prof. robin choudhury john radcliffe hospital oxford, united kingdom
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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De-risking the development programs of CETP inhibitors after the torcetrapib
failure: Structural & functional imaging
Prof. Robin ChoudhuryJohn Radcliffe Hospital
Oxford, United Kingdom
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Objectives in ‘de-risking’Defining likely manifestations of treatmentAvailable ToolsNew data: Dal-PLAQUEFutureConclusions
Overview
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Established
X-ray arteriographyMagnetic resonance imagingIntravascular ultrasound Optical coherence tomographyPositron emission tomographyComputed tomographyCarotid IMT
Developmental
ElastographyThermographyRaman SpectroscopyNear infrared imagingResolved laser induced
fluorescence spectroscopy‘Molecular techniques’
Modalities for atherosclerosis imaging
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Imaging the vessel wall in atherosclerosis
Lindsay and Choudhury, Nature Reviews: Drug Discovery 2008, 7: 517-29
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Atherosclerosis regression on statins – wall imaging with MRI
@12 Months
Vessel wall areaAorta decrease ~ 8%Carotid decrease ~ 15%
Lumen AreaAorta unchangedCarotid unchanged
Max ThicknessAorta decrease ~ 9%Carotid decrease ~ 11%
Corti R et al. Circulation, 2001;104: 249-2525
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Underhill et al. AHJ, 2008;155:584:e1-8
T1W ToF PDW T2W
t = 0
t = 0
t = 2y
~40 patients with US-defined carotid artery stenosis. Randomised to rosuvastatin 5mg vs 20-40 mg / dayNo change in overall plaque burden BUTIn patients (n=16) with lipid rich core – regression of core over 24 months
Plaque composition analysis
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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 diseased10mm segment (of non-stenotic vessel )
Reduced ~8%
Nissen et al, JAMA 2006;305:2257-2368
ASTEROID – Potential for plaque regression with IVUS
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NIssen et al N Engl J Med 2007, 356:1304-1316
IVUS – pooled data suggests regression “tipping point”
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Prospective Pravastatin Pooling Project
19,800 patients primary and secondary3 pooled trials of pravastatin (WOSCOPS, CARE, LIPID)
Heart Protection Study
>20,000 pts CHD,PVD or diabetesSimvastatin 40mg vs placebo
10
15
20
25
30
35
0.5 1.5 2.5 3.5HDL range
Ris
k of
maj
or v
ascu
lar ev
ent
10
15
20
25
30
35
0 1 2 3 4 5
HDL range
Ris
k of
maj
or v
ascu
lar e
vent
placeboplacebo
pravastatinsimvastatin
<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 StudyProspective Pravastatin Pooling Project
Lancet, 2002;360:7-22Sacks FM et al Circualtion 2000;102:1893-900
HDL-cholesterol relationship persists in patients treated with statins
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SCREENINGINDIVIDUAL
PARTICIPATIONCOMPLETED
Established atherosclerosis and HDL-c < 1mmol/LAll treated with statins
Randomised to placebo or Niaspan375mg for 1wk > 500mg for 1 wk > 750mg for 1 wk > 1000mg for 4 wks >
1500mg 4 wks > 2000mg maintenancePrimary end point = change in carotid wall area at 12 months
6 MONTH REVIEWMRI
FASTING BLOODS
12 MONTH REVIEWMRI
FASTING BLOODS
Week 7LFTs, CK
Week 15LFTs, CK
BASELINEMRI
FASTING BLOODS
Effect of nicotinic acid on atherosclerosis progression when added to statin therapy
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T1 weighted T2 weighted
Carotid plaque imaging – multi-contrast MRI
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A B
Vascular FUNCTION – aortic pulse wave velocity and compliance
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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 mm2
= 24.7 mm2
= 27.1 mm2
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Randomised (n=71)
Placebo(n=36)
ExcludedClaustrophobia 2
Completed first MRI(n=34)
Active(n=35)
Completed first MRI(n=33)Excluded
Hyperglycemia 1Nausea / dyspepsia / diarrhoea 3Flushing / itching 3Lost to follow-up 1Withdrew consent 1
ExcludedClaustrophobia 1Withdrew Consent 1
ExcludedNausea / dyspepsia 1Claustrophobia 1Other medical illness 1Withdrew consent 1
ExcludedWithdrew consent 1
Completed second MRI(n=24)
Completed second MRI(n=30)
ExcludedAbnormal baseline blood tests 2
Completed study(n=22)
Completed study(n=29)
Patient flow
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Lee JMS et al; J Am Coll Cardiol, 2009;54:1787-94
Baseline
6 months
12 months
NA
153 ± 32 141 ± 25* 147 ± 26* Total-C (mg/dL) Placebo
161 ± 42 159 ± 35 154 ± 25
NA 39 ± 6 46 ± 9* 48 ± 7* HDL-C (mg/dL) Placebo
37 ± 5 36 ± 6 38 ± 6
NA
85 ± 23 64 ± 16* 69 ± 21* LDL-C (mg/dL) Placebo
84 ± 32 80 ± 28 80 ± 22
NA
168 (134, 206) 150 (91, 190)* 150 (94, 180)* Triglycerides median (IQR) (mg/dL) Placebo
192 (132, 248) 182 (144, 248) 181 (143, 252)
Effect of nicotinic acid on lipoproteins
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Placebo Nicotinic acid
Cha
nge
in c
arot
id w
all a
rea
(mm
2 ) *
*p=0.03 (mixed effect model adjusted for baseline covariates)estimated treatment difference [95% CI] = −1.64 mm2 [−3.12, −0.16]
Lee JMS et al; J Am Coll Cardiol, 2009;54:1787-94
Effect of nicotinic acid on atherosclerosis progression
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Change LDL-C (mg/dL)
Cha
nge
CW
A (m
m2 )
Change HDL-C (mg/dL)
Cha
nge
CW
A (m
m2 )
Lipoproteins in relation to changes in vessel wall area
Lee JMS et al; J Am Coll Cardiol, 2009;54:1787-94
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Tahara et al J Am Coll Cardiol, 2006; 48:1825-1831
18FDG-PET response to 3 months statin treatment
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Tawakol A et al. J Am Coll Cardiol, 2006; 48:1818-1824
17 patients with severe carotid stenosis. PET signal correlated strongly with plaque macrophage count at CEA:but not with smooth muscle cells
18FDG PET signal correlates with macrophage content
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18FDG-PET – plaque measurement parameters
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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 effectsSmall studies and short follow-up
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“Failure of Torcetrapib”
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“Failure of Torcetrapib”
NIssen SE et al N Engl J Med 2007, 356:1304-1316
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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 Investigators1Mount 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
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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 Coll Cardiol. 2007;50:892–896.
Dal-PLAQUE rationale
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• 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
Dal-PLAQUE
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TBR >1.6-inflammation
presentby 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. 2011
130 Treated (1:1 allocation)189 patients screened
Recruitmentn=189 subjects
screened
Double-blind treatment periodSubjects 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 2008Last 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
rand
omisa
tion
12-month MRI
12 months
Dal-PLAQUE: design
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• 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;162:214-221.e2.
Dal-PLAQUE: inclusion
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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
1Hayashi K et al. JCMR 2010; 2Lee JM et al. JACC 2009; 3Underhill HR et al. AHJ 2008; 4Rudd JH et al. JACC 2007
Dal-PLAQUE: end points
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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) 64.6 62.6 BMI, kg/m2 (mean) 29.8 29.6CHD and CHD risk factors CHD, n (%) 54 (82) 57 (89) Symptomatic CAD, n (%) 5 (8) 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
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Placebo (N=66)
Dalcetrapib 600 mg(N=64)
Total cholesterol, mg/dL [mmol/L]a 147.9 ± 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 128.0 (93.0–159.0)[1.45 (1.1–1.8)]
123.5 (85.0–170.0)[1.4 (1.0–1.9)]
Statin use, n (%)c 61 (92) 52 (81)
aMean ± SD; bMedian (interquartile range); cPatients with at least one treatment.
189 patients screened of whom 130 Rx: baseline demographics and lipid parameters similar
Dal-PLAQUE: baseline characteristics
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VariablePlacebo
(N=65)Dalcetrapib
(N=63)Absolute change vs
placebo (90% CI) P valueNo-harm
boundary**
MRI, mean* (SE)†
Total vessel area, mm2 5.72 (1.45) 1.71 (1.43) -4.01(-7.23, -0.80) 0.04 2.0
Wall area, mm2 2.69 (1.05) 0.49 (1.04) -2.20(-4.54, 0.13) 0.12 3.0
Wall thickness, mm 0.05 (0.03) 0.02 (0.03) -0.03(-0.11, 0.04) 0.45 0.02
Normalized wall index, % -0.40 (0.80) 0.30 (0.80) 0.60
(-1.20, 2.50) 0.57 4.00
PET/CT, mean* (SE)‡
Most diseased segment mean of maximum TBR
-0.26 (0.08) -0.19 (0.08) 0.07(-0.11, 0.25) 0.51 0.27
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 baselineNominal P-values
Dal-PLAQUE: MRI (24 months) and PET (6 months) outcomes
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P=0.002 P=0.24P=0.04
Adverse remodeling was seen in the placebo group and not the dalcetrapib groupindividual patient data
Dal-PLAQUE: MRI (24 months): change in total vessel area
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Absolute Change Percent Change
*P=0.001 *P=0.16
ǂP=0.045*P=0.002 *P=0.24
ǂP=0.04
*24 months vs baseline; ǂ dalcterapib vs placebo at 24 months after baseline correction
Placebo Dalcetrapib
Months
TVA
(mm
2 )
0 6 12 18 24 0 6 12 18 24
55
60
65
70
Months
Chan
ge in
TVA
(% in
crea
se fr
om b
asel
ine)
0 6 12 18 24 0 6 12 18 24
0
5
10
15
-2
Placebo Dalcetrapib
Apparent increase in TVA across time in the placebo group, not in dalcetrapib group
Dal-PLAQUE: MRI (24 months): change in total vessel area
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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=0.08
1.00
1.50
2.00
2.50
3.00
MDS
TBR
Placebo dalcetrapibBaseline 6 months Baseline 6 months
P=0.70 P=0.001P=0.08
Dal-PLAQUE: PET-CT (6 months): change in target to background ratio in most diseased segment
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Absolute Change Percent Change
*P=0.71 *P=0.003
ǂP=0.07*P=0.48 *P=0.001
ǂP=0.08
Placebo Dalcetrapib
Months0 3 60 3 6
MDS
TBR
1.5
2.0
2.5
Months0 3 60 3 6
-10
-5
0
5
Chan
ge in
MDS
TBR
(% in
crea
se fr
om b
asel
ine)
Placebo Dalcetrapib
Absolute Change Percent 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 groupFor 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
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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
Placebodalcetrapib
Dal-PLAQUE: PET-CT (6 months): change in target to background ratio in most diseased segment by HDL-c tertile
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• 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
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Biomarker Baselineabsolute mean (SE)
24 monthsabsolute mean (SE)
P-value vs. Placebo
Placebo dalcetrapib Placebo dalcetrapib
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 71.87(3.01)
74.64(2.66)
76.93(3.75)
73.63(2.95) 0.12
*.hs, high sensitivity (values for hs-CRP are median (IQR)); IQR, interquartile range; SE, standard error. P-values 2 sidedCRP = C-Reactive Protein
No significant change in hs-CRP
Dal-PLAQUE: effect on inflammatory markers
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• 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
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• 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
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• 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
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Conclusions
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 ACS5
– will investigate whether CETP inhibition with anacetrapib reduces major CV events in approximately 30,000 patients aged ≥50 years with established vascular disease6