154) Evolocumab (N = 306) Treatment-emergent AEs 68 (44) 70 (45) 134 (44) Common treatment-emergent AEs* Headache Diarrhea Nausea Urinary tract infection Constipation Nasopharyngitis Upper respiratory infection Serious AEs 1 (1) 1 (1) 4 (1) AEs leading to study drug discontinuation 6 (4) 5 (3) 7 (2) Deaths 0 (0) 0 (0) 0 (0) Potential injection site reactions 8 (5) 7 (5) 16 (5) Muscle-related SMQ Myalgia Musculoskeletal pain Neurocognitive AEs 0 (0) 0 (0) 0 (0) CK >5 x ULN 2 (1) 0 (0) 2 (1) ALT or AST >5 x ULN 2 (1) 0 (0) 1 (0.3) Anti-evolocumab antibodies NA NA 0 4 (3) 6 (4) 1 (1) 2 (1) 4 (3) 3 (2) 4 (3) 6 (4) 3 (2) 2 (1) 5 (3) 3 (2) 3 (2) 3 (2) 1 (1) 6 (4) 5 (3) 5 (3) 3 (2) 1 (1) 10 (3) 9 (3) 8 (3) 7 (2) 6 (2) 6 (2) 5 (2) 8 (3) 3 (1) 3 (1) *Reported in 3% of patients in one or more treatment arms. Reported using high-level term grouping, which includes injection site (IS) rash, S inflammation, IS pruritus, IS reaction, and IS urticaria. Standard MedDRA Queries. Binding or neutralizing. 76

ΑΚΑΛΥΠΤΕΣ ΘΕΡΑΠΕΥΤΙΚΕΣ ΑΝΑΓΚΕΣ 1. ΠΟΛY ΑΥΞΗΜΕΝΑ ΑΡΧΙΚΑ ΕΠΙΠΕΔΑ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ (FH) 2. ΔΥΣΑΝΕΞΙΑ ΣΤΙΣ ΣΤΑΤΙΝΕΣ (ΜΥΟΠΑΘΕΙΑ) 3. ΑΣΘΕΝΕΙΣ ΠΟΛΥ ΥΨΗΛΟΥ ΚΙΝΔΥΝΟΥ: ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΩΝ ΚΑΙ ΥΠΟΛΕΙΠΟΜΕΝΟΣ ΚΙΝΔΥΝΟΣ

EVOLOCUMAB ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ ΟΙΚΟΓΕΝΗ ΥΠΕΡΧΟΛΗΣΤΕΡΟΛΑΙΜΙΑ

LDL-C: 154 mg/dl 69 mg/dl 60%

LDL-C: 347 mg/dl 243 mg/dl 420 mg/month s.c 30%

2. EVOLOCUMAB ΣΕ ΑΣΘΕΝΕΙΣ ΠΟΥ ΔΕΝ ΑΝΕΧΟΝΤΑΙ ΜΙΑ ΣΤΑΤΙΝΗ

Θεραπευτικές δυνατότητες σε ασθενείς με δυσανεξία στις στατίνες 1 2 3 4 5 Επιθετική υγιεινοδιαιτητική αγωγή Χορήγηση εζετιμίμπης (10 mg/ημέρα) Χορήγηση συνδυασμού εζετιμίμπης (10 mg/ ημέρα) με κολεσεβελάμη (3.8 g/ ημέρα). Η αναμενόμενη μείωση της LDL χοληστερόλης είναι 30%. Εναλλακτικά μπορεί να χορηγηθεί ο συνδυασμός εζετιμίμπης με φαινοφιμπράτη Ενδεχόμενη προσεκτική χορήγηση πραβαστατίνης 20 mg/ημέρα ή φλουβαστατίνης 40 mg/ημέρα Χορήγηση ροσουβαστατίνης 5 mg ή ατορβαστατίνης 10 mg ανά δεύτερη ημέρα ή δύο φορές την εβδομάδα ή μια φορά την εβδομάδα, σε συνδυασμό με εζετιμίμπη 6 7 Προσδιορισμός των επιπέδων της βιταμίνης 25(OH)D3 και υποκατάστασή της σε περιπτώσεις μειωμένων επιπέδων Χορήγηση τροφοφαρμάκων (ARMOLIPID, 1 δισκίο ημερησίως) σε ασθενείς που εμφανίζουν δυσανεξία στις στατίνες (ή δεν επιθυμούν να πάρουν αγωγή με στατίνη). Τα δισκία αυτά περιέχουν μεταξύ των άλλων κυρίως αντιοξειδωτικών ουσιών, μαγιά του κόκκινου ρυζιού (red yeast rice) που περιέχει μονακολίνες, ουσίες οι οποίες συσχετίζονται με τις στατίνες. Τα τροφοφάρμακα πρέπει να χορηγούνται με ιατρική συνταγή και υπό ιατρική παρακολούθηση Hellenic Journal of Atherosclerosis 2014;5(3): 151-163

GAUSS-2: A Phase 3 Double-blind, Randomized Study to Assess Safety and Efficacy of Evolocumab (AMG 145) in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of Statin Erik Stroes, David Colquhoun, David Sullivan, Fernando Civeira, Robert S Rosenson, Gerald F Watts, Eric Bruckert, Leslie Cho, Ricardo Dent, Beat Knusel, Allen Xue, Rob Scott, Scott M Wasserman, and Michael Rocco for the GAUSS-2 Investigators Goal Achievement after Utilizing an anti-pcsk9 antibody in Statin Intolerant Subjects-2 (NCT01763905) 30 Mar 2014, Late-breaking Clinical Trials Session 402, American College of Cardiology and J Am Coll Cardiol 2014;63:2541 8

Randomization 2:2:1:1 End of study GAUSS-2 Study Design Screening period Evolocumab 140 mg SC Q2W + placebo PO QD N = 103 Fasting LDL-C 5 10 days before randomization Evolocumab 420 mg SC QM + placebo PO QD N = 102 Subcutaneous injection of placebo Placebo SC Q2W + ezetimibe 10 mg PO QD Placebo SC QM + ezetimibe 10 mg PO QD N = 51 N = 51 Co-primary endpoints Percent change from baseline in LDL-C at mean of Weeks 10 and 12 and at Week 12 Secondary endpoints Change from baseline in ApoB, ApoA-I, lipoprotein(a), TG, and HDL-C Achievement of NCEP LDL-C targets Safety endpoints *Phone call for AEs, SAEs. AEs, adverse events; EOS, end of study; LDL-C, low-density lipoprotein cholesterol; SAEs, serious adverse events; SC, subcutaneous; TG, triglycerides PO, oral; Q2W, every 2 weeks (biweekly); QM, monthly 95

LDL-C: 195 mg/dl 95 mg/dl

GAUSS-2: Safety and Tolerability Adverse events (AEs), n (%) Ezetimibe (N = 102) Evolocumab (N = 205) Treatment-emergent AEs 74 (73) 135 (66) Common treatment-emergent AEs ( 5% of patients in either treatment arm) Headache Myalgia Extremity pain Muscle spasms Fatigue Nausea Diarrhea Paresthesia 9 (9) 18 (18) 1 (1) 4 (4) 10 (10) 7 (7) 7 (7) 5 (5) 16 (8) 16 (8) 14 (7) 13 (6) 9 (4) 9 (4) 5 (2) 2 (1) Serious AEs 4 (4) 6 (3) AEs leading to study drug discontinuation 13 (13) 17 (8) Deaths 0 0 Potential injection site reactions * 8 (8) 6 (3) Muscle-related SMQ 23 (23) 25 (12) Neurocognitive AEs 0 0 Anti-evolocumab antibodies NA 0 *Reported using high-level term grouping, including IS - rash, inflammation, pruritus, reaction, urticaria. Standard MedDRA Queries. Searched HLGT terms: deliria (incl confusion); cognitive and attention disorders and disturbances; dementia and amnestic conditions; disturbances in thinking and perception; mental impairment disorders. Binding or neutralizing; data missing for one patient. NA, not applicable 100

3. EVOLOCUMAB ΜΑΖΙ ΜΕ ΣΤΑΤΙΝΗ ΣΕ ΑΣΘΕΝΕΙΣ ΠΟΛΥ ΥΨΗΛΟΥ ΚΑΙ ΥΨΗΛΟΥ ΚΙΝΔΥΝΟΥ

(70 mg/dl) EUROASPIRE IV

Hazard ratio Distribution of achieved LDL-c levels (%) On-statin LDL-c levels and risk of major cardiovascular events 1.00 40 0.75 30 0.50 0.25 LDL-c levels Risk of major CV events 20 10 0 0 50 100 150 200 250 LDL-C (mg/dl) Boekholdt et al., JACC 2014 0

Hellenic Journal of Atherosclerosis 2014;5(3): 151-163 Αλγόριθμος φαρμακευτικής θεραπευτικής προσέγγισης ασθενών με δυσλιπιδαιμία ΔΥΣΛΙΠΙΔΑΙΜΙΑ* ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ** ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ ΤΗΣ ΣΤΑΤΙΝΗΣ*** ΦΥΣΙΟΛΟΓΙΚΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ HDL CHOL CHOL ΥΨΗΛΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΧΑΜΗΛΗ HDL CHOL ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ + ΦΑΙΝΟΦΙΜΠΡΑΤΗ ΣΤΑΤΙΝΗ + ω-3 ΛΙΠΑΡΑ ΟΞΕΑ ΣΤΑΤΙΝΗ + ΕΖΕΤΙΜΙΜΠΗ ΣΤΑΤΙΝΗ + ΚΟΛΕΣΕΒΕΛΑΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL, ΤΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΤΗΝ HDL CHOL ΜΕΓΙΣΤΟ ΚΑΡΔΙΑΓΓΕΙΑΚΟ ΟΦΕΛΟΣ *Αν τριγλυκερίδια νηστείας >500 mg/dl συνιστάται η άμεση χορήγηση μίας φιμπράτης ή/και ω-3 λιπαρών οξέων **Για την επίτευξη του στόχου της αγωγής συνιστάται η χορήγηση μιας στατίνης σε δόση που αναμένεται να επιτύχει το στόχο της θεραπείας ***Κάθε διπλασιασμός της δόσης μίας στατίνης οδηγεί σε 6% περαιτέρω ελάττωση της LDL CHOL

LAPLACE-2: A Phase 3, Double-blind, Randomized, Placebo and Ezetimibe Controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Combination With Statin Therapy in Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia Jennifer G Robinson, Bettina S Nedergaard, William J Rogers, Jonathan Fialkow, Joel M Neutel, David Ramstad, Ransi Somaratne, Jason C Legg, Patric Nelson, Rob Scott, Scott M Wasserman, and Robert Weiss, for the LAPLACE-2 Investigators LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined With Statin ThErapy 2 (NCT01763866) 30 Mar 2014, Late-breaking Clinical Trials Session 402, American College of Cardiology and JAMA 2014;311:1870 82

LAPLACE-2: Study Design Co-primary endpoints Percent change from BL in LDL-C at mean of Weeks 10 and 12 and at Week 12 Total N = 1896 Secondary endpoints Mean LDL-C change from BL at Weeks 10 and 12 and Week 12 Lipid change from BL Proportion of patients achieving LDL-C <70 mg/dl Eligibility: LDL-C at screening 150 mg/dl (3.9 mmol/l): no statin 100 mg/dl (2.6 mmol/l): non-intensive statin 80 mg/dl (2.1 mmol/l): intensive statin *1896 patients were randomized and received at least one dose of study drug. Three patients did not receive study drug. BL, baseline LDL-C, low-density lipoprotein cholesterol; PBO, placebo; EvoMab, evolocumab; EZE, ezetimibe; PO, oral; Q2W, biweekly; QM, monthly; QD, daily; SC, subcutaneous; W, week 108

Mean percent change from baseline in LDL-C and 95% CI LAPLACE-2: LDL-C Response at Mean of Weeks 10 and 12 Evolocumab Q2W & QM: 63 to 75% reductions in LDL-C versus placebo Ezetimibe: 19 to 32% reductions in LDL-C versus placebo LDL-C: 90 36 mg/dl LDL-C: 125 46 mg/dl Atorvastatin 80 mg Rosuvastatin 40 mg Atorvastatin 10 mg Rosuvastatin 5 mg Simvastatin 40 mg Placebo Q2W Placebo QM Ezetimibe QD + Placebo Q2W Ezetimibe QD + Placebo QM Evolocumab Q2W Evolocumab QM All treatment differences versus placebo and ezetimibe were statistically significant (p<0.001). Vertical lines represent 95% CIs. No notable differences were observed between the mean of Weeks 10 and 12 and Week 12 alone. LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly 110

LAPLACE-2: Safety and Tolerability n (%) Any statin + placebo (N = 558) Atorvastatin + ezetimibe (N = 221) Any statin + evolocumab (N = 1117) Treatment-emergent AEs 219 (39) 89 (40) 406 (36) Most common AEs* Back pain Arthralgia Headache Muscle spasms Pain in extremity 14 (3) 9 (2) 15 (3) 6 (1) 7 (1) 7 (3) 4 (2) 5 (2) 6 (3) 3 (1) 20 (2) 19 (2) 19 (2) 17 (2) 17 (2) Serious AEs 13 (2) 2 (1) 23 (2) AEs leading to study drug discontinuation 12 (2) 4 (2) 21 (2) Positively adjudicated CV events 2 (0.4) 2 (0.9) 5 (0.4) CK >5 x ULN 2 (0.4) 0 (0) 1 (0.1) ALT or AST >3 x ULN 6 (1) 3 (1) 4 (0.4) Potential injection site reactions 8 (1) 2 (1) 15 (1) Neurocognitive AEs Disturbance in attention Cognitive disorder Disorientation 0 (0) 0 (0) 0 (0) 1 (0.5) 1 (0.5) 1 (0.5) 0 (0) 0 (0) 1 (0.1) Post-baseline binding antibodies NA NA 1 (0.1) *Top five in evolocumab treatment group. Reported using high-level term groupings including IS - rash, inflammation, pruritus, reaction, urticaria. Searched HLGT terms: deliria (incl confusion); cognitive and attention disorders and disturbances; dementia and amnestic conditions; disturbances in thinking and perception; mental impairment disorders. Binding antibody was present at baseline and at the end of study. No neutralizing antibodies were detected. NA, not applicable 111

Hellenic Journal of Atherosclerosis 2014;5(3): 151-163 Αλγόριθμος φαρμακευτικής θεραπευτικής προσέγγισης ασθενών με δυσλιπιδαιμία ΔΥΣΛΙΠΙΔΑΙΜΙΑ* ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ** ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ ΤΗΣ ΣΤΑΤΙΝΗΣ*** ΦΥΣΙΟΛΟΓΙΚΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ HDL CHOL CHOL ΥΨΗΛΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΧΑΜΗΛΗ HDL CHOL ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ + ΦΑΙΝΟΦΙΜΠΡΑΤΗ ΣΤΑΤΙΝΗ + ω-3 ΛΙΠΑΡΑ ΟΞΕΑ ΣΤΑΤΙΝΗ + ΕΖΕΤΙΜΙΜΠΗ ΣΤΑΤΙΝΗ + ΚΟΛΕΣΕΒΕΛΑΜΗ ΣΤΑΤΙΝΗ + PCSK9 INHIBITOR ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL, ΤΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΤΗΝ HDL CHOL ΜΕΓΙΣΤΟ ΚΑΡΔΙΑΓΓΕΙΑΚΟ ΟΦΕΛΟΣ *Αν τριγλυκερίδια νηστείας >500 mg/dl συνιστάται η άμεση χορήγηση μίας φιμπράτης ή/και ω-3 λιπαρών οξέων **Για την επίτευξη του στόχου της αγωγής συνιστάται η χορήγηση μιας στατίνης σε δόση που αναμένεται να επιτύχει το στόχο της θεραπείας ***Κάθε διπλασιασμός της δόσης μίας στατίνης οδηγεί σε 6% περαιτέρω ελάττωση της LDL CHOL

ΜΑΚΡΟΧΡΟΝΙΑ ΧΟΡΗΓΗΣΗ EVOLOCUMAB

Randomization 2:1 End of Study OSLER Study Design 12-week studies: MENDEL (monotherapy) LAPLACE-TIMI 57 (patients on statins) GAUSS (statin intolerance) RUTHERFORD (Familial hyper-cholesterolemia) Blinded Stabilization Period Year 1 Years 2 5 Standard of Care N = 368 Evolocumab + Standard of Care N = 736 Unblinded Lipid Treatment Evolocumab + Standard of Care 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 117

UC LDL-C Percentage Change from Baseline to Week 52, Mean (SE) OSLER: Percentage Change in LDL-C, by UC, From Baseline to 1 Year 10 0-10 -20-30 -40-50 -60-2% -3% -52% -52% Baseline Parent Study Week 12 12 24 36 48 52 OSLER Study Week 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 118

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< 0.001 120

DESCARTES: Long-term Tolerability and Efficacy of Evolocumab (AMG 145) in Hyperlipidemic Subjects: A 52 Week Phase 3 Double-blind, Randomized, Placebocontrolled Study Dirk J. Blom, Tomas Hala, Michael Bolognese, Michael J Lillestol, Phillip D Toth, Lesley Burgess, Richard Ceska, Eli Roth, Michael J Koren, Christie M Ballantyne, Maria Laura Monsalvo, Kate Tsirtsonis, Jae B Kim, Rob Scott, Scott M Wasserman, and Evan A Stein, for the DESCARTES Investigators Durable Effect of PCSK9 antibody CompARed with placebo Study (NCT01516879) 29 Mar 2014, Featured Clinical Research Session 400, American College of Cardiology and N Engl J Med 2014;370:1809 19

Randomization 2:1 End of study DESCARTES: Study Overview Screening (n = 2120) Assign background Rx based on CV risk, LDL, and +/- prior statin*: 1. No drug 2. Low dose: 10 mg atorvastatin 3. High dose: 80 mg atorvastatin 4. Maximal: 80 mg atorvastatin + 10 mg ezetimibe Lipid stabilization period (n = 1485) Fasting LDL-C 5 10 days before randomization CHD/risk equivalent: LDL <100 mg/dl or No CHD/risk equivalent: LDL <130 mg/dl or On maximal background therapy Placebo SC QM n = 303 Evolocumab 420 mg SC QM n = 602 Period = max. 16 weeks/ min. 4 weeks Visits: Day 1 Week 4 Week 8 Week 52 Evolocumab/placebo once every 4 weeks: Primary endpoint % change from baseline in UC LDL-C at Week 52 *Run-in treatment was tailored in accordance with CV risk; Last dose administered at Week 48. Secondary endpoints LDL-C % change from baseline at Week 12 LDL-C change from baseline at Week 52 % patients achieving <70 mg/dl LDL-C target at Week 52 % changes from baseline for TC, HDL-C, non-hdl-c, ApoB, VLDL- C, triglycerides, and Lp(a) at Week 52 % changes in total cholesterol/hdl cholesterol ratio and apolipoprotein B/apolipoprotein A1 ratio at Week 52 123

Mean Percent Change in UC LDL-C DESCARTES: % Change in UC LDL-C from Baseline at Week 52 20 10 Overall (N=901) Diet Alone (N=111) Atorvastatin 10 mg (N=383) Atorvastatin 80 mg (N=218) Atorvastatin 80 mg + Ezetimibe 10 mg (N=189) 0-10 -20-30 -40-50 -60-70 Placebo Evolocumab Treatment Difference 6.8% increase from baseline in LDL-C observed in placebo group (n=302) 50.1% decrease from baseline in LDL-C observed in evolocumab group (n=599)* 57% treatment difference Error bars represent standard error for treatment difference. Treatment difference are least squares mean derived from a repeated measures model. *Average of all evolocumab patients. UC, ultracentrifugation 125

Hellenic Journal of Atherosclerosis 2014;5(3): 151-163 Αλγόριθμος φαρμακευτικής θεραπευτικής προσέγγισης ασθενών με δυσλιπιδαιμία ΔΥΣΛΙΠΙΔΑΙΜΙΑ* ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ** ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ ΤΗΣ ΣΤΑΤΙΝΗΣ*** ΦΥΣΙΟΛΟΓΙΚΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ HDL CHOL CHOL ΥΨΗΛΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΧΑΜΗΛΗ HDL CHOL ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ + ΦΑΙΝΟΦΙΜΠΡΑΤΗ ΣΤΑΤΙΝΗ + ω-3 ΛΙΠΑΡΑ ΟΞΕΑ ΣΤΑΤΙΝΗ + ΕΖΕΤΙΜΙΜΠΗ ΣΤΑΤΙΝΗ + ΚΟΛΕΣΕΒΕΛΑΜΗ ΣΤΑΤΙΝΗ + PCSK9 INHIBITOR ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL, ΤΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΤΗΝ HDL CHOL ΤΗΝ LDL CHOL ΜΕΓΙΣΤΟ ΚΑΡΔΙΑΓΓΕΙΑΚΟ ΟΦΕΛΟΣ *Αν τριγλυκερίδια νηστείας ΣΤΑΤΙΝΗ >500 mg/dl + συνιστάται EZETIMIBE η άμεση χορήγηση μίας φιμπράτης ή/και ω-3 λιπαρών οξέων **Για την επίτευξη του στόχου της αγωγής συνιστάται η χορήγηση μιας στατίνης σε δόση που αναμένεται να επιτύχει το στόχο της θεραπείας ***Κάθε διπλασιασμός της δόσης μίας στατίνης + οδηγεί σε 6% περαιτέρω ελάττωση της LDL CHOL PCSK9 INHIBITOR

ALIROCUMAB (Praluent, SANOFI-REGENERON) Πλήρως ανθρώπινο μονοκλωνικό αντίσωμα που χορηγείται υποδόρια κάθε 2 εβδομάδες με συσκευή έγχυσης μιας χρήσης (autoinjector)

ALIROCUMAB 72.4%

Τα Δεδομένα της φάσης 2 καθορίζουν την επιλογή της δόσης της φάσης 3: Παρατεταμένη και συνεπής μείωση της LDL-C 57 75 mg και 150 mg Q2W Τα 150 mg έδειξαν ~ 70% μείωση της LDL-C στη φάση 2 Αυτό το μοντέλο δείχνει ότι τα 75 mg αναμένεται να παρέχουν ~ 50% μείωση της LDL-C Δυνατότητα τιτλοποίησης Η τιτλοποίηση παρέχει τη δυνατότητα προσαρμογής της δόσης για την επίτευξη των στόχων των μεμονωμένων ασθενών 1 ml όγκου υποδόρια, συσκευή έγχυσης μιας χρήσης (autoinjector) αξιολογείται στη φάση 3 134

Επισκόπηση του προγράμματος Κλινικών δοκιμών ODYSSEY φάσης 3 12 παγκόσμιες κλινικές δοκιμές φάσης 3 Συμπεριλαμβάνουν περισσότερους από 23.500 ασθενείς σε περισσότερα από 2.000 κέντρα μελέτης Πληθυσμός HeFH Προσθήκη σε μέγ. ανεκτή δόση στατίνης (± άλλες θεραπείες τροποποίησης των λιπιδίων-lmt) ODYSSEY FH I (EFC12492) N=471 LDL-C 70 mg/dl ή LDL-C 100mg/dL 18 μήνες ODYSSEY FH II (CL1112) N=250 LDL-C 70 mg/dl ή LDL-C 100mg/dL 18 μήνες HC σε πληθυσμό που διατρέχει υψηλό κίνδυνο CV Προσθήκη σε μέγ. ανεκτή δόση στατίνης (± άλλες LMT) ODYSSEY COMBO I (EFC11568) N=306 LDL-C 70 mg/dl Ή LDL-C 100 mg/dl 12 μήνες *ODYSSEY COMBO II (EFC11569) N=660 LDL-C 70 mg/dl Ή LDL-C 100 mg/dl 24 μήνες Πρόσθετοι πληθυσμοί ODYSSEY MONO (EFC11716) N=100 Ασθενείς χωρίς ιστορικό LMT LDL-C 100 mg/dl 6 μήνες ODYSSEY ALTERNATIVE (CL1119) N=250 Ασθενείς με καθορισμένη δυσανεξία στη στατίνη LDL-C 70 mg/dl Ή LDL-C 100 mg/dl 6 μήνες ODYSSEY HIGH FH (EFC12732) N=105 LDL-C 160 mg/dl 18 μήνες ODYSSEY CHOICE (CL1308) N=700 LDL-C 70 mg/dl Ή LDL-C 100 mg/dl 12 μήνες ODYSSEY LONG TERM (LTS11717) N=2,100 LDL-C 70 mg/dl 18 μήνες ODYSSEY OPTIONS I (CL1110) N=350 Ασθενείς όχι σε στόχο σε μέτρια δόση ατορβαστατίνης LDL-C 70 mg/dl Ή LDL-C 100 mg/dl 6 μήνες ODYSSEY OUTCOMES (EFC11570) Ν = 18.000 LDL-C 70 mg/dl, συμβάν οξέος στεφανιαίου συνδρόμου (ACS) 4 έως 52 εβδομάδες πριν από τυχαιοποίηση, μέγιστη ανεκτή δόση στατινών ή άλλο LMT HC = υπερχοληστερολαιμία, LMT = θεραπεία τροποποίησης των λιπιδίων *Για την ODYSSEY COMBO II δεν επιτρέπεται άλλο LMT κατά την εισαγωγή ODYSSEY OPTIONS II (CL1118) N=300 Ασθενείς όχι σε στόχο σε μέτρια δόση ροσουβαστατίνης LDL-C 70 mg/dl Ή LDL-C 100 mg/dl 6 μήνες http://www.odysseytrials.com/web/

ALIROCUMAB ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ ΟΙΚΟΓΕΝΗ ΥΠΕΡΧΟΛΗΣΤΕΡΟΛΑΙΜΙΑ

OLE/8 week FU ODYSSEY FH I and FH II Study Design Double-Blind Treatment Period (78 Weeks) HeFH patients on max tolerated statin ± other lipid-lowering therapy 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 Alirocumab 75 mg Q2W SC with potential to 150 mg Q2W SC (single 1-mL injection using prefilled pen for self-administration) n=323 (FH I); n=167 (FH II) n=163 (FH I); n=82 (FH II) Placebo Q2W SC Per-protocol dose possible based on prespecified LDL-C level Assessments W0 W8 W16 W36 W64 W4 W12 W24 W52 W78 Dose if LDL-C >70 mg/dl at W8 Primary efficacy endpoint Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W78 (all patients at least W52) 137 Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT01623115; ODYSSEY FH II: NCT01709500.

LS mean (SE) % change from baseline to Week 24 Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background max-tolerated statin ±other lipid-lowering therapy FH I LDL-C: 155 77 mg/dl FH II Alirocumab Placebo N=322 N=163 N=166 N=81 43.4% had dose increase at W12 38.6% had dose increase at W12 LS mean difference (SE) vs. placebo: 57.9% (2.7) P<0.0001 51.4% (3.4) P<0.0001 138 Intent-to-treat (ITT) Analysis

Safety Analysis (Pooled Data from FH I and FH II) All Data Collected Until Last Patient Visit at Week 52 % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Alirocumab (N=489) Placebo (N=244) TEAEs 74.8% (366) 75.4% (184) Treatment-emergent SAEs 10.0% (49) 9.0% (22) TEAEs leading to death 0.8% (4) 0 TEAEs leading to discontinuation 3.1% (15) 3.7% (9) Adverse Events of Interest Adjudicated CV events 1.6% (8) 1.2% (3) Injection-site reactions 11.5% (56) 9.0% (22) Neurocognitive disorders 0.2% (1) 1.2% (3) ALT >3 x ULN 2.1% (10/488) 1.2% (3/244) Creatine kinase >3 x ULN 3.5% (17/483) 6.2% (15/243) 141 4 TEAE-related deaths were all in alirocumab arm, 2 due to metastatic cancer (non-small cell lung and pancreatic), 2 due to MI (1 acute, 1 sudden cardiac death) Adjudicated CV events include all CV AEs positively adjudicated. The adjudication categories are the following: CHD death, non-fatal MI, fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalisation, congestive heart failure requiring hospitalisation, ischaemia-driven revascularisation procedure (PCI, CABG). Statistical analyses have not been performed.

OLE/8 week FU ODYSSEY HIGH FH Study Design Double-Blind Treatment Period (78 Weeks) All patients on background maximally tolerated statin ± other LLT HeFH patients on maximally tolerated statin ± other LLT N=72 Alirocumab 150 mg Q2W SC (single 1 ml injection using prefilled pen for self-administration) R LDL-C 160 mg/dl N=35 Placebo Q2W SC Assessments W0 W8 W16 W36 W64 W4 W12 W24 W52 W78 142 Primary efficacy endpoint Pre-specified analysis Efficacy: All patients to Week 52 Safety: Baseline-Week 78 (at least 52 weeks for all patients continuing treatment) Clinicaltrials.gov identifier: ODYSSEY HIGH FH NCT01617655. FU, follow-up; HeFH, heterozygous familial hypercholesterolemia; LLT, lipid-lowering therapy; OLE, open-label extension.

LS mean (SE) % change from baseline to Week 24 Significant Alirocumab Reductions in LDL-C at Week 24 Confirmed in Sensitivity Analysis Primary endpoint: % change from baseline to Week 24 in calculated LDL-C All patients on background max-tolerated statin ±other LLT ITT Sensitivity analysis* N=71 N=35 N=62 N=31 Absolute reduction of 15.5 (9.5) mg/dl 188 113 mg/dl Alirocumab Placebo Absolute reduction of 90.8 (6.7) mg/dl P<0.0001 143 LS mean % difference 39.1 (6.0) 48.0 (5.8) (SE) versus placebo: *Sensitivity analysis excludes 13 patients from two sites with serious GCP non-compliance.

2. ALIROCUMAB ΣΕ ΑΣΘΕΝΕΙΣ ΠΟΥ ΔΕΝ ΑΝΕΧΟΝΤΑΙ ΜΙΑ ΣΤΑΤΙΝΗ

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 N=100 N=50 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 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 tolerate *Unable at least to tolerate two different at least statins, two different including statins, one at including the lowest one dose, at the due lowest to muscle-related dose, due to muscle-related symptoms symptoms 147 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.

LS mean (SE) % change from baseline to Week 24 Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Ezetimibe % change from baseline to Week 24 in LDL-C ITT (primary endpoint) On-treatment (key secondary endpoint) n=126 49.5% received 150 mg Q2W at W12 n=122 n=123 n=118 200 157 mg/dl Absolute change of -33 (4.2) mg/dl Absolute change of -38 (4.2) mg/dl Alirocumab Ezetimibe 148 Absolute change of -84 (4.1) mg/dl LS mean difference (SE) vs ezetimibe: -30.4 (3.1); P<0.0001 Absolute change of -96 (3.9) mg/dl 200 92 mg/dl 49.5% of 109 patients who received at least one injection after Week 12 had dose increase. LS mean difference (SE) vs ezetimibe: -35.1 (2.8); P<0.0001

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 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Atorvastatin Ezetimibe Alirocumab 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 4 8 12 16 20 24 28 32 36 Week 153 Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue. ALI, alirocumab; ATV, atorvastatin, EZE, ezetimibe.

3. ALIROCUMAB ΜΑΖΙ ΜΕ ΣΤΑΤΙΝΗ ΣΕ ΑΣΘΕΝΕΙΣ ΠΟΛΥ ΥΨΗΛΟΥ ΚΑΙ ΥΨΗΛΟΥ ΚΙΝΔΥΝΟΥ

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) Ezetimibe 10 mg/day PO + placebo Q2W SC Per-protocol dose possible based on prespecified LDL-C level 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) 157 Other LLT not allowed. Clinicaltrials.gov identifier: NCT01644188.

LS mean (SE) % change from baseline to Week 24 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 n=467 n=240 18.4% had dose increase at W12 109 83 mg/dl Alirocumab Ezetimibe LS mean difference (SE) vs. ezetimibe: 29.8% (2.3); P<0.0001 158 Intent-to-treat (ITT) analysis 109 55 mg/dl

ODYSSEY LONG TERM Study Design HeFH or High CV-risk patients On max-tolerated statin other lipid-lowering therapy LDL-C 1.81 mmol/l [70 mg/dl] Assessments R W0 n=1553 n=788 W4 W8 W12 Double-blind treatment (18 months) Alirocumab 150 mg Q2W SC (single 1-mL injection using prefilled syringe for self-administration) Placebo Q2W SC W16 W24 W36 W52 W64 W78 Follow-up (8 weeks) Primary efficacy endpoint Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W78 (all patients at least W52) 166 86% (2011/2341) 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) ClinicalTrials.gov identifier: NCT01507831.

Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo LS mean (SE) % change from baseline to Week 24 Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background of maximally-tolerated statin ± other lipid-lowering therapy N=1530 N=780 Alirocumab Placebo 123 53 mg/dl 168 Intent-to-treat (ITT) analysis LS mean difference (SE) versus placebo: 61.9% (1.3); P<0.0001

LS mean (SE) % change from baseline to Week 24 Significant Reductions in Secondary Lipid Parameters at Week 24 All patients on background of maximally-tolerated statin ± other lipid-lowering therapy Alirocumab Placebo Non-HDL-C Apo B Lp(a) LS mean difference versus placebo: 52% P<0.0001 54% P<0.0001 26% P<0.0001 171 Adjusted mean (SE) shown for Lp(a).

Adverse Events of Special Interest Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Treatment-emergent local injection site reactions Alirocumab (n=1550) Placebo (n=788) 5.8% (90) 4.3% (34) General allergic reaction events 9.0% (140) 9.0% (71) All cardiovascular events 4.0% (62) 4.4% (35) Neurological events 4.2% (65) 3.9% (31) Neurocognitive disorders 1.2% (18) 0.5% (4) Ophthalmological events 2.5% (38) 1.9% (15) Haemolytic anaemia 0 0 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 hospitalisation, congestive heart failure requiring hospitalisation, ischemia driven coronary revascularisation procedure [PCI, CABG]. Company MedDRA Queries (CMQ). 177 Statistical analyses have not been performed.

LDL ΧΟΛΗΣΤΕΡΟΛΗΣ ΜΕ ANTI-PCSK9 ΚΑΡΔΙΑΓΓΕΙΑΚΟΥ ΚΙΝΔΥΝΟΥ?

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

No health problem

Control Atorvastatin Alirocumab 10 mg/kg Alirocumab 10 mg/kg + Atorvastatin 194

ALIROCUMAB 52 ALIROCUMAB

LATEST UPDATE

Estimated probability of event ODYSSEY LONG TERM: Post-hoc Adjudicated Cardiovascular TEAEs Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) 0.10 0.08 0.06 0.04 Placebo + max-tolerated statin ± other LLT Alirocumab + max-tolerated statin ± other LLT Cox model analysis: HR=0.46 (95% CI: 0.26 to 0.82) Nominal p-value = <0.01 123 48 mg/dl Mean treatment duration: 65 weeks 54% 0.02 No. at Risk Placebo Alirocumab 0.00 0 788 1550 12 776 1534 24 731 1446 36 703 1393 48 682 1352 60 667 1335 72 321 642 84 127 252 96 0 0 Weeks 200 Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy

120 48 mg/dl 53%

55% 50%

ΠΕΡΙΟΡΙΣΜΟΙ ΤΗΣ ΘΕΡΑΠΕΙΑΣ 1. ΑΝΑΓΚΗ ΥΠΟΔΟΡΙΑΣ ΧΟΡΗΓΗΣΗΣ ( 1 ΦΟΡΑ ΤΟΝ ΜΗΝΑ ΜΕ ΕΙΔΙΚΗ ΣΥΣΚΕΥΗ) ( ΣΥΜΜΟΡΦΩΣΗ) 2. ΚΟΣΤΟΣ ΘΕΡΑΠΕΙΑΣ (~1000 /μήνα)

IV. CHOLESTEROL ESTER TRANSFER PROTEIN (CETP) INHIBITORS

ΣΥΜΠΕΡΑΣΜΑ ΣΤΑ ΕΠΟΜΕΝΑ ΧΡΟΝΙΑ ΘΑ ΖΗΣΟΥΜΕ ΜΙΑ ΕΠΑΝΑΣΤΑΣΗ ΣΤΗ ΘΕΡΑΠΕΙΑ ΤΗΣ ΔΥΣΛΙΠΙΔΑΙΜΙΑΣ ΚΑΙ ΤΗΝ ΚΑΡΔΙΑΓΓΕΙΑΚΗ ΠΡΟΛΗΨΗ ΑΝΤΙΣΤΟΙΧΗ (ΑΝ ΟΧΙ ΜΕΓΑΛΥΤΕΡΗ) ΑΥΤΗΣ ΤΩΝ ΣΤΑΤΙΝΩΝ