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De-risking the development programs of CETP inhibitors after the torcetrapib failure: Structural & functional imaging Prof. Robin Choudhury John Radcliffe.

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Presentation on theme: "De-risking the development programs of CETP inhibitors after the torcetrapib failure: Structural & functional imaging Prof. Robin Choudhury John Radcliffe."— Presentation transcript:

1 De-risking the development programs of CETP inhibitors after the torcetrapib failure: Structural & functional imaging Prof. Robin Choudhury John Radcliffe Hospital Oxford, United Kingdom

2 Objectives in ‘de-risking’ Defining likely manifestations of treatment Available Tools New data: Dal-PLAQUE Future Conclusions Overview

3 Established X-ray arteriography Magnetic resonance imaging Intravascular ultrasound Optical coherence tomography Positron emission tomography Computed tomography Carotid IMT Developmental Elastography Thermography Raman Spectroscopy Near infrared imaging Resolved laser induced fluorescence spectroscopy ‘Molecular techniques’ Modalities for atherosclerosis imaging

4 Imaging the vessel wall in atherosclerosis Lindsay and Choudhury, Nature Reviews: Drug Discovery 2008, 7:

5 Atherosclerosis regression on statins – wall imaging with Months Vessel wall area Aorta decrease ~ 8% Carotid decrease ~ 15% Lumen Area Aorta unchanged Carotid unchanged Max Thickness Aorta decrease ~ 9% Carotid decrease ~ 11% Corti R et al. Circulation, 2001;104:

6 Underhill et al. AHJ, 2008;155:584:e1-8 T1W ToF PDW T2W t = 0 t = 2y ~40 patients with US-defined carotid artery stenosis. Randomised to rosuvastatin 5mg vs mg / day No change in overall plaque burden BUT In patients (n=16) with lipid rich core – regression of core over 24 months Plaque composition analysis

7 507 patients with CHD Follow-up on 349 Rosuvastatin treated – no control LDL: 3.4mmol/L >> 1.6mmol/L HDL up by 15% Atheroma volume in most diseased 10mm segment (of non-stenotic vessel ) Reduced ~8% Nissen et al, JAMA 2006;305: ASTEROID – Potential for plaque regression with IVUS

8 NIssen et al N Engl J Med 2007, 356: IVUS – pooled data suggests regression “tipping point”

9 Prospective Pravastatin Pooling Project 19,800 patients primary and secondary 3 pooled trials of pravastatin (WOSCOPS, CARE, LIPID) Heart Protection Study >20,000 pts CHD,PVD or diabetes Simvastatin 40mg vs placebo placebo pravastatin simvastatin <0.90 ≥0.90- < 1.10 ≥1.10 HDL-c (mmol/L) < <1.14 HDL-c (mmol/L) Heart Protection Study Prospective Pravastatin Pooling Project Lancet, 2002;360:7-22 Sacks FM et al Circualtion 2000;102: HDL-cholesterol relationship persists in patients treated with statins

10 SCREENING INDIVIDUAL PARTICIPATION COMPLETED Established atherosclerosis and HDL-c < 1mmol/L All treated with statins Randomised to placebo or Niaspan 375mg for 1wk > 500mg for 1 wk > 750mg for 1 wk > 1000mg for 4 wks > 1500mg 4 wks > 2000mg maintenance Primary end point = change in carotid wall area at 12 months 6 MONTH REVIEW MRI FASTING BLOODS 12 MONTH REVIEW MRI FASTING BLOODS Week 7 LFTs, CK Week 15 LFTs, CK BASELINE MRI FASTING BLOODS Effect of nicotinic acid on atherosclerosis progression when added to statin therapy

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12 T1 weighted T2 weighted Carotid plaque imaging – multi-contrast MRI

13 A B Vascular FUNCTION – aortic pulse wave velocity and compliance

14 Brachial artery flow-mediated vasodilatation Baseline FMD (endothelium-dependent dilatation) Post GTN (endothelium-independent maximal dilatation) 4.5 min cuff inflation (suprasystolic pressure) Repeat baseline => 400 µg GTN s.l. = 21.2 mm 2 = 24.7 mm 2 = 27.1 mm 2

15 Randomised (n=71) Placebo (n=36) Excluded Claustrophobia2 Completed first MRI (n=34) Active (n=35) Completed first MRI (n=33) Excluded Hyperglycemia 1 Nausea / dyspepsia / diarrhoea3 Flushing / itching3 Lost to follow-up1 Withdrew consent1 Excluded Claustrophobia1 Withdrew Consent1 Excluded Nausea / dyspepsia1 Claustrophobia1 Other medical illness1 Withdrew consent1 Excluded Withdrew consent1 Completed second MRI (n=24) Completed second MRI (n=30) Excluded Abnormal baseline blood tests 2 Completed study (n=22) Completed study (n=29) Patient flow

16 Lee JMS et al; J Am Coll Cardiol, 2009;54: Effect of nicotinic acid on lipoproteins

17 Placebo Nicotinic acid Change in carotid wall area (mm 2 ) * * p=0.03 (mixed effect model adjusted for baseline covariates) estimated treatment difference [95% CI] = −1.64 mm 2 [−3.12, −0.16] Lee JMS et al; J Am Coll Cardiol, 2009;54: Effect of nicotinic acid on atherosclerosis progression

18 Change LDL-C (mg/dL) Change CWA (mm 2 ) Change HDL-C (mg/dL) Change CWA (mm 2 ) Lipoproteins in relation to changes in vessel wall area Lee JMS et al; J Am Coll Cardiol, 2009;54:

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20 Tahara et al J Am Coll Cardiol, 2006; 48: FDG-PET response to 3 months statin treatment

21 Tawakol A et al. J Am Coll Cardiol, 2006; 48: patients with severe carotid stenosis. PET signal correlated strongly with plaque macrophage count at CEA: but not with smooth muscle cells 18 FDG PET signal correlates with macrophage content

22 18 FDG-PET – plaque measurement parameters

23 De-risking ‘challenges’ for imaging What is an appropriate imaging surrogate ? Can it be derived from a clearly understood mechanism of drug action ? Can specific perceived risks be targeted ? What tools are available ? What is the optimal study population ? Off target effects Small studies and short follow-up

24 “Failure of Torcetrapib”

25 NIssen SE et al N Engl J Med 2007, 356:

26 Primary results of the dal-PLAQUE study assessing the safety and efficacy of dalcetrapib on structural and inflammatory atherosclerotic disease using non-invasive simultaneous multimodality imaging Zahi A. Fayad 1, Venkatesh Mani 1, Mark Woodward 2, David Kallend 3, Tracy Burgess 4, Marcus Abt 3, Valentin Fuster 1, James H.F. Rudd 5, Ahmed Tawakol 6, Michael E. Farkouh 1,7, on behalf of the dal-PLAQUE Investigators 1 Mount Sinai Medical Center, New York, NY, USA; 2 University of Sydney, Sydney, Australia; 3 F. Hoffmann-La Roche Ltd, Basel, Switzerland; 4 Hoffmann-La Roche Inc., Nutley, NJ, USA; 5 University of Cambridge, Cambridge, UK; 6 Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA; 7 Peter Munk Cardiac Centre and Li Ka Shing Knowledge Institute, Toronto, Canada ClinicalTrials.gov Identifier: NCT Fayad ZA et al Lancet 2011, On line Sept 12

27 To use a dual-imaging approach to determine the effects of dalcetrapib on measures of atherosclerotic plaque inflammation and plaque burden 1 18F-FDG PET/CT uptake to determine changes in plaque inflammation activity 1,2 MRI to measure parameters of plaque morphology, and assess the progression/regression of atherosclerosis 1 1 Fayad et al. Am Heart J. 2011;162: e2; 2 Rudd et al. J Am Coll Cardiol. 2007;50:892–896. Dal-PLAQUE rationale

28 dal-PLAQUE 11 sites US & Canada multicenter study Non-invasive simultaneous multimodality imaging (MRI and PET/CT) to assess structural and inflammatory indices of atherosclerosis 130 CHD or CHD risk (diabetes or 20% 10-year FRS) y patients 600 mg dalcetrapib vs. placebo Baseline average LDL <100 mg/dL (<2.6 mmol/L), TG ≤400 mg/dL (≤4.5 mmol/L) Statins use >80% patient Endpoints: – 6, 12, 24 months – 6 months Dal-PLAQUE

29 TBR >1.6- inflammation present by a central core lab A double-blind, randomized, placebo (S.O.C.)- controlled, parallel group, multi-center (11 sites) study in 130 patients with CHD or CHD equivalent Fayad ZA et al. Am Heart J Treated (1:1 allocation)189 patients screened Recruitment n=189 subjects screened Double-blind treatment period Subjects allocated to dalcetrapib 600 mg/day (n=64) or placebo (n=66) for 24 months 24-month MRI* 6-month MRI 3-month PET/CT Baseline PET/CT at screening *Primary Endpoints 24 months -3 months First patient screened Feb 2008 Last patient randomised Nov 2008 Change in arterial wall 18F-FDG uptake (target to background ratio) within the index vessel (left/right carotid or ascending aorta) after 6 months Structural changes in the arterial wall (total vessel area, wall area, wall thickness, normalised wall index) based on the average of the right and left carotids after 24 months* 6-month PET/CT* Baseline MRI 2 wk before randomisation 0 months 6 months randomisation 12-month MRI 12 months Dal-PLAQUE: design

30 Adult patients, 18–75 years of age CHD, including CHD risk factors Carotid artery or aorta (index vessel) plaque inflammation: TBR ≥1.6 by 18F-FDG-PET (Tawakol A et al. JACC 2006) Appropriately treated for LDL-C – At minimum to target level <100 mg/dL (<2.6 mmol/L) TG <400 mg/dL (4.5 mmol/L) Clinically stable Fayad et al. Am Heart J. 2011;162: e2. Dal-PLAQUE: inclusion

31 Primary MRI: structural changes in the arterial wall, measured by four indices: total vessel area (TVA) 1, wall area (WA) 2, wall thickness (WT) 3, and wall area/total vessel area ratio (normalized wall index [NWI] 2 ), based on the average of the right and left carotids after 24 months PET/CT: change in vascular inflammation at 6 months vs baseline in TBR within the most diseased segment (MDS) 4 of the index vessel 1 Hayashi K et al. JCMR 2010; 2 Lee JM et al. JACC 2009; 3 Underhill HR et al. AHJ 2008; 4 Rudd JH et al. JACC 2007 Dal-PLAQUE: end points

32 Placebo (N=66) Dalcetrapib 600 mg (N=64) Baseline demography Males, n (%)55 (83)51 (80) White race, n (%)62 (94)58 (91) Age, yrs (mean) BMI, kg/m 2 (mean) CHD and CHD risk factors CHD, n (%)54 (82)57 (89) Symptomatic CAD, n (%)5 (8) PAD, n (%)10 (15)6 (9) Abdominal aortic aneurysm, n (%)2 (3)3 (5) Type 2 diabetes, n (%)20 (30)19 (30) Hypertension, n (%)48 (73)47 (73) Current smoker, n (%)8 (12)9 (14) 189 patients screened of whom 130 Rx: baseline demographics and lipid parameters similar Dal-PLAQUE: baseline characteristics

33 Placebo (N=66) Dalcetrapib 600 mg (N=64) Total cholesterol, mg/dL [mmol/L] a ± 28.1 [3.8 ± 0.7]143.7 ± 26.7 [3.7 ± 0.7] HDL-C, mg/dL [mmol/L] a 46.3 ± 15.1 [1.2 ± 0.4] 42.4 ± 11.4 [1.1 ± 0.3] LDL-C, mg/dL [mmol/L] a 74.6 ± 19.8 [1.9 ± 0.5] 73.7 ± 22.3 [1.9 ± 0.6] Triglycerides, mg/dL [mmol/L] b (93.0–159.0) [1.45 (1.1–1.8)] (85.0–170.0) [1.4 (1.0–1.9)] Statin use, n (%) c 61 (92)52 (81) a Mean ± SD; b Median (interquartile range); c Patients with at least one treatment. 189 patients screened of whom 130 Rx: baseline demographics and lipid parameters similar Dal-PLAQUE: baseline characteristics

34 Variable Placebo (N=65) Dalcetrapib (N=63) Absolute change vs placebo (90% CI) P value No-harm boundary** MRI, mean* (SE) † Total vessel area, mm (1.45)1.71 (1.43) (-7.23, -0.80) Wall area, mm (1.05)0.49 (1.04) (-4.54, 0.13) Wall thickness, mm0.05 (0.03)0.02 (0.03) (-0.11, 0.04) Normalized wall index, % (0.80)0.30 (0.80) 0.60 (-1.20, 2.50) PET/CT, mean* (SE) ‡ Most diseased segment mean of maximum TBR (0.08)-0.19 (0.08) 0.07 (-0.11, 0.25) SE = standard error *After adjustment for baseline and centre † Total number of patients with MRI vessel parameter measurements was 56 for placebo and 58 for dalcetrapib ‡ Total number of patients with target-to-background ratio measurements was 56 for placebo and 56 for dalcetrapib. **For upper limit of 90% CI for placebo-corrected change from baseline Nominal P-values Dal-PLAQUE: MRI (24 months) and PET (6 months) outcomes

35 P=0.002P=0.24 P=0.04 Adverse remodeling was seen in the placebo group and not the dalcetrapib group individual patient data Dal-PLAQUE: MRI (24 months): change in total vessel area

36 Absolute ChangePercent Change * P=0.001 * P=0.16 ǂ P=0.045 * P=0.002 * P=0.24 ǂ P=0.04 * 24 months vs baseline; ǂ dalcterapib vs placebo at 24 months after baseline correction PlaceboDalcetrapib Months TVA (mm 2 ) Months Change in TVA (% increase from baseline) PlaceboDalcetrapib Apparent increase in TVA across time in the placebo group, not in dalcetrapib group Dal-PLAQUE: MRI (24 months): change in total vessel area

37 MDS TBR decreased in dalcetrapib (p=0.001) but not in placebo (p=0.7) For the baseline corrected comparison between dalcetrapib vs placebo, p= MDS TBR Placebodalcetrapib Baseline6 monthsBaseline6 months P=0.70 P=0.001 P=0.08 Dal-PLAQUE: PET-CT (6 months): change in target to background ratio in most diseased segment

38 Absolute ChangePercent Change * P=0.71 * P=0.003 ǂ P=0.07 * P=0.48 * P=0.001 ǂ P=0.08 PlaceboDalcetrapib Months MDS TBR Months Change in MDS TBR (% increase from baseline) PlaceboDalcetrapib Absolute ChangePercent Change * 6 months vs baseline; ǂ dalcetrapib vs placebo at 6 months after baseline correction Apparent decrease in TBR across time in the dalcetrapib group, not in placebo group For the baseline corrected comparison between dalcetrapib vs placebo, p=0.08 and 0.07, respectively Dal-PLAQUE: PET-CT (6 months): change in target to background ratio in most diseased segment

39 Significant inverse relationship between change in HDL-C and change in MDS (r=-0.3) 4.3% reduction in MDS TBR observed with each increase in HDL-C tertile Placebo dalcetrapib Dal-PLAQUE: PET-CT (6 months): change in target to background ratio in most diseased segment by HDL-c tertile

40 Dalcetrapib 600 mg for 24 months CETP activity decreased by ~51% from baseline ApoA-I increased by 6.8% vs baseline (placebo-corrected) HDL-C increased by 31% from baseline Dal-PLAQUE: effect on plasma lipids

41 Biomarker Baseline absolute mean (SE) 24 months absolute mean (SE) P-value vs. Placebo PlacebodalcetrapibPlacebodalcetrapib hs-CRP, mg/L* 1.4 (0.80, 2.80) 1.4 (0.60, 3.70) 1.1 (0.70, 3.60) 1.5 (0.60, 3.30) 0.38 IL-6, pg/mL 3.86 (0.79) 3.68 (0.36) 2.59 (0.23) 4.54 (4.70) 0.27 sP-Selectin, ng/mL (3.01) (2.66) (3.75) (2.95) 0.12 *.hs, high sensitivity (values for hs-CRP are median (IQR)); IQR, interquartile range; SE, standard error. P-values 2 sided CRP = C-Reactive Protein No significant change in hs-CRP Dal-PLAQUE: effect on inflammatory markers

42 Dalcetrapib was not associated with an increase in blood pressure compared with placebo There were 7 patients with 13 positively adjudicated CV events on placebo and 2 patients with 2 events on dalcetrapib Fewer drug-related AEs with dalcetrapib (11 [17%]) than placebo (placebo 18 [28%]) Discontinuation rates were similar in both groups Laboratory parameters were comparable between dalcetrapib and placebo Dal-PLAQUE: “safety” variables

43 Primary Endpoint: Assessment of No Harm No evidence of a pathological effect related to the arterial wall over 24 months. No evidence of progression of plaque burden No evidence of pro-inflammatory effect on artery wall Lipids 30% increase in HDL-C, 10% increase in apo-A1 Efficacy Endpoints MRI: evidence of less progression of plaque burden confined to total vessel area after 24 months on dalcetrapib. PET/CT imaging: did not meet primary endpoint….within group reduction with Dalcetrapib but from higher TBR at start Safety Generally well tolerated, with similar safety profile to placebo Dalcetrapib was not associated with an increase in blood pressure Roche, data on file. Dal-PLAQUE: summary

44 Carefully designed imaging studies can ameliorate risk – Patient selection – Informed choice of surrogate – Appropriate modalities Can not “DE”-risk Most recent study – reduced chance that Dalcetrapib is causing harm through adverse effects on cholesterol flux or inflammation Not clearly positive on ‘efficacy’ Conclusions

45 Large clinical outcomes studies are investigating the potential benefits of CETP modulation and CETP inhibition on CV risk –dal-OUTCOMES is investigating whether CETP modulation with dalcetrapib reduces CV morbidity and mortality in approximately 15,600 patients with recent ACS 5 – will investigate whether CETP inhibition with anacetrapib reduces major CV events in approximately 30,000 patients aged ≥50 years with established vascular disease 6


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