1

MR Contrast Agents for Vulnerable Plaque Imaging

Philip Graham, PhDEPIX Medical, Inc.

Cambridge, MA 02142

2

MS-325: Vascular Contrast Agent• Albumin binding

•Extends plasma t1/2

•4-10X increase in signal

•Slows ECS uptake

• Phase III angiography trials ongoing

• Hypothesis: MS-325, an albumin-targeted Gd contrast agent, highlights inflamed vessel wall and facilitates plaque detection

Equilibrium Phase MS-325Arterial Phase

3

Vessel Wall Enhancement with MS-325

Courtesy of: T. Grist (University of Wisconsin, Madison, WI)

4

Jeffrey H. Maki1,2, Gregory J. Wilson1, Randall B. Lauffer3, Robert M. Weisskoff3,

Chun Yuan2

1 - Puget Sound VAHCS, Seattle, WA2 - University of Washington, Seattle, WA

3 - EPIX Medical, Cambridge, MA

Vessel Wall Enhancement with MS-325 MRI Facilitates Plaque Detection and

Characterization

5

Vessel Wall Enhancement with MS-325

• Atherosclerosis = inflammation• Leaky capillaries supplying vessel wall

– Increased albumin conc. in wall• Consistent enhancement of wall in

patients with MS-325• Implications for stenosis identification

and quantitation (and plaque burden)• Enhancement may correlate with risk of

rupture

Aorta

Right IliacArtery

VesselWall

VesselWall

Courtesy of: Dr. J Maki (UW/Puget S VA)

6Arterial Phase Equilibrium Phase MS-325

Source Images - Left External Iliac Artery

Artery

Vein

7

0

0.5

1

1.5

2

2.5

3

Adj to Plaque No Plaque

Wall Thickness (mm) Related to Plaque

Results

Adj to Plaque No Plaque

P < 0.01

8

Results

• Strong wall enhancement with MS-325 because of increased capillary volume and binding to extravasated albumin• Low signal between wall and lumen represents atherosclerotic plaque. • Prolonged enhancement of wall and lumen allows high resolution detection of plaque burden• Potentially straightforward method of plaque visualization and quantification

• ? Follow statin therapy

9

Pharmacological triggerhistamine = vasoconstrictor -> increases mechanical force on fibrous cap -> plaque disruptionRussells viper venom -> triggers blood clotting cascade

fresh thrombus

lipid core?

thin fibrous cap?

fresh thrombusvasoconstriction

pre-trigger

post-trigger disrupted plaque

T2w

Visualization of Plaque Rupture in Rabbit ModelJohnstone MT, Botnar RM, Perez AS, Stewart R, Quist W, Hamilton J, ManningWJ. In Vivo Magnetic Resonance Imaging of Experimental Thrombosis in aRabbit Model. Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1556-60.

Courtesy: Johnstone, Botnar, Manning: BIDMC

10

baseline

MS-325

MS-325 improves Plaque Visualization

plaque

contrast uptake no uptake

wall

plaque

thrombusMS-325Post-trigger

Courtesy: Johnstone, Botnar, Manning: BIDMC

11

Direct Clot Detection with Fibrin-Targeted Contrast Agent

• Fibrin targeting lead discovered in a collaboration with Dyax• MR contrast agents EP-1242 and EP-1873 resulted from

extensive modifications by EPIX of the original leads • Elimination profile similar to Magnevist®

EP-1242 Enhanced Carotid Clot in Guinea PigIn collaboration with Z. Fayad, Ph.D., Mt. Sinai, New York

12

To be annotated, final copy will be printed high definitionPost Gd-BSA (angiography)

Pre contrast1 minute post EP-1873

36 minute post EP-1873

Jugular thrombus

Rabbit Carotid thrombus

Jugular thrombus

Carotid thrombus

In collaboration with E. Kent Yucel, Lee Zhou (?) Brigham & Women’s, Boston

13

Pre contrast

10min

1.5h

1h

Post EP-1873 (fibrin agent)

aorta

thrombus

thrombus

thrombus

Botnar RM, Perez AP, Johnstone MT, Manning WJ

14

Pre contrast

10min

1.5h

1h

Post EP-1873 (fibrin agent)

Botnar RM, Perez AP, Manning WJ, Johnstone MT

15

Pre contrast 10min 1.5h

Post EP-1873 (fibrin agent)

aorta

thrombus thrombus

Botnar RM, Perez AP, Manning WJ, Johnstone MT

16

Summary

• Prototype clot-enhancing agents for MRI– High binding affinity and selectivity to human fibrin– Rapid Enhancement of arterial and venous clots– Good in vivo clot uptake and enhancement– No effects on clotting cascade

• Thrombotic consequences of plaque rupture directly visible on standard MR scans– Potential for assessing thromboembolic risk in a variety of

vascular beds– Follow clot resolution after treatment administration?