2. Photodynamic Therapy Daniel Simon, MD Director of the Molecular and Cellular Interventional Cardiology Research Laboratory Brigham and Women’s Hospital Boston, MA

3. Photosensitizing agent to accumulate in desired tissue (vascular tissue) Tissue accessible to uniform illumination with endovascularly delivered light of a specific wavelength Photodynamic Therapy Requirements

4. Cardiovascular applications Photodynamic Therapy Reduction of atherosclerosis lesion severity Stabilization of vulnerable plaques Restenosis prevention after stenting or balloon In-stent restenosis treatment Diagnosis of vulnerable plaque

5. Primary treatment Photodynamic Therapy Targets macrophages and other cellular components of plaque Induces apoptosis in the vascular cells Potentially allows for vascular-cell dropout and lesion regression and plaque stabilization

6. Drug in blood stream Step 1: Photosensitizer administration Step 2: Plaque accumulation Photodynamic Therapy The procedure:1 Images © Pharmacylics, Inc

7. Step 3: Plaque accumulation Step 4: Plasma clearance Photodynamic Therapy The procedure:2 Images © Pharmacylics, Inc

8. Catheter placement Step 5: Light fiber Step 6: Photo-illumination Photodynamic Therapy The procedure:3 Images © Pharmacylics, Inc

9. Step 7: Plaque ablation Step 8: ?Plaque stabilization Photodynamic Therapy The procedure:4 Images © Pharmacylics, Inc

10. 3 of 4 Photodynamic Therapy Who’s working on it Pharmacyclics Drug: motexafin lutetium (Antrin™) QLT (Medtronic/AVE) Drug: verteporfin (Visudyne®) Miravant Drug: tin ethyl etiopurpurin (Purlytin™)

11. 3 of 4 Photodynamic Therapy Phase II PAD study A Multicenter, Double-Blind, Dose-Ranging Clinical Trial of Antrin PA for the Prevention of Restenosis and Primary Treatment of De Novo Atherosclerotic Lesions in Peripheral Arteries Eligible subjects Symptomatic claudication Suitable lesions in the femoral or popliteal arteries ABI < 0.85 at rest or induced by exercise Ipsilateral toe pressure  60 mm Hg Antrin 2 mg/kg 400 J/cm-f n = 125 Antrin 4 mg/kg 781 J/cm-f n = 125 Antrin 4 mg/kg No light n = 125 Randomization

12. Side effects are almost exclusively related to the photosensitizing compounds. Some have a long plasma half-life, and could be activated by ambient light (phototoxicity). This is less and less of an issue with newer drugs, which possess short plasma half-lives and are activated by far-red light. 2 of 4 Photodynamic Therapy Side effects

13. Challenges Photodynamic Therapy There is an 18-24 hour interval between drug administration and procedure Light fiber is delivered by using a transit catheter, but the illumination adds 12 minutes to the procedure. Uniform illumination over a 30-50 mm segment.

14. The future Photodynamic Therapy Phase I peripheral study shows hints of clinical efficacy At this point its clinical efficacy remains unproven Treatment options as both primary treatment and as prevention of restenosis Diagnosis of vulnerable plaque through fluorescence

15. Diagnostic use Photodynamic Therapy Motexafin Lutetium (Antrin™) Image courtesy Daniel Simon

16. Drug interactions Photodynamic Therapy Little information about interactions with established cardiovascular drugs Phase I studies involving Antrin™ have seen no evidence of such interactions Real safety issues will have to wait for phase II and beyond

17. Diode LaserOptical Fiber Photodynamic Therapy Equipment Images © Pharmacylics, Inc

18. Cost Photodynamic Therapy The far-red activated compounds require just a diode laser that costs tens of thousands of dollars. Within the range of rotational atheroectomy, other therapies already in use in the cath lab.