1. PH Treatments: What's on the Horizon Ivan M. Robbins, MD Vanderbilt University Pulmonary Vascular Center

2. PPH: a new disorder Dresdale et al, 1951: –Reported three patients with unexplained pulmonary hypertension –Clinical, hemodynamic, and pathological features –Coined the term PPH –First attempt at treatment using tolazoline (Priscoline), an adrenergic inhibitor Dresdale et al, 1954: first report of familial PAH Dresdale, Am J Med, 1951 Dresdale, Bull NY Acad Med, 1954

3. PAH: initial treatment Vasodilators: -tolazoline, tetraethylammonium chloride and hexamethonium (autonomic blocking agents), reserpine, acetylcholine, and O 2 Digoxin Mercurial diuretics Calcium channel blockers

5. Lancet, 1984

6. Humbert M et al. N Engl J Med. 2004;351:1425-1436. Targets for current PAH-specific therapy Big Endothelin Endothelin- converting Enzyme Endothelin Receptor A Endothelin Receptor B Vasoconstriction and Proliferation Endothelin Receptor Antagonists Endothelin-1 Endothelin Pathway Arginine Nitric Oxide Synthase Vasodilatation and Antiproliferation Nitric Oxide cGMP Exogenous Nitric Oxide Phosphodiesterase Type-5 Phosphodiesterase Type-5 Inhibitors Nitric Oxide Pathway Arachidonic Acid Prostacyclin Synthase Vasodilatation and Antiproliferation Prostacyclin cAMP Prostacyclin Derivatives Prostacyclin Pathway

7. FDA-approved therapies for PAH Prostacyclin Derivatives Epoprostenol: IV Iloprost: inhaled Treprostinil: subcutaneous, IV, inhaled Endothelin Receptor Antagonists Bosentan: oral Ambrisentan: oral Phosphodiesterase Type-5 Inhibitors Sildenafil: oral Tadalafil: oral

8. Current PAH-specific treatment: Monotherapy 20 RCTs with 9 medications as monotherapy completed in PAH patients –8 studies with prostaglandins –9 studies with endothelin receptor antagonists (ERAs) –2 studies with phosphodiesterase type 5 inhibitors (PDE-5Is) “Optimal agent for PAH monotherapy remains unclear” Barst et al, JACC, 2009

9. Current PAH-specific treatment: Combination therapy 6 RCTs of combination therapy in PAH have been completed –IV epoprostenol with ERA and with PDE-5I –2 studies with inhaled iloprost with ERA –Inhaled treprostinil with ERA and/or PDE-5I –ERA and PDE-5I Other combination studies on-going “Optimal combination on the basis of overall risk- benefit considerations remains unknown” Barst et al, JACC, 2009

10. Treatment of PAH: 2010 Treatment of PAH: 2010 Currently approved therapies: – Improve symptoms, exercise capacity, ?survival – No therapy is curative – Modest improvement in hemodynamics – Very expensive

11. Vascular Remodeling Other Risk Factors Altered Pathways and Mediators Genetic Predisposition Pathogenesis of PAH 2010: An Integrated View Proliferation Vasoconstriction Thrombosis Inflammation

12. Newman J Circulation 2004: 109: 2947-52 PAH: A complex vascular remodeling disease

13. Modified from Newman J Circulation 2004: 109: 2947-52 and Elliott G, 2009 Targets for potential new therapies for PAH HIF-1ά activation mitochondria dichloroacetate Extracellular matrix PPARÝ Thiazolidinediones Aviptadil (VIP) Kinase inhibitors STr inhibitor IPR AC-065A302

14. Some new therapeutic approaches (clinical trials completed or underway*)  Imatinib (tyrosine kinase Inhibitor)  Sorafenib (multi-kinase Inhibitor)  Endothelial progenitor cells –Canada only  BAY 63-2521 (Riociguat) (sGC stimulator)  ACT-064992 (Macitentan) (tissue ERA)  Escitalopram (STr Inhibitor) -France * Clinical trials.gov

15. Recent clinical trials in PAH that were stopped early or negative  6R-BH4 (NOS co-factor)  Cicletanine (eNOS coupler, vasodilator, diuretic)  Simvastatin (HMG-CoA reductase inhibitor)  Bosentan, sildenafil in sickle cell disease- associated PH

16. Imatinib inhibits tumor growth and angiogenesis

17. Imatinib Phase 2 study of 59 PAH patients –Add on to prostacyclin analogues, PDE5I and ERAs 24 week, placebo-controlled 42/59 completed the study, well tolerated –3 deaths in placebo and active drug group No significant change in 6MWD –Post-hoc analysis: improvement in 6MWD and hemodynamics in those with PVR>1000

18. Sorafenib inhibits tumor growth and angiogenesis Sorafenib inhibits tumor growth and angiogenesis

19. Sorafenib  Phase 1b 16 week study of 12, FC I-III PAH patients  Add on to prostacyclin analogues, PDE5I and ERAs  11/12 completed study  All patients experienced at least one study drug-related SE, not severe  All 5 patients on epoprostenol had improvement in ras  No significant improvement in 6 min walk  Significant improvement in CO Gomberg-Maitland, et al, Clin Pharmacol Ther, 2009

20. Humbert M et al. N Engl J Med. 2004;351:1425-1436. Targets for current PAH-specific therapy Arachidonic Acid Prostacyclin Synthase Vasodilatation and Antiproliferation Prostacyclin cAMP Derivatives Prostacyclin Derivatives Prostacyclin Pathway PGI2 receptor ACT-293987

21.  Phase 2a, placebo controlled study of 43 PAH patients (33 received active drug)  Add on therapy to PDE5Is or ERAs  17 week study of FC II/III patients  No statistical improvement in 6MWD  Significant decrease in PVR  Main side effects:  H/A, jaw pain, extremity pain, nausea and nasopharyngitis

22. Corbin and Francis J Biol Chem 1999; 274:13729 Riociguat Riociguat PDE5 Riociguat oral stimulator of the enzyme that converts nitric oxide to cGMP, the main effector molecule of nitric oxide Tadalafil

23. Riociguat Phase 2 study in 78 patients with PAH and CTEPH (27/41) 12 weeks study, FC II/III Improvement in 6MWD Sustained improvement with long-term open label f/u an average of 14 months later

24. Endothelial Progenitor Cells (EPCs) in PAH ■Circulating bone marrow–derived endothelial progenitor cells (EPCs) play an important role in repair of endothelial injury and participate directly in postnatal vasculogenesis and angiogenesis in systemic vascular beds ■EPCs are involved in pulmonary endothelial repair and regeneration

25. Endothelial Progenitor cells (EPCs)  EPCs transfected with endothelial nitric oxide synthase  Cells delivered via PA catheter line  18 patients, 5 doses

26. Clinical trials to start soon Ambrisentan/tadalafil vs ambristen or tadalafil Nilotinib (Kinase inhibitor) Sunitinib (Kinase inhibitor) AC-065A302 (PGI2 receptor agonist)

27. Average response to any new drug Maitland van der Zee AH Eur J Pharmacol 2000; 410: 121 - 130 30% Can we personalize PAH pharmacotherapy?

28. Research is the Way Forward A community of hope

29.  Focus on emerging molecular targets  Treat proliferation and apoptosis resistance  Intervene earlier  Personalize pharmacotherapy Pulmonary Hypertension Management: The Way Forward