Come cambia l approccio clinico alla dislipidemia con le evidenze degli inibitori del PCSK9

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1 Come cambia l approccio clinico alla dislipidemia con le evidenze degli inibitori del PCSK9 Gian Piero Perna Dipartimento Scienze Cardiovascolari Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona

2 Conflitto di interesse Nessuno Livello A per potenziale conflitto di interesse nella attività di Consultant AIFA ( )

3 The relationship between mean LDL-C and change in percent atheroma volume (PAV) in IVUS studies 2 Change in Percent Atheroma Volume* (%) REVERSAL 5 atorvastatin ASTEROID 3 rosuvastatin ACTIVATE 1 placebo Mean LDL-C (mg/dl) CAMELOT 4 placebo A-Plus 2 placebo REVERSAL 5 pravastatin Progression Regression ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin therapies but included placebo arms who received background statin therapy (62%, 80% and 84% respectively). *Median change in PAV from ASTEROID and REVERSAL; LS mean change in PAV from A-PLUS, ACTIVATE AND CAMELOT 1 Nissen S et al. N Engl J Med 2006;354: Tardif J et al. Circulation 2004;110: Nissen S et al. JAMA 2006;295 (13): Nissen S et al. JAMA 2004;292: Nissen S et al. JAMA 2004; 291:

4 The Lower The Better Even Lower even better

5 Logit of the primary endpoint IMPROVE-IT: Reduction of LDL-C below vs above 50 mg/dl reduces CV risk by a further 10% <50 vs 50 mg/dl Adjusted* HR 0.90 ( ) p= Very High Risk Patients LDL-C (mg/dl) at Month 1 *Model covariates: age, BMI, sex, race, region, Hx diabetes, current smoker, Hx hypertension, Hx MI, Hx PCI BMI, body mass index; HR, hazard ratio; Hx, family history of; MI, myocardial infarction; PCI, percutaneous coronary intervention. Guigliano RP, et al. Presented at European Society of Cardiology, London,

6 OMT : Lifestyle and pharmacological interventions that lower the risk of death, MACE and MI With Revascularization Without Revascularization Disease-modifying medication GP Perna Syntax Study ; Iqbal et al, Circulation 2015

7 Patient Populations with an Unmet Need for Additional LDL-C Lowering 7 Familial Hypercholesterolemia Genetic disorder High risk of early CHD HeFH prevalence 1:200 to 1:250 1,2 Untreated LDL-C of mg/dl 3 High / Very High CV Risk Population Previous MI / stroke / CVD or multiple CV risk factors incl. T2DM Difficult to achieve LDL-C goals, despite current therapies 5 Statin-Intolerant Population 10-15% on high-intensity statins show intolerance 6 Many discontinue due to muscle pain and/or weakness 79% with HeFH not at goal (<100 mg/dl [2.6 mmol/l]) 4 20% with CHD not at goal (<100 mg/dl [2.6 mol/l]) 59% at very high CV risk not at goal (<70 mg/dl [1.8 mmol/l]) Nearly all patients who need considerable LDL-C reductions will not reach goal Nordestgaard et al. Eur Heart J 2013;34: Sjouke et al. Eur Heart J Mar 1;36(9): ESC/EAS Guidelines for the management of dyslipidaemias Eur Heart J. 2011;32(14): Pijlman et al. Atherosclerosis 2010;209: Virani et al. Am Heart J 2011;161: Arca et al. Diabetes Metab Syndr Obes 2011;4:

8 d azione complementare Meccanismi d azione: Diversi Complementari Non DDI Sommatori sugli effetti farmacologici Insieme, ezetimibe in combinazione con una statina fornisce: Pool di Colesterolo (Micelle) NPC1L1 X STATINE EZETIMIBE Ezetimibe Statine Recettori Remnant H MG-CoA X Colesterolo 1 Pool di Colesterolo 1 Riduzione di colesterolo epatico 2 Aumento dell espressione del recettore LDL 3 Aumentata clearance di C-LDL plasmatico FEGATO Alirocumab Evolocumab 2 I-PCSK9 Espressione Recettore LDL 3 CM R C-LDL CM Sangue ATEROMA N PC1L1 = N iemann-pick C1-like 1; H MG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron remnan 1. Grigore L et al. Vas H ealth Risk Manag. 2008;4: VAS HEALTH RISK MANAG 2008;4:

9 A) Regulation of hepatic LDL receptor expression by proprotein convertase subtilisin/kexin type 9. Liver Systemic Circulation Liver, Intestines, Kidneys, Lungs, Pancreas, Adipose Tissue (B) Mechanism of LDL reduction by PCSK9 inhibitors LDL-R Recycling Expression LDL-R LDL

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11 Overview of ODYSSEY Phase 3 Alirocumab Clinical Trial Program 14 global phase 3 trials including >23,500 patients across >2,000 study centers HeFH population Add-on to max-tolerated statin (± other LMT) ODYSSEY FH I (NCT ; EFC12492) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=486; 18 months ODYSSEY FH II (NCT ; CL1112) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=249; 18 months HC in high CV risk population Add-on to max-tolerated statin (± other LMT) ODYSSEY COMBO I (NCT ; EFC11568) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=316; 12 months *ODYSSEY COMBO II (NCT ; EFC11569) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=720; 24 months Additional populations (Intolerance-No/mild LLT) ODYSSEY MONO (NCT ; EFC11716) Patients on no background LMTs LDL-C 100 mg/dl N=100; 6 months ODYSSEY ALTERNATIVE (NCT ; CL1119) Patients with defined statin intolerance LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=250; 6 months ODYSSEY HIGH FH (NCT ; EFC12732) LDL-C 160 mg/dl N=107; 18 months ODYSSEY OLE (NCT ; LTS 13463) Open-label study for FH from EFC 12492, CL 1112, EFC or LTS N 1000; 30 months ODYSSEY LONG TERM (NCT ; LTS11717) LDL-C 70 mg/dl N=2,100; 18 months ODYSSEY CHOICE I (NCT ; CL1308) LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=803; 12 months ODYSSEY OUTCOMES (NCT ; EFC11570) LDL-C 70 mg/dl N=18,000; 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, ODYSSEY CHOICE II (NCT ; EFC13786) Patients not treated with a statin LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=233; 6 months ODYSSEY OPTIONS I (NCT ; CL1110) Patients not at goal on moderate dose atorvastatin LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=355; 6 months ODYSSEY OPTIONS II (NCT ; CL1118) Patients not at goal on moderate dose rosuvastatin LDL-C 70 mg/dl OR LDL-C 100 mg/dl N=305; 6 months

12 Evolocumab: Programma PROFICIO >35,000 patients Terapia di Associazione Monoterapia Phase 2 (n=631) Phase 2 (n=411) Phase 3 (n=1896) Phase 3 (n=614) Intolleranti a statine Phase 2 (n=160) Phase 3 (n=307) Phase 3 (n=519) Ipercolesterolemia Familiare Eterozigote HoFH/ Severa FH Sicurezza e efficacia a Lungo Termine Estensione Open-label Aterosclerosi Prevenzione Secondaria Neurocognition Phase 2 (n=168) Phase 2/3 (n=58) Phase 2 (n=1324) Phase 3 (n=329) Phase 2/3 (n=300) Phase 3 (n=901) Phase 3 (n=4428) Phase 3 (n=950) Phase 3 (n=27,564) Phase 3 (n=1972) HeFH, Ipercolesterolemia Familiare eterozigote; HoFH, Ipercolesterolemia Familiare omozigote. ClinicalTrials.gov. Accessed September

13 LDL-C, mean (SE), mg/dl Odissey Alternative 250 Alirocumab 51% 42% Ezetimibe 6% 4% < 100 < 70 < 100 < mg/dl 97 mg/dl Δ 59 mg/dl 157 mg/dl 92 mg/dl Δ 65 mg/dl % received 150 mg Q2W at W Week Moriarty PM, Oral Presentation at AHA 2014

14 LS mean LDL-C level (SE), mmol/l ODYSSEY FH I and FH II (ESC 2015) 486 pts, 249 pts with inadequate LDL-C control on LLT Mean Calculated LDL-C Levels (mitt) Pool of LONG TERM (HeFH Patients only) and HIGH FH (Alirocumab 150 mg Q2W) ΔW24 : (2.4)%) ΔW52 : (2.8)% ΔW78 : (2.8)% mg/dl All % changes P< versus placebo Study Week 14 ΔW24/52/78 defined as LS mean (SE) % difference versus placebo in calculated LDL-C from baseline to Week 24/52/78. Figure shows on-treatment analysis on modified ITT population, including all lipid data throughout the duration of study collected while the patients were still receiving study treatment.

15 Cumulative Probability of Event ODYSSEY LONG TERM Cumulative Incidence % OSLER I e II ODYSSEY LONG TERM Time to First Adjudicated Major CV Events Placebo + max tolerated statin ± other LLT Alirocumab + max tolerated statin ± other LLT HR= 0.52 (95% CI ) Nominal p=< Time (weeks) - 48% ODYSSEY LONG TERM and OSLER I e II were published on March 15, 2015, at NEJM.org OSLER I e II Cumulative Incidence of CV Events HR= 0.47 (95% CI ) p=<0.003 Standard Therapy - 53% Evolocumab Days since Randomization

16 Myocardial Infarction

17 CV Mortality Total Mortality

18 FOURIER - Study Design A randomized, double-blind, placebo-controlled study Patients with MI, stroke, or PAD and additional risk factors (1 major or 2 minor) + on optimal background lipid therapy (effective statin dose ± ezetimibe) LDL-C 70 mg/dl or non-hdl-c 100 mg/dl R n~13,750 n~13,750 Evolocumab 140 mg Q2W or 420 mg QM (per subject preference) Placebo Q2W or QM (corresponding to study drug dosing) Randomization Weeks R D1 W4 W12 W24 Maximum 15 weeks leading up to randomization Q24W # key 2 endpts achieved Primary composite endpoint: time to cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina or coronary revascularization Patients received a placebo run-in injection (single, 1-mL SC injection) to assess tolerability of SC injections during screening (max of 15 weeks). No ability to down-titrate when LDL-C is very low (<15 mg/dl). PAD: Peripheral Arterial Disease MI: Myocardial Infarction QM: Monthly Q2W: Every 2 weeks Sabatine, et al. Am Heart J. 2016;173: events RRR > 15%

19 FOURIER : RAGGIUNTO END-POINT PRIMARIO Threshold: Unnecessary to go very low CHD Risk Curvilinear: The lower, the better, but with reduced effects Linear: The lower, the better LDL-C (mg/dl)

20 ODYSSEY OUTCOMES & FOURIER Study Designs Patient population ODYSSEY OUTCOMES Patients with recent ACS on maximally tolerated statin other LLT LDL-C 70 mg/dl or non-hdl-c 100 mg/dl or apolipoprotein B 80 mg/dl) pts (9000 vs 9000) FOURIER Patients with MI, stroke, or PAD and additional risk factors (1 major or 2 minor) + on optimal background lipid therapy (effective statin dose ± ezetimibe) LDL-C 70 mg/dl or non-hdl-c 100 mg/dl Primary End Point Time to Coronary Heart Disease death, non-fatal myocardial infarction, ischemic stroke, Unstable Angina requiring hospitalization Time to Cardiovascular Death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for Unstable Angina or coronary revascularization LDL-C reduction Management of Low LDL-C Treat-to-target approach Patient started on 75Q2W (~50% LDL-C reduction) up- titration to 150Q2W if LDL-C 50 mg/dl With down-titration from 150Q2W to 75Q2W if 2 consecutive LDL-C <25mg/dL, or from 75Q2W to placebo if 2 consecutive LDL- C <15 mg/dl Lower-the-better approach with one dose fits all Patients on 140Q2W/420QM 60% LDL-C reduction No down-titration or switch to placebo if low LDL-C level Baseline LDL-C Mean Exposure to Study Drug and Follow-up 86.5mg/dL (median) Mean 3 years 2-to-5 years follow-up 91.5mg/dL (median) Mean 2 years 1-to-3.5 years follow-up Sabatin 8 e, et al. Am Heart J. 2016;173: ; Schwartz GG, et al. Am Heart J. 2014;168: e1.

21 Change in % PAV The relationship between mean LDL-C and change in percent atheroma volume (PAV) in IVUS studies 2 1 CAMELOT 4 placebo REVERSAL 5 pravastatin 0-1 REVERSAL 5 atorvastatin ASTEROID 3 rosuvastatin ACTIVATE 1 placebo Mean LDL-C (mg/dl) A-Plus 2 placebo Progression Regression GLAGOV PCSK-9 Nissen S. et Al, 2016

22 GLAGOV (968 pts Statin vs Statin + PCSK-9Inhib.) Total Population (> 90 mg/dl) 0,5 Percent Atheroma Volume 0 Total Exploratory -0,5 Exploratory Subgroup (< 70 mg/dl) -1-1,5 * * p < ,5 Statin Evolocumab *

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24 Safety Analysis (Pool of Four Phase 2 and 10 Phase 3 trials ) Ezetimibe-controlled pool (n=1482; 28%) Placebo-controlled pool (n=3752; 72%) Alirocumab Ezetimibe Alirocumab Placebo n TEAEs, n (%) 607 (70.3) 421 (68.1) 1876 (75.8) 975 (76.4) Treatment-emergent SAEs 113 (13.1) 69 (11.2) 340 (13.7) 182 (14.3) TEAEs leading to death 2 (0.2) 7 (1.1) 13 (0.5) 11 (0.9) TEAEs leading to discontinuation 76 (8.8) 60 (9.7) 131 (5.3) 65 (5.1) Safety events of interest, n (%) Adjudicated CV events 27 (3.1) 12 (1.9) 83 (3.6) 41 (3.5) Injection-site reactions (HLT) 26 (3.0) 13 (2.1) 180 (7.3) 66 (5.2) General allergic TEAE (CMQ) 59 (6.8) 33 (5.3) 213 (8.6) 99 (7.8) Pruritus (PT) 7 (0.8) 3 (0.5) 28 (1.1) 5 (0.4) General allergic serious TEAE (CMQ) 1 (0.1) 2 (0.3) 9 (0.4) 5 (0.4) Neurocognitive disorders (CMQ) 8 (0.9) 6 (1.0) 21 (0.8) 9 (0.7) ALT >3 x ULN (PCSA) 9/850 (1.1) 1/612 (0.2) 41/2455 (1.7) 18/1266 (1.4) 24 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 weeks Safety for COMBO, : FH, Serious HIGH FH and Adverse LONG TERM Events studies. : 2-6% ; 2-10% discontinuation Safety data pool includes alirocumab 75 mg Q2W and alirocumab 150 mg Q2W doses only. Includes CHD death, non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalisation, congestive heart failure requiring hospitalisation, and ischaemia-driven coronary revascularisation procedure. Tolerability : Injection Site Reaction (85% at 1 y taking Drug in ODISSEY COMBO II) Calculated using n values of 2318 for alirocumab and 1174 for placebo (excludes Phase 2). ALT, alanine aminotransferase; CMQ, custom MedDRA query; HLT, high-level term, PCSA, potentially clinically significant abnormalities; PT, preferred term; ULN, upper limit of normal. Table shows safety analysis performed on safety population.

25 Reazioni avverse nei pazienti che presentano LDL-C <25 o 15 mg/dl nei 14 trial di Alirocumab Pooled controlli (n=1894) Pooled Alirocumab (n=3340) Pooled Alirocumab LDL-C < 25 mg/dl (n=796) Pooled Alirocumab LDL-C < 15 mg/dl (n=288) Infezioni Alterazioni muscoloscheletriche Reazioni in sede di iniezione Alterazioni Sistema nervoso Centrale Diabete Cancro TEAE : Treatment Emergent Adverse Event Poster presented at: 64th Annual Scientific Sessions of the American College of Cardiology; March 14-16, 2015; San Diego, CA. Abstract 1164M

26 Condizioni di rimborsabilità Ipercolesterolemia Familiare Omozigote Ipercolesterolemia Familiare Eterozigote Ipercolesterolemia Non Familiare e dislipidemia mista in pazienti ad alto rischio In associazione a statine/llt in pazienti che non raggiungono il target di LDL In monoterapia o in associazione in pazienti con intolleranza o controindicazione a statina G.U. 7/2/2017

27 The spectrum of cardiovascular risk Risk of a major cardiovascular event: death, myocardial infarction, stroke (n. of events/100 subjects/year) Normal subjects (any age) = <2 High-risk primary prevention = 2-4 Post-MI (chronic phase), poststroke, and stable CAD = >4 ACS = >10 Redrawn from Halvorsen S et al., JACC :

28 Effects of ezetimibe by TRAP 2P risk score in IMPROVE-IT NNT = 16 NNT = 45 Bohula EA et al. (2016)