Inhibition de PCSK9 : Mecanisme et Impacts sur la Plaque d Atherome

Transcription

1 JPS, AE2BM 216 : Museum National d Histoire Naturelle, Paris Is there a clinical need Inhibition de PCSK9 : Mecanisme et Impacts sur la Plaque d Atherome for additional lowering agents? M. John Chapman BSc (Hons), Ph.D., D.Sc., FESC Director Emeritus, INSERM, Research Professor, University of Pierre and Marie Curie Past-President, European Atherosclerosis Society 215 Laureate, Antonio M Gotto International Prize for Atherosclerosis Research, International Atherosclerosis Society Pitié-Salpetriere University Hospital, Paris, France Recommendations for treatment targets for Is there a clinical need for additional lowering agents? Recommendations - ESC/EAS Guideline recommendations - Role of LDL in Plaque pathophysiology - Therapeutic impact of lowering - Current trans-european status of goal attainment in very high risk patients Class Level In patients at VERY HIGH CV risk (established CVD, type 2 diabetes, type 1 diabetes with target organ damage, moderate to severe CKD or a SCORE level 1%) the goal is < 1.8 mmol/l (less than 7 mg/dl) and/or 5% reduction when target level cannot be reached. I A In patients at HIGH CV risk (markedly elevated single risk factors, a SCORE level 5 to < 1%) an goal < 2.5 mmol/l (less than 1 mg/dl) should be considered. IIa A In subjects at MODERATE risk (SCORE level > 1 to 5%) an goal < 3. mmol/l (less than 115 mg/dl) should be considered. IIa C The correlation between and each index Marked Statin-mediated LDL lowering stops atherosclerosis progression 1-1 y=.3x-4.19 r=.39 p= Mean % atheroma volume (PAV) 95% CI -2% On'treatmentLDL'C(mg/dL) Nicholls et al. JAMA 27;297: % Change in Fibrous Volume Index (%) % Change in 6 8 Fibrous volume index 4 y= -.24x+1.2 r= -.38 P= % Change in Fujita Health University % Change in Lipid Volume Index 2 % -1% Lipid volume index 3 % Change in Fibrous Cap Thickness 1% ΔPAV Plaque volume index % Change in Plaque Volume Index 2% European Heart Journal (211) 32, y=.63x+8.68 r=.4 p= % Change in 6 8 Fibrous cap thickness y= -.46x r= -.4 p= % Change in 6 8 Hattori K, Ozaki Y et al. J Am Coll Cardiol Img 212;5:169 77

2 Very low levels are associated with plaque structural features consistent with enhanced stability Clinical benefit of lower is determined by absolute exposure to lower LDL <5mg/dL (87 plaques) 5 7mg/dL (81 plaques) P 7 1mg/dL >1mg/dL (117 plaques) (13 plaques) Plaque microstructures in lipid plaques (n=293) Fibrous cap ± ± ± ± thickness (µm) Plaque rupture, 1/42 2/46 7/91 12/ n (%) (2.3) (4.3) (7.6) (1.5) Thrombus, /42 1/46 2/91 3/ n (%) (.) (2.1) (2.1) (2.6) Proportional reduction in CHD risk (log scale) 3% 2% 1% PCSK9 rs NPC1L1 rs ABCG5/8 rs HMGCR rs12916 LDLR rs PCSK9 rs Genetically lower NPC1L1 score HMGCR score HMGCR score NPC1L1 score LDLR rs Combined NPC1L1 & HMGCR score A to Z GISSI-P SEARCH PCSK9 46L rs Pharmacologically lower IMPROVE-IT 54.5% reduction in CHD risk for each 1mmol/L (38mg/dL) lower ALLHAT-LLT 17.2% reduction in CHD risk for each 1mmol/L (38mg/dL) lower Plaque microstructure was more stable in statin-treated patients with lower levels Lower (mg/dl) Kataoka et al. Atherosclerosis 215;242: Ference et al. J Am Coll Cardiol 215;65: Coronary& Untreated& disease&&&death& coronary&disease& before&age&2& before&age&55/6& High%risk)pa,ents)with)HeFH) )do)not)a4ain)recommended)ldl%c)goals) Cumulative**(mmol) Homozygous FH 12.5yrs& Start&low& &dose& sta5n& Thresh old for CHD Start& high& dose& sta5n& Heterozygous FH 35yrs& 48yrs& 53yrs& Without FH / general population 55yr& Age in years Female sex Smoking Hypertensio n Diabetes Triglycerid es HDL-C Lipoprotei n(a) ANainmentoftarget(%) %achievedLDL'C<2.6mmol/L(1mg/ dl) OfthosenotachievingLDL'C<2.6mmol/L, 73%&werenotreceivingmaximallipid' loweringtherapy LDL'Ctarget(mmol/L) Nordestgaardetal,EHJ213;EASConsensusPanel Pijlmanetal.Atherosclerosis21;29: JUPITER reduction 2 mg rosuvastatin 46.3% > 5% 42.8% -5% 1.8% NO reduction PCSK9 antibodies Statins Atherogenic Dyslipidemia Ezetimibe ASO- apob1 MTP inhibitor Other nonstatin drugs... Fibrates, Niacin Resins Ridker et al, Europ Heart J, 216, in press Chapman,MJ. unpublished

3 What is PCSK9? Control of plasma LDL- cholesterol levels: Key role of the cellular LDL receptor DOMAINS I II III IV V VI VII EXONS Chromosome: 1p32.3 Gene: 12 exons cdna 3617 bp Protein: 692 amino acids Ligand binding (292 (292 aa) aa) Epidermal growth factor precursor homology (4 aa) NH 2 A B C NARC-1 : Neural apoptosis regulated convertase 1; neurogenesis Expressed in liver, kidney, intestine Undergoes autocatalytic cleavage in the ER to active conformation Appears to play the role of an intracellular protein chaperone [Accessed 19 July 211] Abifadel M, et al. Nature Genet 23;34: Horton JD, et al. Trends Biochem Sci 27;32:71 7. Abifadel M, et al. Hum Mutat 29;3:52 9. Chen SN, et al JACC 25;45: O-linked sugars (58 aa) Membranespanning (22 aa) Cytoplasmic (5 aa) COOH [Accessed 6 August 215] Control of hepatic LDL-Receptor activity PCSK9andtheLDLReceptor LigandJbinding& domain& - Intracellular levels of cholesterol (reflecting uptake of cholesterol contained in LDL, VLDL and chylomicron remnants, and HDL), endogenous cholesterol synthesis, cholesterol conversion to bile acids, and excretion of bile acids and biliary cholesterol) via the SREBP pathway - PCSK9 β& propeller& Prodomain& CarboxylJ terminus& LDLR& EGFJlike& repeats& Cataly5c& domain& PCSK9& HortonJD,etal.J"Lipid"Res.29;5:S172'S177. Role of PCSK9 in regulation of the surface expression of LDL receptors PCSK9 Inhibitors: From Target Discovery to Phase III to the Clinic LDL# particles# PCSK9&(NARCJ1)& discovered& PCSK9GOF muta^ons associatedwith ADH* PCSK9&LOF&Muta5ons&found&with& 28%&&LDLJC&and&88%&&CHD&risk& HumansnullforPCSK9have LDL'C~15mg/dL PlasmaPCSK9bindstoLDL'R First&Pa5ents& with&fh& /&nonjfh&treated& with&pcsk9i&mab& 1 st &FDA&/&EMEA& PCSK9i&filing& and&approval& LDL-R# PCSK9#routes## LDL-R#for## lysosomal## degradation# LDL-R# recycling# blocked# 23& 24& 25& 26& 27& 28& 29& 21& 211& 212& 213& 214 to& 216& Adenoviralexpressionin mice PCSK9&KO&mouse&LDLJC& First&subject&treated&with& PCSK9&mAb& "LDL'Cinmiceand non'humanprimatestreated withan^'pcsk9mab First& publica5on& POC&in& pa5ents& PCSK9#secretion# Chan#JC,#et#al."Proc#Natl#Acad#Sci#USA#29;16: " *ADH:AutosomalDominantHypercholesterolemia;SeidahNG.ProcNatlAcadSciUS23;1(3):928'33,AbifadelM.NatGenet23;34(2):154'6,MaxwellKN.ProcNatlAcadSci US24;11(18):71'5,RashidS.ProcNatlAcadSciUS25;12(15):5374'79,LagaceTAetal.JCI26;116:2995'35CohenJC.NEnglJMed26;354(12):1264'72,ZhaoZ.AmJ HumGenet26;79(3):514'23,HooperAJ.Atherosderosis27;193(2):445'8,ChanJC.ProcNatlAcadSciUS29;16(24):982'5:SteinetatNEnglJMed212;366:118'18; SteinmodifiedfromSwergold,Regeneron.

4 Evolocumab and Alirocumab Monoclonal antibodies to PCSK9 Bind and eliminate plasma PCSK9 as an Ab-Ag complex Monoclonal antibodies Evolocumab, (Amgen) Alirocumab, (Regeneron/Sanofi) Bococizumab (Pfizer) Fully human PCSK9 monoclonal antibodies Less likely to have immune side effects: Neutropenia Thrombocytopenia Hemolytic anemia Hypersensitivity reactions 2 Alirocumab: Dynamic Relationship Between mab Levels, PCSK9 and 2 Increased LDLR surface concentration PCSK9 LDLR LDLR recycling Free/total PCSK9 Conc. (ng/ml) Total alirocumab (ng/ml) X.1 Anti-PCSK9 mab Total alirocumab Free PCSK W Chan JC, et al. Proc Natl Acad Sci USA 29;16: global phase 3 trials including >23,5 patients across >2, study centers HeFH population HC in high CV risk population Add-on to max-tolerated statin (± other LMT) Add-on to max-tolerated statin (± other LMT) ODYSSEY COMBO I (NCT ; EFC11568) 7 mg/dl OR 1 mg/dl N=36; 12 months ODYSSEY FH II (NCT1795; CL1112) *ODYSSEY COMBO II (NCT ; EFC11569) 7 mg/dl OR 1 mg/dl N=25; 18 months 7 mg/dl OR 1 mg/dl N=66; 24 months Additional populations ODYSSEY MONO (NCT ; EFC11716) Patients on no background LMTs 1 mg/dl N=1; 6 months Patients with defined statin intolerance 7 mg/dl OR 1 mg/dl N=25; 6 months ODYSSEY CHOICE I (NCT ; CL138) 7 mg/dl OR 1 mg/dl N=7; 12 months 16 mg/dl N=15; 18 months Time (hours) PROFICIO:Evolocumab ODYSSEY CHOICE II (NCT223879; EFC13786) Patients not treated with a statin 7 mg/dl OR 1 mg/dl N=2; 6 months ODYSSEY OLE (NCT ; LTS 13463) Open-label study for FH from EFC 12492, CL 1112, EFC or LTS N 1; 3 months ODYSSEY LONG TERM (NCT157831; LTS11717) 7 mg/dl N=2,1; 18 months ODYSSEY OUTCOMES (NCT166342; EFC1157) 7 mg/dl N=18,; 64 months FH=familial hypercholesterolemia; HC=hypercholesterolemia; LMT=lipid-modifying therapy; OLE=open-label extension. *For the ODYSSEY COMBO II other LMT not allowed at entry. ClinicalTrials.gov. ODYSSEY Phase 3 Trials. Accessed February 12, 214. ODYSSEY OPTIONS I (NCT1734; CL111) Patients not at goal on moderate dose atorvastatin 7 mg/dl OR 1 mg/dl N=35; 6 months ODYSSEY OPTIONS II (NCT17353; CL1118) Patients not at goal on moderate dose rosuvastatin 7 mg/dl OR 1 mg/dl N=3; 6 months >35,&pa5ents& Combina^on therapy (n=631)& Monotherapy (n=411)& Sta^nintolerant ODYSSEY ALTERNATIVE (NCT179513; CL1119) ODYSSEY HIGH FH (NCT ; EFC12732) 1 Stein EA et al. New Engl J Med 212;366: ODYSSEY Phase 3 Clinical Trial Program ODYSSEY FH I (NCT ; EFC12492) 7 mg/dl OR 1 mg/dl N=471; 18 months mean % change Impact of an anti-pcsk9 monoclonal antibody on LDL-R expression (n=16)& Phase3 (n=267) (n=615)& (n=37)& (n=511)*& HeFH (n=168)& (n=331)& HoFH/SevereFH Phase&2/3& (n=58)& Phase&2/3& (n=3)& (n=114)& (n=3671)*& Long'term safetyandefficacy Open'label extension Atherosclerosis Secondary Preven^on Neurocogni^on (n=95)& Phase3 (n=97) Phase3 (n=27,564) Phase3 (n=1971)* Completed& HeFH,heterozygoushypercholesterolaemia;HoFH,homozygoushypercholesterolaemia.Clintrials.gov.*Amgendataonfile. trials&

5 SPIRE&Bococizumab&Clinical&Development&Programme) Unmet)Needs)in)the)Management)of)CVD)in)High)Risk)Pa,ents) EvolocumabQ2WorQM: consistentldl'creduc^onsacrossdifferentstudies SPIRE&(Studies&of&PCSK9&Inhibi5on&and&& the&reduc5on&of&vascular&events)&n=~3,& Evolocumabvsplacebo: consistentreduc^oninldl'c,q2wandqm Evolocumabvseze5mibe: consistentreduc^oninldl'c,q2wandqm SPIRE&Lipid&Lowering&Studies& SPIRE&HR&(n=3)& SPIRE&LDL&(n=1,932)& Onsta^n Onsta^n HighriskofCVevent HighriskofCVevent LDL'C 7or 1mg/dL LDL'C 7mg/dL SPIRE&CV&Outcome&Studies& SPIREJ1&(n=17,)& SPIREJ2&(n=9,)& HighRiskPrimaryand HighRiskPrimaryand SecondaryPreven^on SecondaryPreven^on LDL'C 7to<1mg/dL LDL'C 1mg/dLon onsta^ns(orsta^n sta^ns(orsta^nintolerant) intolerant) Treatment differencefor %change frombaseline inldl'c SPIRE&FH&(n=3)& HeFH(gene^cdiagnosisor SimonBroomeCriteria), LDL>7mg/dL SPIRE&SI&(n=15)& Sta^nintolerant LDL'C 7mg/dL SPIRE&LL&(n=69)& Onsta^n High/veryhighriskof CVevent LDL'C 1mg/dL Studies&on&PCSK9&Inhibi5on&and&the&& Reduc5on&of&Vascular&Events NCT#:hNps://clinicaltrials.gov SPIREHR:NCT SPIRELDL:NCT SPIREHF:NCT SPIRE'LL:NCT21514 SPIRE'SI:NCT SPIRE'1:NCT SPIRE'2:NCT Monotx MENDEL'2 N=614 Combotx LAPLACE'2 N=1896 HeFH RUTHERFORD'2 N=329 Evolocumab14mgQ2W LongTerm DESCARTES N=91 Monotx MENDEL'2 N=614 Evolocumab42mgQM Combotx LAPLACE'2 N=1896 SI GAUSS'2 N=37 Resultsareforthemeanofweeks1and12exceptforDESCARTES,whichareforweek52. MENDEL'2:KorenMJ,etal.JAmCollCardiol214;63:2531 4;LAPLACE'2:RobinsonJG,etal.JAMA214;311:187 82;RUTHERFORD'2:RaalFJ,etal. Lancet215;385:331 4;DESCARTES:BlomDJ,etal.NEnglJMed214;37:189 19;GAUSS'2:StroesE,etal.JAmCollCardiol214;63: RUTHERFORD-2: Goal Achievement < 1.8 mmol/l 66%* Week 12 61%* Weeks 1 and 12 65%* 79%* 8% Efficacy of lowering by Evolocumab in heterozygous FH patients : RUTHERFORD-2 Evolocumab 14 mg Q2W Evolocumab 42 mg QM Proportion of patients (%) 68% 63% 67% 2% 2% 2% 2% Placebo Q2W (N = 54) Evolocumab 14 mg Q2W (N = 11) Placebo QM (N = 55) Evolocumab 42 mg QM (N = 11) *P<.1 evolocumab treatment difference vs placebo. Raal FJ, et al. Lancet 214; doi.org/1.116/s (14) and supplementary material. Raal FJ, et al. Lancet 214; doi.org/1.116/s (14) and supplementary material. In addition to LDL.. Do other atherogenic lipoproteins contribute to atherosclerotic vascular disease and cardiovascular events? Do PCSK9 inhibitors impact such lipoproteins? TG-rich LPs; Remnants Lipoprotein& (a)&

6 Copenhagen&City&Heart&Study&and&Copenhagen&General&Popula5on&Study& Myocardial&infarc5on& N&=&96,394&(Events&=&3,287)& 6 Hazard&ra5o&(95%CI)& Nonfas5ng&triglycerides,&mmol/L& Nordestgaard"&"Varbo,"Lancet"214;"384:"626?635" Reduction in Lipoprotein(a) With Evolocumab: Analysis of > 1,3 Patients in 4 Phase II Trials Error bars represent standard error. * P <.1 No meaningful between-group imbalances in TEAEs Select TEAEs 2% incidence in any group in the pooled group and ODYSSEY LONG TERM (1) Primary system organ class, % (n) Preferred term, % (n) control (n=1894) alirocumab (n=334) <25 mg/ dl (n=796) <15 mg/ dl (n=288) LONG TERM <25 mg/dl (n=562) Infections and infestations 36.3 (687) 38.5 (1286) 34. (271) 35.4 (12) 39. (219) Nasopharyngitis 9.3 (176) 9.8 (326) 8.3 (66) 1.1 (29) 1. (56) Upper respiratory tract 6.7 (126) 6.1 (23) 4.5 (36) 5.2 (15) 5.7 (32) infection Urinary tract infection 4.1 (77) 4.1 (137) 4.6 (37) 4.9 (14) 5.5 (31) Influenza 3.9 (73) 5.2 (173) 3.6 (29) 4.2 (12) 4.1 (23) Bronchitis 3.3 (63) 3.8 (126) 4.4 (35) 3.1 (9) 5.2 (29) Sinusitis 2.7 (51) 2.6 (87) 2.6 (21) 3.1 (9) 3. (17) Lower respiratory tract 1.4 (26) 1.6 (53) 2. (16) 2.1 (6) 2.8 (16) infection Gastroenteritis 2.3 (43) 1.9 (62).6 (5) 1. (3).7 (4) Musculoskeletal and connective tissue disorders 25.2 (478) 24.2 (88) 21.1 (168) 2.1 (58) 22.6 (127) Back pain 4.3 (82) 4. (133) 4.3 (34) 4.2 (12) 5. (28) Arthralgia 5. (95) 4. (134) 3.1 (25) 2.1 (6) 3.2 (18) Myalgia 4.8 (91) 4.9 (162) 3.1 (25) 3.8 (11) 3. (17) Muscle spasms 2.4 (45) 2.8 (94) 2.5 (2) 3.5 (1) 2.8 (16) Pain in extremity 3.4 (64) 2.4 (81) 2.1 (17) 1.4 (4) 2.1 (12) Osteoarthritis 2.2 (42) 2.1 (69) 1.8 (14) 1. (3) 2.1 (12) Musculoskeletal pain 1.4 (27) 1.9 (65) 1. (8) 1. (3) 1.4 (8) Raal et al JACC 214;():. doi:1.116/j.jacc Online First 34 J.Robinsonetal.,N"Engl"J"Med"215March15;Epubaheadofprint No meaningful between-group imbalances in TEAEs Select TEAEs 2% incidence in any group in the pooled group and ODYSSEY LONG TERM (2) Alirocumab : TEAEs in Patients With 2 Consecutive <25 mg/dl Primary system organ class, % (n) 35 Preferred term, % (n) control (n=1894) alirocumab (n=334) <25 mg/ dl (n=796) <15 mg/ dl (n=288) LONG TERM LDL- C <25 mg/dl (n=562) Gastrointestinal disorders 16.8 (318) 17. (567) 12.7 (11) 1.1 (29) 13.7 (77) Diarrhea 3.9 (74) 4.3 (142) 3. (24) 1.4 (4) 3.9 (22) Nausea 2.5 (47) 2.2 (74).9 (7) 1. (3).9 (5) General disorders and administration-site conditions 14.9 (282) 15.1 (54) 1.2 (81) 6.9 (2) 11. (62) Injection-site reaction 3.9 (73) 5.7 (191) 3. (24) 3.5 (1) 3.6 (2) Fatigue 2.5 (48) 2.8 (93) 2.6 (21) 2.4 (7) 3. (17) Non-cardiac chest pain 1.8 (35) 1.6 (54) 1.8 (14).3 (1) 2. (11) Nervous system disorders 14.9 (283) 14.9 (497) 1.3 (82) 9. (26) 11.2 (63) Dizziness 3.6 (69) 3. (1) 1.8 (14) 1.4 (4) 1.4 (8) Headache 4.6 (87) 4.6 (153) 1.8 (14) 1.4 (4) 1.8 (1) Hemorrhagic stroke.1 (1).1 (2) Metabolism and nutrition disorders 6.3 (12) 6.9 (232) 7. (56) 7.3 (21) 8. (45) Type 2 diabetes mellitus.7 (14) 1.1 (36) 1.8 (14) 1.4 (4) 2.5 (14) Diabetes mellitus 1.3 (24) 1.2 (39) 1.5 (12) 2.4 (7) 1.4 (8) Eye disorders 3.7 (71) 4.6 (152) 5.3 (42) 6.9 (2) 6.4 (36) Cataract.9 (17).8 (26) 1.5 (12) 2.4 (7) 1.8 (1) Neoplasms benign, malignant and unspecified (incl. cysts and polyps) 2.5 (48) 2.5 (85) 2.8 (22) 2.4 (7) 3. (17) % (n) of patients All pts on background of maximally tolerated statin ± other lipid-lowering therapy J.Robinsonetal.,N"Engl"J"Med"215March15;Epubaheadofprint 36 Company MedDRA Queries (CMQ). Alirocumab (n=155) Alirocumab with 2 consecutive <25 mg/dl (n=562) Placebo (n=788) General allergic reaction events* 9.% (14) 6.% (34) 9.% (71) Treatment-emergent local injection site reactions 5.8% (9) 3.7% (21) 4.3% (34) Neurological events 4.2% (65) 1.8% (1) 3.9% (31) All cardiovascular events 4.% (62) 3.2% (18) 4.4% (35) Ophthalmological events 2.5% (38) 1.8% (1) 1.9% (15) Neurocognitive disorders 1.2% (18).5% (3).5% (4) Haemolytic anaemia Safety Analysis (at least 52 weeks for all patients continuing treatment, including 67 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, 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].

7 INTRODUCTORY GUIDE PCSK9 INHIBITION New Therapies in Cardiovascular Risk Reduction DOWNLOAD&& FREE&EJBOOK MEMBERSHIP&FREE&TO&ALL& HEALTHCARE&PROFESSIONALS& REGISTERNOW: Ongoing clinical trials.. GLAGOV: Study Design EBBINGHAUS: Evaluating PCSK9 Binding antibody Influence on cognitive HeAlth in high cardiovascular risk Subjects (FOURIER substudy) Screening and placebo run-in period Clinically indicated coronary angiogram IVUS based on coronary angiogram results SC injection of 3 ml placebo Up to 4-week lipid stabilization period Assigned to background statin therapy 2 4 weeks Randomization 1:1 to study drug Placebo SC every month Evolocumab 42 mg SC every month End Of Study Randomised into study FOURIER ~2, patients Excludes patients with current or known past diagnosis of dementia or mild cognitive impairment Randomisation Evolocumab SC Q2W or QM + effective statin dose Placebo Q2W or QM + effective statin dose Total follow-up 4 years Results before 217 Maximum 6 weeks D1 W4 W12 W24 W36 W52 W64 W76 Study visits: Study drug was administered monthly at home or in the clinic Last Last dose of IVUS Primary endpoint: 1,2 study procedure Nominal change in PAV from baseline to week 78 drug Key secondary endpoints: 1,2 Nominal change in TAV from baseline to week 78 Percentage of patients demonstrating regression (any reduction from baseline) in either PAV or TAV from baseline to week Puri R, et al. Am Heart J. doi: 1.116/j.ahj ClinicalTrials.gov. NCT Accessed March 15,216. W78 W8 EOS Ongoing trial to show effect of evolocumab on cognitive health (evaluated by Spatial Working Memory strategy index of executive function) EBBINGHAUS. term=ebbinghaus+and+evolocumab&rank=1. Accessed 1 Jan 216. Study Who? PCSK9 mab Outcomes Trials FOURIER Patients aged 4-85 with history of clinically evident CVD at high risk for recurrent event ODYSSEY OUTCOMES Patients aged 4 hospitalized for ACS recently (<52 weeks) SPIRE-1 SPIRE-2 Background lipid lowering treatment and at high risk of a CV event N 27,5 18, 17, 9 Primary endpt Time to CV death, MI, hospitalization for UA, stroke, or coronary revasc, whichever occurs first 7 mg/dl (or non- HDL-C 1 mg/ dl) Time to CHD death, any nonfatal MI, fatal and non-fatal ischemic stroke, hospitalization for UA 7 mg/dl Confirmed major cardiovascular event [CV death, non- fatal MI, non-fatal stroke, and hospitalization for UA needing urgent revascularization] 7 and <1 mg/ dl (or non-hdl-c 1 mg/dl and <13 mg/dl) 1 mg/dl (or non HDL C 13 mg/dl) & &Ques5ons& Which&dose,&which&periodicity&of&injec5on,& and&what&ldljc&level&bring&op5mal&clinical& benefit&?& Which&pa5ents&at&very&high&CV&risk&urgently& require&substan5al&addi5onal&ldljc&reduc5on& to&akain&an&ldljc&goal&of&<7&mg/dl&?& 41

8 Sustained PCSK9 inhibition gives stable reduction % Change from baseline Unbound PCSK9 % Change from baseline Time (Weeks) Time (Weeks) 28mg SC QM 42mg SC QM EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM pdf. Accessed 25 Feb 216.