SHAPE Society

1. 29821.1
ANTRINANTRIN®®
(Motexafin Lutetium)(Motexafin Lutetium)
PhotoangioplastyPhotoangioplasty
Pharmacyclics
Sunnyvale, CA

2. 29821.2
Absorption Fluorescence
Phosphorescence
1
Sens
1
Sens
3
Sens
Type I
Type II
Biological Radicals
1
O2
3
O2
Biological Substrates
* 1
Sens+
Oxidative Damage
to Proteins & Lipids
hυ
*
*
Intersystem
Crossing
Photodynamic Therapy

3. 29821.3
ANTRINANTRIN®®
Spectral ProfileSpectral Profile

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ANTRINANTRIN®®
Localization in Atheromatous PlaqueLocalization in Atheromatous Plaque
Intravenous AdministrationIntravenous Administration
Rabbit aorta, 10 mg/kg, analysis at 24 hrs
Fluorescent
image
850800750700650
0
100
200
300
400
Plaque
Aortic Wall
Wavelength (nm)
FluorescenceIntensity
Plaque
Aortic Wall
Woodburn K, et al. J Clin Laser Med Surg. 1996

5. 29821.5
Key Properties of ANTRINKey Properties of ANTRIN®®
Generic Name Motexafin Lutetium (MLu)
Molecule Expanded synthetic porphyrin
Water-soluble formulation
Absorption peaks in vis-
nir
470 nm (Soret band)
732 nm (Q-band) – therapeutic wavelength
Tissue penetration Deeper than other PS under development.
Plasma pK T1/2α ~ 0.24 hr; T1/2β ~ 7.2 hr
Biolocalization Accummulates in atheromas, tumors, and neovascular
tissue.
Fluorescence Peak emission at 750 nm @ 470 - 480 nm excitation
Toxicity No significant phototoxicity
Dose limited by renal toxicity

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Balloon Injury Rabbit ModelBalloon Injury Rabbit Model
Immunoperoxidase staining with RAM11
Hayase et al. Cardiovascular Research 2001; 49:449-455
Control Treated
Effect on Macrophages

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Treatment Site
Below
Above
Hyperlipidemic Rabbit ModelHyperlipidemic Rabbit Model
Woodburn K, et al. J Clin Laser Med Surg.1996
2% cholesterol diet, 3-4 mos.
10 mg/kg Antrin IV, 24h
39-377 mW/cm-fiber, intra-balloon
Histology at 2 wks.

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Summary – Preclinical DataSummary – Preclinical Data
• MLu localizes in atheromatous plaque and in intimal
hyperplasia
• Variably reduces plaque in rabbit and rat models of
atherosclerosis
• No endothelial damage
• Consistent depletion of macrophages
• Potential treatment modality for atherosclerosis,
including that resulting from vascular tissue grafts

9. 29821.9
MLu Localization in Human svSMC,MLu Localization in Human svSMC, in vitroin vitro
Overlay
f
h
Mitochondria
Lysosomes
ER
Motexafin lutetiumFluores. Probe
Mitotracker
Green
Rhodamine B
Hexyl ester
Lysotracker
Red
Woodburn et al. J. Porphyrins Phthalocyanines 2001; 5: 130-133

10. 29821.10
Motexafin Lutetium PhotoangioplastyMotexafin Lutetium Photoangioplasty
Induced Cell DeathInduced Cell Death
732 nm light
5 mW/cm2
2J/cm2
dark
motexafin
lutetium
Macrophages SMC
732 nm light
motexafin
lutetium

11. 29821.11
Clinical ProgramClinical Program
Peripheral Arterial Disease
Completed. Phase II Multi-center, double-blind,
randomized trial, for prevention of restenosis
and primary treatment of De Novo lesions.
Coronary Arterial Disease
Completed. Phase I drug and light dose
escalation in subjects with CAD undergoing PCI
with stent placement.

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Optical DevicesOptical Devices
730 nm Diode Laser (Diomed)
Diffusing Fibers (CardioFocus)

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Antrin Photoangioplasty - PADAntrin Photoangioplasty - PAD

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Summary – Clinical ResultsSummary – Clinical Results
• No dose-limiting vascular toxicity in drug and light
doses tested
• No clinically relevant treatment-related serum
chemistry or hematology abnormalities noted
• Transient paresthesias seen in subjects receiving
> 2.0 mg/kg
• Mild rash; not in light-exposed areas - no
phototoxicity
• 24 hrs post-dosing, the plasma drug concentration
decreases to about 6% of Cmax