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29821.1
ANTRINANTRIN®®
(Motexafin Lutetium)(Motexafin Lutetium)
PhotoangioplastyPhotoangioplasty
Pharmacyclics
Sunnyvale, ...
29821.2
Absorption Fluorescence
Phosphorescence
1
Sens
1
Sens
3
Sens
Type I
Type II
Biological Radicals
1
O2
3
O2
Biologic...
29821.3
ANTRINANTRIN®®
Spectral ProfileSpectral Profile
29821.4
ANTRINANTRIN®®
Localization in Atheromatous PlaqueLocalization in Atheromatous Plaque
Intravenous AdministrationIn...
29821.5
Key Properties of ANTRINKey Properties of ANTRIN®®
Generic Name Motexafin Lutetium (MLu)
Molecule Expanded synthet...
29821.6
Balloon Injury Rabbit ModelBalloon Injury Rabbit Model
Immunoperoxidase staining with RAM11
Hayase et al. Cardiova...
29821.7
Treatment Site
Below
Above
Hyperlipidemic Rabbit ModelHyperlipidemic Rabbit Model
Woodburn K, et al. J Clin Laser ...
29821.8
Summary – Preclinical DataSummary – Preclinical Data
• MLu localizes in atheromatous plaque and in intimal
hyperpl...
29821.9
MLu Localization in Human svSMC,MLu Localization in Human svSMC, in vitroin vitro
Overlay
f
h
Mitochondria
Lysosom...
29821.10
Motexafin Lutetium PhotoangioplastyMotexafin Lutetium Photoangioplasty
Induced Cell DeathInduced Cell Death
732 n...
29821.11
Clinical ProgramClinical Program
Peripheral Arterial Disease
Completed. Phase II Multi-center, double-blind,
rand...
29821.12
Optical DevicesOptical Devices
730 nm Diode Laser (Diomed)
Diffusing Fibers (CardioFocus)
29821.13
Antrin Photoangioplasty - PADAntrin Photoangioplasty - PAD
29821.14
Summary – Clinical ResultsSummary – Clinical Results
• No dose-limiting vascular toxicity in drug and light
doses...
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Antrin (motexafin lutetium) photoangioplasty

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Antrin (motexafin lutetium) photoangioplasty

  1. 1. 29821.1 ANTRINANTRIN®® (Motexafin Lutetium)(Motexafin Lutetium) PhotoangioplastyPhotoangioplasty Pharmacyclics Sunnyvale, CA
  2. 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. 3. 29821.3 ANTRINANTRIN®® Spectral ProfileSpectral Profile
  4. 4. 29821.4 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. 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
  6. 6. 29821.6 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
  7. 7. 29821.7 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.
  8. 8. 29821.8 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. 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. 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. 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.
  12. 12. 29821.12 Optical DevicesOptical Devices 730 nm Diode Laser (Diomed) Diffusing Fibers (CardioFocus)
  13. 13. 29821.13 Antrin Photoangioplasty - PADAntrin Photoangioplasty - PAD
  14. 14. 29821.14 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

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