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Prof. Robin Choudhury John Radcliffe Hospital Oxford, United Kingdom

De-risking the development programs of CETP inhibitors after the torcetrapib failure: Structural & functional imaging . Prof. Robin Choudhury John Radcliffe Hospital Oxford, United Kingdom. Overview. Objectives in ‘de-risking’ Defining likely manifestations of treatment Available Tools

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Prof. Robin Choudhury John Radcliffe Hospital Oxford, United Kingdom

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

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

  4. Imaging the vessel wall in atherosclerosis Lindsay and Choudhury, Nature Reviews: Drug Discovery 2008, 7: 517-29

  5. Atherosclerosis regression on statins – wall imaging with MRI @12 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: 249-252 5

  6. Plaque composition analysis t = 0 t = 0 t = 2y T1W ToF PDW T2W ~40 patients with US-defined carotid artery stenosis. Randomised to rosuvastatin 5mg vs 20-40 mg / day No change in overall plaque burden BUT In patients (n=16) with lipid rich core – regression of core over 24 months Underhill et al. AHJ, 2008;155:584:e1-8

  7. ASTEROID – Potential for plaque regression with IVUS 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-stenoticvessel ) Reduced ~8% Nissen et al, JAMA 2006;305:2257-2368

  8. IVUS – pooled data suggests regression “tipping point” NIssen et al N Engl J Med 2007, 356:1304-1316

  9. HDL-cholesterol relationship persists in patients treated with statins placebo placebo pravastatin simvastatin <0.90 ≥0.90- < 1.10 ≥1.10 HDL-c (mmol/L) <0.78 0.80-0.88 0.90-0.98 1.00-1.14 <1.14 HDL-c (mmol/L) Heart Protection Study Prospective Pravastatin Pooling Project 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 Lancet, 2002;360:7-22 Sacks FM et alCircualtion 2000;102:1893-900

  10. Effect of nicotinic acid on atherosclerosis progression when added to statin therapy 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 Week 7 LFTs, CK Week 15 LFTs, CK INDIVIDUAL PARTICIPATION COMPLETED SCREENING 6 MONTH REVIEW MRI FASTING BLOODS BASELINE MRI FASTING BLOODS 12 MONTH REVIEW MRI FASTING BLOODS

  11. Carotid plaque imaging – multi-contrast MRI T2 weighted T1 weighted

  12. Vascular FUNCTION – aortic pulse wave velocity and compliance B A

  13. Brachial artery flow-mediated vasodilatation = 21.2 mm2 = 24.7 mm2 = 27.1 mm2 Repeat baseline => 400 µg GTN s.l. Baseline Post GTN (endothelium-independent maximal dilatation) 4.5 min cuff inflation (suprasystolic pressure) FMD (endothelium-dependent dilatation)

  14. Patient flow Randomised (n=71) Placebo (n=36) Active (n=35) Excluded Abnormal baseline blood tests 2 Excluded Claustrophobia 2 Completed first MRI (n=34) Completed first MRI (n=33) Excluded Hyperglycemia 1 Nausea / dyspepsia / diarrhoea 3 Flushing / itching 3 Lost to follow-up 1 Withdrew consent 1 Excluded Nausea / dyspepsia 1 Claustrophobia 1 Other medical illness 1 Withdrew consent 1 Completed second MRI (n=30) Completed second MRI (n=24) Excluded Claustrophobia 1 Withdrew Consent 1 Excluded Withdrew consent 1 Completed study (n=29) Completed study (n=22)

  15. Effect of nicotinic acid on lipoproteins Lee JMS et al; J Am Coll Cardiol, 2009;54:1787-94

  16. Effect of nicotinic acid on atherosclerosis progression Change in carotid wall area (mm2) Placebo Nicotinic acid * *p=0.03 (mixed effect model adjusted for baseline covariates) estimated treatment difference [95% CI] = −1.64mm2 [−3.12, −0.16] Lee JMS et al; J Am CollCardiol, 2009;54:1787-94

  17. Lipoproteins in relation to changes in vessel wall area Change CWA (mm2) Change CWA (mm2) Change HDL-C (mg/dL) Change LDL-C (mg/dL) Lee JMS et al; J Am CollCardiol, 2009;54:1787-94

  18. 18FDG-PET response to 3 months statin treatment Taharaet al J Am CollCardiol, 2006; 48:1825-1831

  19. 18FDG PET signal correlates with macrophage content 17 patients with severe carotid stenosis. PET signal correlated strongly with plaque macrophage count at CEA: but not with smooth muscle cells Tawakol A et al. J Am Coll Cardiol, 2006; 48:1818-1824

  20. 18FDG-PET – plaque measurement parameters

  21. 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

  22. “Failure of Torcetrapib”

  23. “Failure of Torcetrapib” NIssen SE et al N Engl J Med 2007, 356:1304-1316

  24. 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. Fayad1, Venkatesh Mani1, Mark Woodward2, David Kallend3, Tracy Burgess4, Marcus Abt3, Valentin Fuster1, James H.F. Rudd5, Ahmed Tawakol6, Michael E. Farkouh1,7, on behalf of the dal-PLAQUE Investigators 1Mount Sinai Medical Center, New York, NY, USA; 2University of Sydney, Sydney, Australia; 3F. Hoffmann-La Roche Ltd, Basel, Switzerland; 4Hoffmann-La Roche Inc., Nutley, NJ, USA; 5University of Cambridge, Cambridge, UK; 6Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA; 7Peter Munk Cardiac Centre and Li Ka Shing Knowledge Institute, Toronto, Canada ClinicalTrials.gov Identifier: NCT00655473. Fayad ZA et al Lancet 2011, On line Sept 12

  25. Dal-PLAQUE rationale To use a dual-imaging approach to determine the effects of dalcetrapib on measures of atherosclerotic plaque inflammation and plaque burden1 • 18F-FDG PET/CT uptake to determine changes in plaque inflammation activity1,2 • MRI to measure parameters of plaque morphology, and assess the progression/regression of atherosclerosis1 1Fayad et al. Am Heart J. 2011;162:214-221.e2; 2Rudd et al. J Am CollCardiol. 2007;50:892–896.

  26. Dal-PLAQUE • 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) 18-75 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: • MRI @ 6, 12, 24 months • PET@3, 6 months

  27. Dal-PLAQUE: design • A double-blind, randomized, placebo (S.O.C.)- controlled, parallel group,multi-center (11 sites) study in 130 patients with CHD or CHD equivalent 189 patients screened 130 Treated (1:1 allocation) randomisation First patient screened Feb 2008Last patient randomised Nov 2008 Double-blind treatment period Subjects allocated to dalcetrapib 600 mg/day (n=64) or placebo (n=66) for 24 months Recruitmentn=189 subjects screened TBR >1.6-inflammation present by a central core lab 12 months -3 months 0 months 6 months 24 months 3-month PET/CT 6-month PET/CT* Baseline PET/CT at screening 6-month MRI Baseline MRI 2 wk before randomisation 24-month MRI* 12-month MRI *Primary Endpoints 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* Fayad ZA et al. Am Heart J. 2011

  28. Dal-PLAQUE: inclusion • 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 (TawakolA 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;162:214-221.e2.

  29. Dal-PLAQUE: end points 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 vsbaseline in TBR within the most diseased segment (MDS)4 of the index vessel 1Hayashi K et al. JCMR 2010; 2Lee JM et al. JACC 2009; 3Underhill HR et al. AHJ 2008; 4Rudd JH et al. JACC 2007

  30. Dal-PLAQUE: baseline characteristics • 189 patients screened of whom 130 Rx: baseline demographics and lipid parameters similar

  31. Dal-PLAQUE: baseline characteristics aMean ± SD; bMedian (interquartile range); cPatients with at least one treatment. • 189 patients screened of whom 130 Rx: baseline demographics and lipid parameters similar

  32. Dal-PLAQUE: MRI (24 months) and PET (6 months) outcomes 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

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

  34. Dal-PLAQUE: MRI (24 months): change in total vessel area ǂP=0.045 ǂP=0.04 *P=0.002 *P=0.24 *P=0.001 *P=0.16 70 15 Placebo Dalcetrapib Placebo Dalcetrapib 10 65 Change in TVA(% increase from baseline) TVA (mm2) 5 60 0 -2 55 24 0 6 12 18 0 6 12 18 24 0 6 12 18 24 0 6 12 18 24 Months Months Absolute Change Percent Change *24 months vsbaseline; ǂdalcterapibvs placebo at 24 months after baseline correction • Apparent increase in TVA across time in the placebo group, not in dalcetrapibgroup

  35. Dal-PLAQUE: PET-CT (6 months): change in target to background ratio in most diseased segment P=0.08 P=0.001 P=0.70 3.00 2.50 2.00 MDS TBR 1.50 1.00 Baseline 6 months Baseline 6 months dalcetrapib Placebo • MDS TBR decreased in dalcetrapib(p=0.001) but not in placebo (p=0.7) • For the baseline corrected comparison between dalcetrapibvs placebo, p=0.08

  36. Dal-PLAQUE: PET-CT (6 months): change in target to background ratio in most diseased segment ǂP=0.07 ǂP=0.08 *P=0.71 *P=0.48 *P=0.003 *P=0.001 Placebo Dalcetrapib Placebo Dalcetrapib 2.5 5 0 2.0 Change in MDS TBR(% increase from baseline) MDS TBR -5 -10 1.5 0 3 6 0 3 6 0 3 6 0 3 6 Months Months Absolute Change Percent Change *6 months vsbaseline;ǂdalcetrapibvs placebo at 6 months after baseline correction Absolute Change Percent Change • Apparent decrease in TBR across time in the dalcetrapibgroup, not in placebo group • For the baseline corrected comparison between dalcetrapibvs placebo, p=0.08 and 0.07, respectively

  37. Dal-PLAQUE: PET-CT (6 months): change in target to background ratio in most diseased segment by HDL-c tertile Placebo dalcetrapib • 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

  38. Dal-PLAQUE: effect on plasma lipids • Dalcetrapib600 mg for 24 months • CETP activity decreased by ~51% from baseline • ApoA-I increased by 6.8% vsbaseline(placebo-corrected) • HDL-C increased by 31% from baseline

  39. Dal-PLAQUE: effect on inflammatory markers *.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

  40. Dal-PLAQUE: “safety” variables • Dalcetrapibwas 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 dalcetrapiband placebo

  41. Dal-PLAQUE: summary • 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.

  42. Conclusions • 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’

  43. Conclusions Large clinical outcomes studies are investigating the potential benefits of CETP modulation and CETP inhibition on CV risk • dal-OUTCOMESis investigating whether CETP modulation with dalcetrapib reduces CV morbidity and mortality in approximately 15,600 patients with recent ACS5 • will investigate whether CETP inhibition with anacetrapib reduces major CV events in approximately 30,000 patients aged ≥50 years with established vascular disease6

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