Regression of atherosclerosis and related CV diseases

Regression of atherosclerosis and related CV diseases Jean-Claude Tardif MD, FRCPC, FACC, FCAHS Director, MHI Research Center Professor of Medicine UdeM Endowed Research Chair in Atherosclerosis Montreal Heart Institute Université de Montréal

Change in atheroma volume in 6 weeks in statin-naïve patients Relative change Nominal change -.5-1 -.54 ±.89 2 1.21 Adjusted mean ± SE -1.5-2 -2.5-3 -3.5-4 -4.5-5 P =.2 Chronic statin therapy prior to ACS (n = 38) -4.71 ±.96 Newly initiated statin therapy following ACS (n = 36) Median (IQR) -2-4 -6-8 -1 P =.3 Chronic statin therapy prior to ACS (n = 38) -9.1 Newly initiated statin therapy following ACS (n = 36) Rodes J and Tardif JC, Am J Cardiol 29;14:75-7

Substantial Risk of CHD Events Remains for Many Patients on Statin Therapy Trial (N) WOSCOPS b (6595) AFCAPS/TexCAPS b (665) ASCOT-LLA b (1,35) 4S b (4444) CARE c (4159) LIPID c (914) HPS c (2,536) PROSPER c (584) Statin treatment Pravastatin 4 mg Lovastatin 2 or 4 mg Atorvastatin 1 mg Simvastatin 2 mg Pravastatin 4 mg Pravastatin 4 mg Simvastatin 4 mg Pravastatin 4 mg Risk reduction vs placebo 31% 37% 36% 26% 24% 24% 27% 19% Clinical events a Remaining risk 69% 63% 64% 74% 76% 76% 73% 81% a Nonfatal myocardial infarction and coronary heart death; b Primary prevention trial; c Secondary prevention trial WOSCOPS=West of Scotland Coronary Prevention Study; AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT-LLA=Anglo- Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm; 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol and Recurrent Events; LIPID=Long-Term Intervention with Pravastatin in Ischemic Disease; HPS=Heart Protection Study; PROSPER=Prospective Study of Pravastatin in the Elderly at Risk Adapted from Mahley RW, Bersot TP. In: Goodman & Gilman s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division, 26:933 966; Bays HE. Expert Rev Cardiovasc Ther. 24;2:485 51; Shepherd J et al. N Engl J Med. 1995;333:131 137; Downs JR et al. JAMA. 1998;279:1615 1622; Sever PS et al. Lancet. 23;361:1149 1158; Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383 1389; Sacks FM et al. N Engl J Med. 1996;335:11 19; Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Eng J Med. 1998;339:1349 1357; Heart Protection Study Collaborative Group. Lancet. 22;36:7 22; Shepherd J et al. Lancet. 22;36:1623 163.

Risk of death according to presence of metabolic syndrome Survival (all-cause) 1..75.5 Survival (CV) 1. p <.1 p <.1.75.5.25 No WHO metabolic syndrome WHO metabolic syndrome 5 1 15 2 Time (years) No at risk No MS MS 23813 178 2796 877 17854 673 1978 388.25 5 1 15 2 Time (years) 23122 154 No WHO metabolic syndrome WHO metabolic syndrome 211 853 17233 651 1611 376 Nigam A, Bourassa MG, Fortier A, Guertin MC, Tardif JC. Am Heart J 26; 151: 514-21

Lipoprotein metabolism Liver LDL receptor ACAT MTP FC CE 27-hydroxylase ApoB ABCG1 B E VLDL C-II LPL B E IDL C-II LPL LDL B Oxidation CD36 SR-A FC CE ACAT Bile Intestine FC CE ACAT IBAT CETP A-1 A-1 LCAT HDL PL TP HL Nascent HDL Cholesterol pool ABC1 Macrophage

Change in plaque volume A+ 3-mm segment, intent-to-treat population mm 3 6 5.1 ± 3. 4 p =.58 (unadjusted) p =.17 (adjusted) Mean change (±SD) 2-2 1.2 ± 24.2 1.9 ± 33.1-4 -2.5 ± 26.6 Placebo (n=19) Avasimibe Avasimibe Avasimibe 5 mg 25 mg 75 mg (n = 18) (n = 98) (n = 117) Tardif et al Circulation 24; 11:3372-7

Long-Term Safety of Intravascular Ultrasound A+ Coronary change score 2 New lesions Disease progression (mm) -.2 -.4 -.6 -.8 p =.35 (% of patients) 15 1 5 p =.84* p =.27* -.1 Instrumented (IVUS-related arteries) Non-instrumented (Non-IVUS arteries) J Am Coll Cardiol 25;45:559-564

IVUS assessment - Atherosclerosis regression 2% reduction in plaque burden Baseline Follow-up Plaque volume (mm 3 ): 272.9 EEM volume (mm 3 ): 69.5 Plaque volume (mm 3 ): 197.3 EEM volume (mm 3 ): 445.9

6 4 2 Correlations between changes in plaque, vessel and lumen areas in pts with regression Mean vessel area (mm 2 ) n = 227 r =.64 p <.1 Mean lumen area (mm 2 ) 6 4 2 n = 227 r =.2 p =.3-2 -4-6 -4-3.5-3 -2.5-2 -1.5-1 -.5 Change in mean plaque area (mm 2 ) -2-4 -6-4 -3.5-3 -2.5-2 -1.5-1 -.5 Change in mean plaque area (mm 2 ) Tardif et al. Am J Cardiol 26;98-23-7

IVUS results in patients with angiographic progression vs no progression by QCA in the IVUS-related artery Mean plaque volume (mm 3 ) 25 225 2 175 Progression No progression 217.2 ± 72.1 p =.5 197.1 ± 73.6 226.8 ± 69.9 p =.89 196. ± 71.3 15 Baseline Follow-up P-value for mean change in plaque volume:.283 Circulation 27;115:1851-7

Prognostic significance of angiographic progression of coronary atherosclerosis 1. Any coronary event ( n = 112) 1. Death or MI (n = 4) Non progressors Proportion event free.75.5.25 Non progressors Progressors 2 4 6 8 Months Proportion event free.75 p <.1 p <.1.5.25 Progressors (N = 26) (N = 137) (N = ) (N = ) (N = 39) (N = 192) (N = 5) (N = 1) 2 4 6 8 Months Circulation 1993; 87: 167-75

Canadian Atherosclerosis Imaging Network Clinical Translation and Practice Correlation of coronary and carotid atherosclerosis and their changes over time and links with clinical outcomes 2 patients undergoing coronary angiography, IVUS (with virtual histology) and carotid ultrasound (IMT and plaques) at baseline and 24 months 5-year follow-up for cardio/cerebrovascular events NIRS, PET/CT, MRI and microvascular substudies Genomic (including mirnas) and biomarker biobanks Proteomic and metabolomic analyses Application of this knowledge and framework in clinical trials of novel anti-atherosclerotic agents

Beyond statin-induced LDL-C reduction CETP inhibitors HDL infusions/mimetics 5-LO/FLAP inhibitors PLA2 inhibitors Serpins Heart rate reduction? Tardif JC, Heinonen T. Nature Clin Pract CV Med 26;3:366-7

INHIBITION OF ATHEROSCLEROSIS BY HDL Monocyte HDL INHIBITS ADHESION MOLECULE EXPRESSION HDL INHIBITS MCP-1 1 EXPRESSION LDL Adhesion Molecule Cytokines MCP-1 LDL MODIFIED LDL HDL INHIBITS OXIDATION OF LDL Macrophage HDL PROMOTES CHOLESTEROL EFFLUX Foam Cell

Effects of rapo-a1 Milano on coronary atherosclerosis Change in atheroma volume 1 Change in % atheroma volume -4-8 mm 3 % -12-16 -2-2.9 ± 23.3 Placebo (n = 11) -15.1 ± 5.6 15 mg/kg (n = 21) -12.6 ± 15.3 45 mg/kg (n = 15) ETC-216-14.1 ± 39.5 p =.97 p =.2 p =.7 p <.1 Combined (n = 36) -1-2.14 ± 3.9 Placebo (n = 11) -1.29 ± 3.48 15 mg/kg (n = 21) -.73 ± 2.75 45 mg/kg (n = 15) ETC-216-1.6 ± 3.17 p =.3 p =.45 p =.2 Combined (n = 36) JAMA 23; 29:2292-23

Change in atheroma volume on IVUS Median percent change The ERASE trial Median nominal change -.5-1 -1.5-2 p=ns -1.62 p =.7 % mm 3-1 -2-3 p=ns -2.33 P=.4-2.5-3 -3.5-4 -3.41 p <.1 CSL-111 (n = 89) Placebo (n = 47) Plaque volume at baseline: 146. mm 3 for CSL-111, 151.4 mm 3 for placebo Interval between IVUS examinations : 43 ± 6 days in both groups -4-5 -6-5.34 p <.1 CSL-111 (n = 89) Placebo (n = 47) Tardif et al. JAMA 27;297:1675-82

The ERASE trial Changes in plaque characterization indexes.2 Arc index.2 Inner perimeter index Least square means.1 -.1 -.83.137 Least square means.1 -.1 -.97 p =.1 p =.1.128 -.2 CSL-111 Placebo -.2 CSL-111 Placebo Tardif et al. JAMA 27;297:1675-82

The ERASE trial Changes in coronary score on QCA Least square means (mm) -.2 -.4 -.6 -.8 There was a significant interaction between study treatment and baseline coronary score (p =.3) 1.76 mm 1st quartile CSL-111 4 mg/kg 2. mm Median Placebo p =.3 2.26 mm 3rd quartile Coronary score at baseline JAMA 27;297:1675-82

ILLUSTRATE Primary endpoint Change in Percent Atheroma Volume,35,3 p =.72 Change in percent atheroma volume,25,2,15,19,12,1,5 *LS Mean change p value from ANCOVA Atorvastatin monotherapy Torcetrapibatorvastatin Nissen, Tardif, et al. N Engl J Med 27; 356:134-16

ILLUMINATE - Primary Endpoint Time to First MCVE*: Kaplan-Meier Plot Event Free (%) 1 98 96 94 92 Atorvastatin (A) events = 373 Hazard Ratio 1.25 P=.1 9 Torcetrapib/Atorvastatin (T/A) events = 464 9 18 27 36 45 54 63 72 81 Days from Randomization *Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable angina NEJM 27;357:219-2122 2122

Post-hoc Exploratory Analyses in the Torcetrapib/Atorvastatin Group CHD Death or Non-Fatal MI (Hazard Ratio) 1..8.6.4.2 Hazard ratios for CHD Death or Non-Fatal MI by quintile of on-trial HDL-C (referent group is HDL-C C < 6 mg/dl stratum) 1..67.47.57.43 <6 6-7 71-8 81-93 >93 Quintiles of HDL-C C (mg/dl) at Month 3 *P<.5 Cox proportional hazard model adjusted for age, gender and baseline HDL-C. Excludes 265 patients with missing month 3 HDL-C. Preliminary analysis initiated and authorised by P Barter and d conducted by Pfizer * * *

Lack of Effect of Dalcetrapib vs Torcetrapib on Aldosterone Secretion 7 6 RO467381 5 Torcetrapib Aldosterone fmole/µg protein 4 3 2 1,1,5,1,25,1 1 2,5 5 7,5 1 AngII 1 nm Concentration of Torcetrapib or RO467381 (µm)

The dal-heart Program dalcetrapib HDL Evaluation, Atherosclerosis & Reverse cholesterol Transport The dal-heart Program tests a novel hypothesis: enhancing HDL efficacy through CETP modulation treats the underlying disease of atherosclerosis and will attenuate CV risk dal- OUTCOMES 1 15,6 patients recently hospitalized for ACS To evaluate the effect of dalcetrapib on CV outcomes RECRUITMENT COMPLETE dal-vessel 2 45 patients with CHD or CHD risk equivalent To evaluate the effect of dalcetrapib on endothelial function and blood pressure, measured by FMD and ABPM RECRUITMENT COMPLETE dal-plaque 3 13 patients with CHD To evaluate the effect of dalcetrapib on inflammation, plaque size and burden, measured by PET/CT and MRI RECRUITMENT COMPLETE dal-plaque-2 4 9 patients with CAD To evaluate the effect of dalcetrapib on atherosclerotic disease progression, assessed by IVUS and carotid B-mode ultrasound RECRUITING 1 Schwartz et al. Am Heart J 29;158:896-91; 2 http://clinicaltrials.gov/ct2/show/nct655538 Accessed April 1st 21; 3 http://clinicaltrials.gov/ct2/show/nct655473 Accessed April 1st 21; 4 http://clinicaltrials.gov/ct2/show/nct159682 Accessed April 1st 21.

DAL-OUTCOMES Study Design A double-blind, randomized, placebo-controlled, parallel group, multi-centre study in 15,6 patients recently hospitalized for ACS Double-blind Single-blind Placebo Run-in 4-12 Weeks Dalcetrapib 6 mg Placebo Until 16 events occur but at least a minimum of 2 years Visit 1 Visit 2 Visit 3 randomization 1 : 1 Follow up 1 st year: every 3 months Following years: every 4 months

dal-plaque-2: Study Design Objective: to assess the effect of dalcetrapib versus placebo on atherosclerotic disease progression in patients with CAD A double-blind, randomized, placebo-controlled, parallel-group multicenter study in 9 patients with CAD Double-blind Pre-rando phase Screening phase up to 8 weeks Baseline IVUS, QCA and CIMT Randomization dalcetrapib 6 mg placebo Background of contemporary evidence-based therapy for CAD and CV risk factors Primary endpoints: IVUS and CIMT at 24 months Other assessments: CIMT at 6+12 months; QCA at 24 months 24 months

dal-plaque-2 Primary endpoints Co-primary endpoints Nominal change from baseline to study end in coronary percent atheroma volume (PAV) for all anatomically comparable slices in a 3-mm segment of the target coronary artery assessed by IVUS Rate of change from baseline to study end in intima-media thickness (IMT), defined as the per scan average of the far wall MEAN IMT values of the right and left common carotid, carotid bulb and internal carotid arterial segments as assessed by carotid B-mode ultrasound

British Journal of Pharmacology 28; 154:765-773

Aortic valve area during treatment Aortic valve area (mm 2 ) 26 25 24 23 22 21 2 19 18 17 Control Treated ** * * 5 1 15 *p<.5 **p<.1 Days Stop cholesterol diet + Vit D 2 Start ApoA-I mimetic peptide treatment Br J Pharmacol 28;154:765-773 29

The dual PPAR agonist aleglitazar and change in HDL-C 35 Placebo.5.15.3.6 Pioglitazone 3 p<.1 p<.1 p<.1 % BL of HDL - C 25 2 15 1 p=.312 p<.14 5 54 54 54 53 54 57 n BC2214 Investigator Meeting

Aleglitazar 15 μg Provides Beneficial Effects on Cardiovascular Biomarkers 2 Placebo Aleglitazar 15 µg Pioglitazone 45 mg Mean Absolute Change From Baseline 15 1 5-5 -1-15 -2-25 -3-35 -4 1,1-35,4 9 1-1 -2-3 -,1-1,6-1,7-5 -1-3,7-5 -7,3 Fibrinogen (mg/dl) hscrp (mg/dl) PAI-1 (µg/ml) Placebo Aleglitazar 15 µg Pioglitazone 45 mg Fibrinogen baseline (mg/dl) 337.25 342.92 328.67 hscrp baseline (mg/dl) 4.97 3.85 4. PAI-1 baseline (µg/ml) 22.26 22.67 22.3

ALECARDIO Study Design Run-in Period 2 6 (+ 6) weeks Treatment Period at least 2.5 years 4 weeks Index ACS Event Screened Patients Aleglitazar 15 µg Placebo Follow-up Standard of care (diabetes and other CV risk factors) BC2214 Investigator Meeting

Potential therapeutic targets in CV diseases

VIA-2291 Decreases ex Vivo Whole Blood LTB4 Production from Baseline through Week 12 Mean LTB4 Production [pg/ml] 16,. 14,. 12,. 1,. 8,. 6,. 4,. 2,.. -2 2 4 6 8 1 12 14 Error Bars represent 95% CI ** p <.1 ANCOVA Change from Baseline Placebo 25mg 5mg 1mg Study Weeks ** ** Tardif et al. Circulation Cardiovasc Imaging 21;3:298-37 **

Significant Decrease in hs-crp in VIA-2291 1 mg Group versus Placebo at 24 Weeks

Change in non-calcified plaque volume and patients with new plaque lesions on serial coronary CT scans in the VIA-2291 groups versus placebo at 24 Weeks Plaque volume (mm 3 ) Pts with new plaques (%) 7 3 5 3 25 p <.1 p <.1 2 1 15-1 1-3 5-5 Placebo All VIA-2291 Placebo All VIA-2291 Tardif et al. Circulation Cardiovasc Imaging 21;3:298-37

Serp-1 Phase 2a Results: Myocardial Enzymes TroponinI:Adjusted Geometric Mean CK-MB: Adjusted Geometric Mean Troponin I (ng/ml) 1.9.8.7.6.5.4.3 Placebo 5 µg/kg Dose 15 µg/kg Dose CK-MB (ng/ml) 7 6 5 4 3 Placebo 5 µg/kg Dose 15 µg/kg Dose.2.1 2 Predose 8 hr 16 hr 24 hr 48 hr 54 hr Day 14 Day 28 1 Predose 8 hr 16 hr 24 hr 48 hr 54 hr Day 14 Day 28 VT VT VT VT VT VT =statistically significant (p<.5 vs control) VT = timing of doses Dose-dependent reduction in biomarkers of cardiac damage observed in the first 24 hours Tardif et al. Circulation Cardiovasc Interventions 21 (in press) 37

1..9 Mortality by resting heart rate Overall mortality 1..9 CV mortality Cumulative survival.8.7.6.5 RHR in quintiles 62 bpm 63-7 bpm 71-76 bpm 77-82 bpm 83 bpm.8.7.6.5 5 1 15 2 Years after enrolment 5 1 15 2 Years after enrolment Adjusted for age, gender, hypertension, diabetes, smoking, NDCV, ejection fraction, recreational activity, medications including β-blockers, plus BMI for CV mortality Diaz A, Bourassa MG, Guertin MC, Tardif JC. Eur Heart J 25; 26: 967-74

Ivabradine prevents endothelial dysfunction associated with dyslipidemia in mice Dilation (% of maximal dilation) 1 9 8 7 6 5 4 3 2 1 Wild WT type Dyslipidemia DL DL+Ivabradine + IVA RENAL * * # Dilation (% of maximal dilation) 6 5 4 3 2 1 Wild WT type Dyslipidemia DL DL+Ivabradine + IVA CEREBRAL #.1.1.1 1 1.1.1.1.1 1 1 ACh (µm) ACh (µm) E max : P <.5 vs. to WT; # P <.5 vs. to DL pd 2 : * P <.5 vs. WT and DL Drouin et al. Br J Pharmacol. 28;154:749-757.

TED at trough of drug activity n Ivabradine vs atenolol Favors ATE Favors IVA INITIATIVE E (95% CI) P for non inferiority IVA 5 mg bid vs ATE 5 mg od at M1 595 286 6.7 (-7.4; 2.8) p <.1 IVA 7.5 mg bid vs ATE 1 mg od at M4 3 286 1.3 (-8.3; 28.8) p <.1 IVA 1 mg bid vs ATE 1 mg od at M4 298 15.7 (-2.9; 34.3) 286 p <.1-35 sec + 35 sec Equivalence interval Tardif JC et al. Eur Heart J 25; 26:2529-36

Ivabradine increases all ETT parameters in patients already receiving beta-blockers 889 stable angina patients, 2 countries 6 Ivabradine + atenolol Placebo + atenolol P<.1 P<.1 Change in ETT criteria* (s) at 4 months 5 4 3 2 P<.1 P<.1 1 Total exercise duration Time to limiting angina Time to angina onset Time to 1mm ST segment depression *Evaluated at trough of drug activity Tardif JC, et al. Eur Heart J. 29;3:54-548.

Effect of Ivabradine on hospitalisation for fatal and non-fatal MI (HR 7 bpm) % with hospitalisation for fatal and non-fatal MI 8 6 4 Hazard ratio =.64 (.49.84) RR = -36% P =.1 Placebo 2 Ivabradine.5 1 1.5 2 Years Lancet Online August 31, 28.

Primary composite endpoint (CV death or hospital admission for worsening HF) 43 Cumulative frequency (%) 4 3 HR =.82 (.75.9) P <.1 Placebo 18% 2 Ivabradine 1 6 12 18 24 3 Swedberg K, et al. Lancet. 21;online August 29. Months

Population Outpatients with stable CAD without LVSD (EF > 4%) or clinical signs of HF, with appropriate CV medication Ivabradine Starting dose 7.5 mg bid Run in 2-4 weeks Target HR: 55-6 bpm Placebo bid M M3 M6 Every 6 months Methods Events: 4.5% per year in the placebo group 17 primary composite endpoints (cardiovascular death and non fatal MI N = 11 33, mean follow up = 2.5 years; RRR = 18%, α bilateral 5%, power 9%

Canadian Atherosclerosis Imaging Network Hearts and Minds Stems from CIHR s 27 consensus conference on imaging Five-year (28-213) 1M$ operating grant from CIHR Infrastructure grant 25M$ from CFI in June 29 Unique network combining in vivo imaging of vessel wall disease, endorgan disease, clinical and pathological endpoints Enables cross-sectional and longitudinal clinical studies of coronary, carotid and peripheral vascular beds International resource for studying the natural history of atherosclerosis and novel therapeutic interventions

Canadian Atherosclerosis Imaging Network CAIN one imaging network for one entire country Imaging Core Analysis Laboratories (vascular) IVUS, 3-D US, QCA, MDCT, MRI, PET/CT, SPECT Imaging Core Analysis Laboratories (end-organ) Pan-canadian network of 45 partner sites Data coordinating and image repository center (MHICC) Genetic, pharmacogenomic and biomarker biobanks Proteomic and metabolomic analyses Tissue samples

CAIN Research themes Hearts and Minds Vascular biology of atherosclerotic plaque Vascular imaging technology development and assessment Translation to clinical research and clinical practice

Canadian Atherosclerosis Imaging Network 1- Vascular Biology of Atherosclerotic Plaque Assess natural history of the plaque from 3 time points (MRI): Plaque initiation, progression and complication Evaluate inflammation, neovascularization and hemorrhage Determine the role of stimuli such as Db and hyperlipidemia Study the genetics of atheroma Assess the role of hypertension, hemodynamics and the interaction with blood constituents at the site of plaque rupture

Canadian Atherosclerosis Imaging Network 2- Vascular Imaging Technology Development and Assessment Validation of developing technologies through quantitative histological examination of surgical specimens Includes: Carotid ultrasound - surface morphology, plaque vulnerability and plaque volume 18FDG-PET metabolic activity and inflammation Ultrasound microbubbles plaque neovascularity

Canadian Atherosclerosis Imaging Network 3- Translation to Clinical Research/Practice Correlation of coronary and carotid atherosclerosis and their changes over time and links with clinical outcomes 2 patients undergoing coronary angiography, IVUS (with virtual histology) and carotid ultrasound (IMT and plaques) at baseline and 24 months 5-year follow-up for cardio/cerebrovascular events NIRS, PET/CT, MRI and microvascular substudies Genomic (including mirnas) and biomarker biobanks Proteomic and metabolomic analyses Application of this knowledge and framework in clinical trials of novel anti-atherosclerotic agents

Canadian Atherosclerosis Imaging Network CAIN one imaging network for one entire country www.canadianimagingnetwork.org therese.heinonen@mhicc.org