1. PHA Thanks the Medical Education Fund Sponsors!

2. Christopher Barnett, M.D., MPH; Co-chair Oksana A. Shlobin, M.D., FCCP; Co-chair Janet Arp Daniel C. Grinnan, M.D. Denise Lewis, RN, BSN Stephen Mathai, M.D., MHS Betsie Miklos Gerilynn Connors, B.S., RRT,MAACVPR, FAARC Rachel Damico, M.D., Ph.D. Jason M. Elinoff, M.D. Karen Fagan, M.D. Grant Farr, D.O. Mardi Gomberg-Maitland, M.D., MSc Hunter Groninger, M.D., FACP, FAAHPM Shilpa Johri, M.D. Todd M. Kolb, M.D., Ph.D. Katherine Kroner Tunay Kuru, M.D. Janet Pinson, MSN, ACNP Gautam Ramani, M.D. Virginia Steen, M.D. Nargues Weir, M.D. PHA Thanks the Washington, DC Planning Committee and Presenters!

3. PH Patients and Families Education Forum A Program of the Pulmonary Hypertension Association Medical Education Fund Washington, D.C. October 1, 2016

4. Jason M. Elinoff, MD Critical Care Medicine Department Mark O. Hatfield Clinical Center National Institutes of Health Where We Are, Where We Are Going, and How Do We Get There?

5. Disclosure I have no relevant financial disclosures

6. Disclaimer The content of this presentation does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

7. Where We Began Adapted from D’Alonzo GE Ann Intern Med 1991 Years From Time of Diagnosis Survival (%) No treatment available Less than 50% of people with PAH lived more than 3 years from the time of diagnosis 100 0

8. Where We Are Adapted from Benza RL Chest 2012 Years From Time of Diagnosis 100 0 Survival (%)

9. Where We Are Adapted from Benza RL Chest 2012 Years From Time of Diagnosis 100 0 More People Are Living Longer With PAH Survival (%)

10. Timeline of PAH Drug Development Macitentan Epoprostenol Bosentan Treprostinil subcutaneous 1995200120022005200720092010200420132014 Iloprost Treprostinil intravenous Sildenafil Tadalafil Treprostinil inhaled Room temperature stable epoprostenol Ambrisentan Riociguat Treprostinil oral 2015 Selexipag Courtesy of Dr. Harold I. Palevsky

11. PAH: Therapeutic Targets

14. Adapted from Humbert et al. NEJM 2004

15. PAH: Therapeutic Targets Pulmonary artery endothelial cells Adapted from Humbert et al. NEJM 2004

16. PAH: Therapeutic Targets Pulmonary artery endothelial cells Pulmonary artery smooth muscle cells Adapted from Humbert et al. NEJM 2004

17. Endothelin Pathway Smooth muscle cell Endothelial cell Endothelin receptor A Vasoconstriction Endothelin receptor B Endothelin production Adapted from Humbert et al. NEJM 2004

18. Endothelin Pathway Endothelin production Endothelin receptor antagonists (ERAs) Endothelin receptor A Endothelin receptor B Smooth muscle cell Endothelial cell Adapted from Humbert et al. NEJM 2004

19. Endothelin Pathway 1.Bosentan (Tracleer ® ) 2.Ambrisentan (Letaris ® ) 3.Macitentan (Opsimut ® ) Adapted from Humbert et al. NEJM 2004

20. Nitric Oxide (NO) Pathway cGMP NO Guanylate cyclase Vasodilation NO production Smooth muscle cell Endothelial cell Adapted from Humbert et al. NEJM 2004

21. Nitric Oxide (NO) Pathway cGMP NO Guanylate cyclase Phosphodiesterase type 5 PDE5 Inhibitors NO production Smooth muscle cell Endothelial cell Vasodilation Adapted from Humbert et al. NEJM 2004

22. Nitric Oxide (NO) Pathway cGMP NO Guanylate cyclase Phosphodiesterase type 5 PDE5 inhibitors Guanylate cyclase stimulators NO production Smooth muscle cell Endothelial cell Vasodilation Adapted from Humbert et al. NEJM 2004

23. Nitric Oxide (NO) Pathway cGMP NO Guanylate cyclase Phosphodiesterase type 5 PDE5 inhibitors Guanylate cyclase stimulators NO production Smooth muscle cell Endothelial cell Vasodilation Adapted from Humbert et al. NEJM 2004

24. Nitric Oxide (NO) Pathway 1.Sildenafil (Revatio ® ) 2.Tadalafil (Adcirca ® ) 3.Riociguat (Adempas ® ) Adapted from Humbert et al. NEJM 2004

25. Prostacyclin (PGI 2 ) Pathway Prostacyclin receptor Vasodilation PGI 2 production PGI 2 Smooth muscle cell Endothelial cell Adapted from Humbert et al. NEJM 2004

26. Prostacyclin receptor Prostacyclin derivatives Prostacyclin receptor agonists PGI 2 production Smooth muscle cell Endothelial cell Vasodilation Prostacyclin (PGI 2 ) Pathway Adapted from Humbert et al. NEJM 2004

27. Prostacyclin (PGI 2 ) Pathway 1.Epoprostenol (Flolan ®, Veletri ® ) 2.Treprostinil (Remodulin ®, Tyvaso ®, Orenitram ® ) 3.Iloprost (Ventavis ® ) 4.Selexipag (Uptravi ® ) Adapted from Humbert et al. NEJM 2004

28. Goals of PAH Treatment Improve survival Maintain or improve quality of life Decrease symptoms Improve exercise capacity Minimize side-effects of treatment

29. Advances In Clinical Trials Patients without an Event (%) 100 80 90 70 60 40 30 10 50 20 0 061218243036 Months 12-16 weeks Hospitalization for worsening PAH Decreased 6 MWD AND worse symptoms needing additional treatment Need for continuous prostacyclin treatment Lung transplant Death

30. Advances In Clinical Trials Months PlaceboN=574 Selexipag (Uptravi®) N=582 100 80 90 70 60 40 30 10 50 20 0 061218243036 N Engl J Med 2013 and 2015. Patients without an Event (%) 100 80 90 70 60 40 30 10 50 20 0 061218243036 Months PlaceboN=250 N=250, 3 mg Macitentan (Opsimut ® ) N=242, 10 mg

31. Advances In Clinical Trials Months PlaceboN=574 Selexipag (Uptravi ® ) N=582 100 80 90 70 60 40 30 10 50 20 0 061218243036 Patients without an Event (%) 100 80 90 70 60 40 30 10 50 20 0 061218243036 Months PlaceboN=250 N=250, 3 mg Macitentan (Opsimut ® ) N=242, 10 mg Over 700 Patients Participated Over 1000 Patients Participated N Engl J Med 2013 and 2015.

32. Participants with No Event (%) 100 80 60 40 20 0 02448120144168192 Weeks 9672 Advances In Clinical Trials

33. Is Initial Combination Therapy Superior To Either Drug Alone? Participants with No Event (%) 100 80 60 40 20 0 02448120144168192 Weeks 9672 N Engl J Med 2015 Hospitalization for worsening PAH or Decreased 6 MWD AND severe symptoms (class III/IV) or Lack of long term clinical improvement or Death

34. Yes, Initial Combination Therapy Is Better Than Either Drug Alone 100 80 60 40 20 0 02448120144168192 Weeks 9672 Ambrisentan (Letaris ® ) or Tadalafil (Adcirca ® ) N=247 Ambrisentan (Letaris ® ) AND Tadalafil (Adcirca ® ) N=253 Participants with No Event (%) N Engl J Med 2015

35. General Medical Management Prevent fluid retention (dietary changes, monitoring your weight and use of diuretics) Regular exercise if able (Pulmonary Rehab) Prevent low oxygen levels (oxygen therapy and/or nocturnal CPAP) Use of blood thinners

36. General Medical Management Immunizations (e.g. influenza and Prevnar/Pneumvax) Avoidance of pregnancy Communication with your other medical providers

37. More options = more decisions Treatment decisions are individualized and based largely on the severity of your PH Other considerations: Patient preferences Social support Other medical conditions Side effects How Does Your PH Physician Determine The Right Treatment For You?

38. Variables in the equation -How severe are your symptoms? (i.e. your functional classification) -How is the right side of your heart performing? -Are your symptoms worsening quickly? -Six minute walk distance -Laboratory blood tests Determining Risk…. Part Science & Part Art Courtesy of Dr. Harold I. Palevsky We use data from multiple sources to make final judgments…a key is the experience of the healthcare provider!

39. “Because that’s where the money is….” Courtesy of Dr. Harold I. Palevsky In PAH – the major determinant of symptom severity, risk of progression & survival is right ventricular function (NOT the pulmonary arterial pressures!)

40. How Do We Know When To Escalate PAH Therapy? Failure to improve with current therapy Improved, but not enough (symptoms, exercise tolerance, quality of life, etc.) Improved for a period of time, but now deteriorating

41. How Do We Know When To Escalate PAH Therapy? Other mitigating factors? Diet, abnormal heart rhythm, low blood count (anemia), blood clot in the lung (pulmonary embolism), worsening of other medical conditions Go back to the variables in the equation…. Patient preferences Social support Other medical conditions Side effects Echocardiogram 6 minute walk test Blood tests Catheterization

42. Taking Aim At New Targets

43. Pulmonary HTN ↑Pulmonary vascular resistance ↑Mean pulmonary artery pressure Treatment Targets

44. Increased cell proliferaton Increased cell proliferaton Right Ventricular Adaptation Altered cell metabolism InflammationEstrogen Vasodilation ↓ Pulmonary artery pressure ↓ Pulmonary vascular resistance

45. Tacrolimus (FK-506) Mutations in the BMPR2 gene are the most common genetic cause of PAH Impaired BMPR2 signaling is very common even in PAH patients who do not have a gene mutation Identified by molecular techniques searching for drugs that activate BMPR2 signaling (“drug repurposing”) Drug Repurposing: “Old” Drugs For New Purposes JCI 2013 and AJRCCM 2015

46. Tacrolimus (FK-506) Demonstrated promising effects in PH animal models Phase II study – early clinical trial to determine safety and efficacy Target enrollment = 40 patients Stopped early due to slow enrollment at a single center but a multi-center study is planned JCI 2013 and AJRCCM 2015 Drug Repurposing: “Old” Drugs For New Purposes

47. Anastrazole (Aromatase inhibitor) Used in the treatment of breast cancer Prevents conversion of androgens to estrogens Rationale is to reduce estrogen levels that may contribute to the harmful changes in the pulmonary arteries associated with PAH Drug Repurposing: “Old” Drugs For New Purposes AJRCCM 2016

48. Drug Repurposing: “Old” Drugs For New Purposes Anastrazole (Aromatase inhibitor) Pilot randomized, placebo-controlled study Primary outcome was change in blood levels of estradiol as well as effect on the right ventricle 12 PAH patients treated with anastrazole and 6 treated with placebo Duration was 3 months

49. Drug Repurposing: “Old” Drugs For New Purposes Anastrazole (Aromatase inhibitor) Anastrazole reduced blood estrogen levels, increased 6 MWD and did not change measures of right heart function by echo There were no serious side effects and no differences in side effects between the two groups AJRCCM 2016

50. Trials 2013 Spironolactone (Aldactone) In patients with left heart failure, spironolactone improves blood vessel function, inflammation and survival Spironolactone treatment is beneficial in PH animal models Drug Repurposing: “Old” Drugs For New Purposes

51. Spironolactone (Aldactone) Baylor University: Effect of spironolactone on blood levels of collagen/fibrosis markers as well as safety and tolerability ® ) Brigham and Women’s Hospital: Effect of ambrisentan (Letaris ® ) + spironolactone on exercise capacity NIH Clinical Center: Effect of spironolactone on exercise capacity, clinical worsening and inflammation NCT01468571, NCT02253394 and NCT01712620

52. Rituximab Depletes immune cells that make antibodies Phase II study in patients with Scleroderma associated PAH Primary outcome is change in pulmonary vascular resistance A subset of patients will undergo cardiac MRI to determine effects on the right ventricle AJRCCM 2016 NCT01086540 Drug Repurposing: “Old” Drugs For New Purposes

53. ASK1 Inhibitor (GS-4997; ARROW Trial) Suppresses of inflammation and cell proliferation Phase II study assessing change in pulmonary vascular resistance Long-term extension study planned New Drugs Targeting New Pathways AJRCCM 2016 NCT02234141

54. Bardoxolone Methyl (LARIAT Trial) Suppresses inflammation and cell proliferation Phase II, dose finding study assessing change in 6MWD PAH, PH due to interstitial lung disease and PH due to sarcoidosis Long-term extension study planned AJRCCM 2016 NCT02036970 New Drugs Targeting New Pathways

55. Ubenimex (Bestatin™; LIBERTY Study Ubenimex (Bestatin™; LIBERTY Study) Inhibits the inflammatory mediator LTB 4 Used in Japan to treat patients with leukemia Phase II study assessing change in pulmonary vascular resistance Long term extension study is planned AJRCCM 2016 NCT01086540 New Drugs Targeting New Pathways

56. Participating In Clinical Research

57. Where We Want To Be Adapted from Benza RL Chest 2012 Survival (%) Years From Time of Diagnosis 100 0

58. Research involving human volunteers with the goal of adding to medical knowledge A clinical research study that follows a specific protocol Two general types of clinical trials: Observational study Interventional study What Is A Clinical Trial?

59. Observational Study Choose a convenient study population Collect data over time or review data from prior records Look for patterns or associations Generate new hypotheses Interventional Study Carefully selected participants Participants and the researchers may be “blinded” Typically includes a control group to compare to the intervention group Types of Clinical Trials

60. Generate knowledge that will help us understand, diagnose and/or treat PH now or in the future Without clinical research we are unable to improve our understanding of human disease Early access to new tests or treatments Frequent contact with health care providers What Are The Benefits Of Participating In A Clinical Trial?

61. Early access to new tests or treatments Side effects from medications or adverse effects from study procedures Frequent contact with health care providers Time investment The test or treatment may be ineffective or even harmful What Are The Risks Of Participating In A Clinical Trial?

62. How Do I Learn More About Current PH Studies? Ask your PH health care team!

63. How Do I Learn More About Current PH Studies? https://clinicaltrials.gov/https://clinicaltrials.gov/ or ask your PH specialist!

64. How Do I Learn More About Current PH Studies? https://clinicaltrials.gov/https://clinicaltrials.gov/ or ask your PH specialist!

65. Jason M. Elinoff, MD Oksana Shlobin, MD Stephen C. Mathai, MD, MHS Thank You! Questions?