De-risking the development programs of CETP inhibitors after the torcetrapib

failure: Structural & functional imaging

Prof. Robin ChoudhuryJohn Radcliffe Hospital

Oxford, United Kingdom

Objectives in ‘de-risking’

Defining likely manifestations of treatment

Available Tools

New data: Dal-PLAQUE

Future

Conclusions

Overview

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

Imaging the vessel wall in atherosclerosis

Lindsay and Choudhury, Nature Reviews: Drug Discovery 2008, 7: 517-29

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

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

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

NIssen et al N Engl J Med 2007, 356:1304-1316

IVUS – pooled data suggests regression “tipping point”

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

Risk

of m

ajor

vas

cula

r eve

nt

10

15

20

25

30

35

0 1 2 3 4 5

HDL range

Ris

k o

f m

ajo

r va

scu

lar

even

t

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

SCREENING

INDIVIDUALPARTICIPATION

COMPLETED

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

T1 weighted T2 weighted

Carotid plaque imaging – multi-contrast MRI

A B

Vascular FUNCTION – aortic pulse wave velocity and compliance

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

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

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

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

Change LDL-C (mg/dL)

Cha

nge

CW

A (

mm

2)

Change HDL-C (mg/dL)

Cha

nge

CW

A (

mm

2)

Lipoproteins in relation to changes in vessel wall area

Lee JMS et al; J Am Coll Cardiol, 2009;54:1787-94

Tahara et al J Am Coll Cardiol, 2006; 48:1825-1831

18FDG-PET response to 3 months statin treatment

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

18FDG-PET – plaque measurement parameters

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

“Failure of Torcetrapib”

“Failure of Torcetrapib”

NIssen SE et al N Engl J Med 2007, 356:1304-1316

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

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

• 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

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

omis

ation

12-month MRI

12 months

Dal-PLAQUE: design

• 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

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

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

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

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

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

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

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

MD

S TB

R

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

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

MD

S TB

R

1.5

2.0

2.5

Months0 3 60 3 6

-10

-5

0

5

Chan

ge in

MD

S TB

R(%

incr

ease

from

bas

elin

e)

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

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

• 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

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 sided

CRP = C-Reactive Protein

No significant change in hs-CRP

Dal-PLAQUE: effect on inflammatory markers

• 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

• 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 pressureRoche, data on file.

Dal-PLAQUE: summary

• 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

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