1. ART-RIM, 25-Jan-09 1 Mitigation of Chronic Radiation Injuries by ACE Inhibitors and AII Blockers John Moulder, Ph.D. Center for Medical Countermeasures Against Radiological Terrorism Medical College of Wisconsin

2. ART-RIM, 25-Jan-09 2 PRERADIATIONCLINICAL SYMPTOMS PROPHYLAXIS/ PROTECTION MITIGATIONTREATMENT Why Mitigation Rather than Treatment? Practical: –Rather than get the injuries treated, most cancer survivors would prefer not to have the injuries in the first place. Medical: –Known interventions work best if they are started before the injury is clinically evident.

3. ART-RIM, 25-Jan-09 3 Can Late Effects Be Mitigated? Mitigation proven in at least two experimental systems: Kidney (ACE inhibitors, AII blockers) Lung (ACE inhibitors, AII blockers, SOD/catalase mimetics) CNS (ACE inhibitors) Skin (ACE inhibitors) Promising mitigation data in one experimental system: Kidney (SOD/catalase mimetics, selenium) Lung (statins, genistein, curcumin?) CNS (statins) Skin (SOD/catalase mimetics) Cardiac (AII blockers, curcumin) Combined injury (ACE inhibitors, SOD/catalase mimetics)

4. ART-RIM, 25-Jan-09 4 Can Late Effects Be Mitigated? Mitigation proven in at least two experimental systems: Kidney (ACE inhibitors, AII blockers) Lung (ACE inhibitors, AII blockers, SOD/catalase mimetics) CNS (ACE inhibitors) Skin (ACE inhibitors) Promising mitigation data in one experimental system: Kidney (SOD/catalase mimetics, selenium) Lung (statins, genistein, curcumin?) CNS (statins) Skin (SOD/catalase mimetics) Cardiac (AII blockers, curcumin) Combined injury (ACE inhibitors, SOD/catalase mimetics)

5. ART-RIM, 25-Jan-09 5 Mitigation of Radiation Nephropathy (Moulder, Fish, Cohen et al, MCW) Mitigator: Captopril (an FDA-approved ACE inhibitor) started 10 days after TBI. Azotemia (as BUN in mg/dl) after 26 wks TBI Dose (Gy) 81012 TBI + Captopril TBI Alone 20 40 100 200 60 Normal

6. ART-RIM, 25-Jan-09 6 Mitigation of Pulmonary Vascular Injury (Ghosh et al, Int J Rad Oncol Biol Phys, ’08) Planar angiograms 2 months after irradiation Irradiation causes vascular drop-out in the lung within 2 months after irradiation. Captopril can mitigate this effect. Mitigator: Captopril (an FDA-approved ACE inhibitor) started after irradiation Unirradiated10 Gy whole-thorax + captopril

7. ART-RIM, 25-Jan-09 7 Mitigation of Pulmonary Fibrosis (Medhora et al, MCW) Unirradiated12 Gy whole-thorax12 Gy + captopril Masson’s trichrome stained un-inflated lung 8 months after irradiation Mitigator: Captopril (an FDA-approved ACE inhibitor) started after irradiation

8. ART-RIM, 25-Jan-09 8 Untreated control30 Gy30 Gy + Ramipril Mitigation of Optic Neuropathy (Kim, Brown et al, Radiat. Res., ‘04) Myelin staining (Luxol Fast Blue) of the optic nerves 6 months after irradiation. Luxol Blue staining is normal for a functioning neuron. Mitigator: Ramipril (an FDA-approved ACE inhibitor) started 2 wks after irradiation

9. ART-RIM, 25-Jan-09 9 Mitigation of Cardiac Injury (Baker et al, Int J Rad Biol, ‘09) Cardiac injury 120 days after TBI Mitigator: Cozaar ® (losartan, an FDA-approved AII blocker) started 5 days after TBI. %0 30%60% Global Radial Strain Control Control + losartan 10 Gy 10 Gy + losartan

10. ART-RIM, 25-Jan-09 10 Mitigation of a Combined Injury (Lazarova et al, MCW) 30 Gy + vehicle 30 Gy + captopril 1 month after irradiation + wounding Combined injury: Skin irradiation (4 x 7.5 cm) plus wound (8 mm full-thickness punch biopsy) Mitigator: Captopril (an FDA-approved ACE inhibitor) started 2 days after irradiation

11. ART-RIM, 25-Jan-09 11 Mitigation of Radiation Injuries in Humans Clinically, there are no proven mitigators of radiation injury: –ACE inhibition is as close as we have come. Two clinical trials to date: –A Phase II RTOG trial of captopril after lung irradiation. Terminated because of poor accrual. –A single-institution Phase III trial of captopril after TBI/BMT. Cohen et al, Int J Rad Oncol Biol Phys, 2008

12. ART-RIM, 25-Jan-09 12 ACE Inhibition after TBI/BMT (Cohen et al, 2008) Adults and children receiving TBI as preparation for BMT. –Captopril (ACE inhibitor) started at engraftment and continued for one year. Not proof of mitigation of radiation injuries: –Radiation is not the only cause of chronic renal failure in these patients. Incidence of Bone Marrow Transplant Nephropathy Years after Irradiation 0% 20% 40% Captopril No Drug P=0.07 8624100

13. ART-RIM, 25-Jan-09 13 ACE Inhibition after TBI/BMT (Cohen, Irving et al, MCW) Survival continues to diverge after the last incidence of BMT nephropathy. Something in addition to radiation nephropathy is being mitigated. 100% 50% 75% 0% Patient Survival Captopril No drug P=0.03 Years after Irradiation 8 624100 25%

14. ART-RIM, 25-Jan-09 14 Mitigation via Suppression of the Renin-Angiotensin System ACE inhibitors and AII blockers have shown mitigation efficacy in a broad range of experimental models. –An ACE inhibitor (captopril) has shown mitigation efficacy in humans. These are FDA-approved drugs being used at doses (on a g/m 2 /day basis) equivalent to current human use. –The drugs have good safety profiles. –The drugs are widely available and cheap. As mitigators, these drugs could be used “off-label”. –This is legal under the “practice of medicine” rule as long as it is done on an individual patient basis. –But the “practice of medicine rule” does not allow a government agency (or anyone else??) to advocate such “off-label” use.

15. ART-RIM, 25-Jan-09 15 Barriers to Widespread Use as Mitigators They are not FDA-labeled for this indication. –And there is no obvious route to getting them labeled as such. The drugs are off-patent and relatively cheap. –No one has a financial motive to develop them for this indication. Their mechanism of action (as mitigators) is unclear. –This is not necessarily a problem for use in radiation oncology. –This is an issue for labeling via the FDA “animal efficacy rule.” There may be toxicity issues. –They are teratogens. –They may exacerbate radiation-induced GI injury if given immediately after irradiation.

16. ART-RIM, 25-Jan-09 16 Can they mitigate chronic radiation-induced injuries? Yes, in experimental models Possibly, in humans Can they mitigate at FDA-approved doses? Yes Will they be FDA-labeled for this purpose? Unlikely under current rules and conditions Will they be used in radiation oncology? They have already been used off-label Bottom Line: ACE Inhibitors and AII Blockers as Mitigators