1. AARON WAXMAN, MD Assistant Professor of Medicine Director, Pulmonary Vascular Disease Pulmonary and Critical Care Unit Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Current Controversies in PAH

2. 2 Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants should be able to: ̶ Debate clinical management options for patients with symptoms of PAH who do not fall within the diagnostic cut-off values for initiating PAH therapy ̶ Report on the changes to the PAH diagnostic criteria and how this impacts patients with exercise-related symptoms of PAH who do not demonstrate PAH at rest ̶ Discuss the current controversies in PAH treatment with regard to initial therapy selection and agent sequencing, including choice of drug class and drugs within a class ̶ Discuss the current controversies in PAH management with regard to providing de novo combination therapy in patients with NYHA Class III or IV disease severity

3. Controversy #1 Is “Pre-PAH” a Distinct Entity?

4. 4 Updated Definition of PAH Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66 Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294. Increased mean pulmonary arterial pressure (mPAP)* >25 mm Hg at rest Normal pulmonary capillary wedge pressure (PCWP) <15 mm Hg Increased pulmonary vascular resistance (PVR) † >3 Wood units Right Heart Catheterization Confirmed * Normal resting mPAP = 8 – 20 mm Hg. † In ACCP/AHA expert consensus; in 4th World Symposium on PH, increased PVR given without a value. Significance of mPAP from 21 – 24 mm Hg unclear.

5. 5 Gap Between Normal mPAP and mPAP Diagnostic of PAH Normal mPAP in healthy volunteers 8 – 20 mm Hg at rest mPAP diagnostic of PAH>25 mm Hg at rest What should be done with patients in the mPAP gap? — Pursue alternate diagnoses? — Watchful waiting? — Consider therapy? Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(Suppl 1):S55–S66.

6. 6 Is the Gap an Important Clinical Issue? mPAP Reported in Selected Clinical Trials Study MedicationBaseline mPAP (mm Hg) Control/ Placebo Active Epoprostenol 1 59 +/- 261 +/- 2 Treprostinil (SC) 2 60 +/- 162 +/- 1 Sildenafil 3 56 +/-1649 to 54 Ambrisentan 4 (ARIES-1)50 +/- 1547 to 51 Bosentan 5 (EARLY)52.3 +/- 1652.5 +/- 18.5 1. Barst RJ, et al. N Engl J Med. 1996;334:296–302. 2. Simonneau G, et al. Am J Respir Crit Care Med. 2002;165:800-844. 3. Galie N, et al. N Engl J Med. 2005;353:2148-2157. 4. Galie N, et al. Circulation. 2008; 117:3010-3019. 5. Galie N, et al. Lancet. 2008; 371:2093–2100.

7. 7 Increasing mPAPs Affect Outcomes: Survival in IPF Stratified by mPAP mPAP <17 mm Hg mPAP >17 mm Hg N = 78. Hamada K, et al. Chest. 2007;131(3):650-656. 1.8.6.4.2 0 0102030405060 Survival rate Survival time (months)

8. 8 Improvement of mPAP During PAH Therapy Galie N, et al. Eur Heart J. 2009;30(4):394-403. Supplementary material available online. Meta-analysis of mPAP value improvements in clinical trials of PAH therapy No successful study reported normalization of mPAP. Statistically significant improvements seen in all trials. Study ID Rubin – 1990 Barst – 1996 Badesch – 2000 Channick – 2001 Simmoneau – 2002 Galiè – 2002 Olschewski – 2002 Barst – 2003 Galiè – 2005 Galiè – 2006 McLaughlin – 2006 Galiè – 2008 Simmoneau – 2008 Overall % WeightES (95% CI) -9.30 (-32.50, 13.90)0.00 -1.00 (-4.40, 2.40)0.08 -5.97 (-8.98, -2.96)0.11 -6.70 (-11.90, -1.50)0.04 -3.00 (-3.10, -2.89)87.06 -2.00 (-2.30, -1.65)9.09 -4.40 (-6.60, -2.10)0.19 -1.00 (-1.57, -0.42)2.90 -3.70 (-7.60, 1.25)0.05 -5.50 (-10.40, -0.60)0.04 -8.00 (-11.20, -4.70)0.09 -5.70 (-10.40, -0.90)0.04 -3.90 (-5.60, -2.10)0.31 -2.87 (-2.96, -2.77)100.00 -30-20-100102030 Favors Treatment | Favors Control Pulmonary Artery Pressure (mmHg)

9. 9 Does Pre-PAH Progress to PAH? PHAROS Data in SSc-PAH Among 156 high risk* SSc patients followed over 2 years VariablePre PAH Race (%AA^) 1829 % Nucleolar Ab1226 DLCO %50.540.1 Hsu VM. Presented at the ACR/ACHP Scientific Meeting. Oct. 17-21, 2009. Philadelphia, PA. 1199. Significant Variables in Progression to PAH 50 40 30 10 20 0 00.511.522.5 Years New PAH (n=14) % developing new PAH Time from Baseline to New PAH *High risk = DLCO 1.6, PASP >40 mm Hg. ^AA = African-American ^

10. 10 Intervention in Early PAH No data exists on treating patients in WHO functional class I with PAH-specific medication Longitudinal data have not yet identified risk factors associated with progression to PAH

11. 11 Bosentan (n=86) Placebo (n=91) 3 Months 6 Months Mean Change in 6-Minute Walking Distance (m) 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 EARLY Trial: 6MWD Results With Bosentan for NYHA Class II PAH Galie N, et al. Lancet. 2008; 371:2093–2100. Note: 15% of both groups also received open-label sildenafil.

12. 12 Conclusions “Pre-PAH” appears to define a group of patients who may be at future risk for developing PAH No data currently exists regarding therapy for patients in this category Patients in high-risk groups (genetic markers, systemic sclerosis) should be carefully monitored

13. Controversy #2 Exercise-Induced PAH

14. 14 Exercise Eliminated from Diagnostic Criteria for PAH Badesch DB, et al. J Am Coll Cardiol. 2009;54(Suppl 1):S55–S66. Increased mean pulmonary arterial pressure (mPAP) >25 mm Hg at restor >30 mm Hg during exercise 2003 Criteria: Increased mean pulmonary arterial pressure (mPAP) >25 mm Hg at rest 2009 Criteria:

15. 15 Reasoning Behind Eliminating Exercise- induced PAH in Diagnostic Criteria Level, type, and posture of exercise to reveal exercise-induced PAH not well defined Normal exercise pulmonary artery pressures vary with age Prior descriptions of exercise-induced PAH have utilized echocardiography — Test not validated during exercise, difficult to perform PVR values also not addressed in previous descriptive efforts Badesch DB, et al. J Am Coll Cardiol. 2009;54(Suppl 1):S55–S66. Tolle JJ, et al. Circulation. 2008;118:2183–2189.

16. 16 Relationship Between mPAP and CO in Healthy Volunteers Undergoing Stress Echo Adapted from: Argiento P, et al. EJR Express. 2009; doi: 10.1183/09031936.00076009. N =- 25. 0 5 10 15 20 25 30 35 40 45 051015202530 Cardiac Output, Q (L/min) mPAP (mmHg)

17. 17 Calculated sPAP in Normal Adult Men and Highly-conditioned Athletes Bossone E, et al. Ann NY Acad Sci. 1999;33:1662– 1666. Highly-conditioned athletes (n = 26) and healthy, active, non-athlete volunteers (n = 14). sPAP (mm Hg) Workload (watts) RestWP80160240 Legs up40120200 70 60 50 40 30 20 10 p = 0.0001 Athletes Non-athletes

18. 18 PA Pressures During Exercise Vary With Age in Healthy Adults Kovacs G, et al. Eur Respir J. 2009;34:888-894. 18 – 29 years (n = 144) 30 – 49 years (n = 169) >50 years (n = 91) From a retrospective analysis of RHC data from 1,187 healthy individuals. Rest 0 10 20 30 40 mPAP (mm Hg) Slight Exercise

19. 19 Reasons To Believe Exercised-induced PAH Might Be an Important Clinical Entity Initial presenting symptoms for vast majority of PAH patients includes dyspnea on exercise NYHA/WHO functional classification break- points are defined, in part, on increasing levels of exertional dyspnea Tolle JJ, et al. Circulation. 2008;118:2183–2189.

20. 20 Relationship of Exercise Capacity to PASP in Scleroderma Allkotob ML, et al. Chest. 2006;130:176-181. N = 65 patients with scleroderma. Evaluated during Doppler stress echocardiography. 1st2nd3rd4th 0 10 20 30 50 40 Lowest  Highest, Exercise Time Quantities PASP METS

21. 21 Normal vs Abnormal Exercise Response in Asymptomatic Carriers of FPAH Gene Normal Responders n = 27 Abnormal Responders n = 14 All abnormal responders to exercise testing were carriers of disease- associated haplotype compared with 2 of 27 normal responders. Resting PASPs were normal in both groups. Grunig E, et al. Circulation. 2000;102:1145-1150. PASP (mm Hg) Rest50100150 100 90 80 70 60 50 40 30 20 10 0 Rest50100150 100 90 80 70 60 50 40 30 20 10 0

22. 22 p<0.05 % Frequency of Positive Exercise Echo An increase of 20 mmHg on exercise echocardiogram significantly correlated with  DLCO and  FVC/DLCO. 81% of patients with a positive exercise echo had PAH or exercise PH. Exercise Echocardiogram Correlated with Exercise Catheterization in PAH-SSc DLCO>50%DLCO<50% FVC/DLCO>1.6 FVC/DLCO<1.6 Steen V, et al. Chest. 2008;134:146-151.

23. 23 Increases in sPAP During Stress Echo of Patients with Connective Tissue Disorders n = 50. sPAP >35 mm Hg seen in 59% of evaluable patients among registrants of an autoimmune disease database undergoing stress echocardiography. Collins N, et al. Eur J Echocardiography. 2006;7:439-466. mm Hg 1 sPAP Pre 2 sPAP Post 90 80 70 60 50 40 30 20 10 0

24. 24 Differences in Resting TRJ Velocity Indicates Exercise-induced PAH Phenotype Bossone E, et al. Int J Card Imag. 2000;16:429-436. N = 52. Patients undergoing Doppler echocardiography. Tricuspid Regurgitation Velocity m/sec 76543217654321 PHTEx PHTNormal

25. 25 Exercise-induced PAH Measured by Right Heart Catheterization: mPAP Tolle JJ, et al. Circulation. 2008;118:2183–2189. mPAP (mm Hg) n = 109. From a series of patients undergoing RHC with exercise, primarily for exercise intolerance.

26. 26 mPAP Patterns Measured by Right Heart Catheterization During Exercise Tolle JJ, et al. Circulation. 2008;118:2183–2189. Representative Plateau Pattern Representative Take-off Pattern n = 109. From a series of patients undergoing RHC, primarily for exercise intolerance. Normals = 14 take-off, 1 plateau. Exercise PAH = 40 take-off, 32 plateau, 4 uninterpretable. Resting PAH = 2 take-off, 9 plateau, 4 uninterpretable. Log mPAP (mmHg) Log VO 2 (% Predicted) m1 m2 Log mPAP (mmHg) Log VO 2 (% Predicted) 1.7 1.6 1.5 1.4 1.3 1.2 2.02.53.03.54.0 m1 m2 1.8 1.6 1.4 1.2 1.0 2.42.62.83.03.23.43.6

27. Controversy #3 Therapy Selection and Sequencing

28. 28 PAH-specific Therapies Approved for Use in the US Endothelin Receptor Antagonists Phosphodiesterase- type 5 Inhibitors Prostanoids – Prostacyclin Analogs Ambrisentan (PO)Sildenafil (PO)Epoprostenol (IV) Bosentan (PO)Tadalafil (PO) Iloprost (inhaled) Treprostinil (IV, SC, and inhaled) FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction= Search.Search_Drug_Name. Accessed November 1, 2009.

29. 29 Mechanisms of Action of Approved Therapies for PH Humbert M, et al. N Engl J Med. 2004;351(14):1425-1436. Nitric oxide cGMP Vasodilation and antiproliferation Endothelial cells Nitric oxide pathway PreproendothelinProendothelin L-arginine NOS Arachidonic acidProstaglandin I 2 cAMP Vasodilation and antiproliferation Vasoconstriction and proliferation Endothelin- receptor A Endothelin- receptor B Endothelin pathwayProstacyclin pathway Endothelin-1 Endothelin- receptor antagonists Exogenous nitric oxide Prostacyclin derivates Phosphodiesterase type 5 inhibitor Phosphodiesterase type 5

30. 30 Cellular Processes Implicated in PAH: Potential Targets for Future Therapies Newman JH, et al. Circulation. 2004;109:2947-2952. B A KDR TIE tenascin-c elastase 5HT Transporter ALK/End or BMPR 1-2 NO Blocks K + channels Platelets growth cytokines apoptosis Circulating Cells and Mediators angiopoietin PO – 4 gene activation or repression O–2O–2 proliferative phenotype Nuclear Transcription Factors AML1 Cell Surface Receptors ERK JNH VEGF BMPs or TGF  endothelin EGF TNF  ANG II PDGF 5HT (serotonin) other products apoptosis SMADs MAP Kinases G protein Intracellular Signaling apoptsosis SMC tone ES Receptor anorexigens NO restores hypoxia blocks Virus infection? HIV, HHV-8 Estrogen + – + + + – –

31. 31 2 agents currently approved in US — Ambrisentan, bosentan Indicated for improvement of exercise tolerance and to delay clinical worsening Once-daily (ambrisentan) or twice-daily dosing (bosentan) Generally safe and tolerable — Monthly liver function tests Decision Analysis: First Class of Oral Agent 2 agents currently approved — Sildenafil, tadalafil Indicated for improvement of exercise tolerance (both) and delay clinical worsening (sildenafil) Safe and tolerable — Adverse effects generally mild Once-daily (tadalafil) or three times-daily dosing (sildenafil) Potential synergy with prostacyclins ERAsPDE5 Inhibitors Full prescribing information for ambrisentan, bosentan, sildenafil, and tadalafil.

32. 32 Proven survival benefit (epoprostenol) Most appropriate for sickest patients Difficult administration Ubiquitous adverse effects — Including adverse effects of routes of administration Indicated to improve walk distance (treprostinil) or composite endpoint (iloprost) Cumbersome administration — Taken 6 to 9 times a day (iloprost) Adverse effect of cough limits tolerability Decision Analysis: First Class of PAH Agent Inhaled Prostacyclins (iloprost, treprostinil) Parenteral Prostacyclin (IV epoprostenol or IV/SC treprostinil) Full prescribing information for epoprostenol, Iloprost, and inhaled and parenteral treprostinil. Opitz CF, et al. Eur Heart J. 2005;26:1895-1902.

33. 33 Issues in Selection of First ERA BosentanAmbrisentan DosingTwice-dailyOnce-daily TitratabilityNo * Yes † Important Drug- Drug Interactions Warfarin, sildenafil, cyclosporin A, glyburide Cyclosporin A MonitoringMonthly liver function tests required SafetyAnemia Peripheral edema Elevated LFTs Anemia Peripheral edema Minimal LFT increases *Bosentan full prescribing information. 2009. Initiate treatment at 62.5 mg bid for 4 weeks and then increase to the maintenance dose of 125 mg bid. † Ambrisentan full prescribing information. 2007. Initiate treatment at 5 mg once daily and consider increasing the dose to 10 mg once daily if 5 mg is tolerated.

34. 34 ARIES-1: Change in 6-Minute Walk Distance at Week 12 With Ambrisentan N=202. Placebo-adjusted change: 10 mg: +51.4 meters (P=0.0001). 5 mg: +30.6 meters (P=0.0084). -25 0 25 50 Week 0Week 4Week 8Week 12 Change in 6-Minute Walk Distance (meters) Placebo Ambrisentan 5 mg 10 mg +43.6 m +22.8 m -7.8 m Galie N, et al. Circulation. 2008;117:3010-3019.

35. 35 BREATHE-1: Impact of Bosentan on 6-Minute Walk Distance in WHO Classes III and IV Rubin LJ, et al. N Engl J Med. 2002;346:896-903. *P<0.001 versus placebo. † P<0.01 versus placebo. * † Bosentan 250 mg (n=70) Bosentan 125 mg (n=74) 60 40 20 0 -20 04816 Placebo (n=69) Weeks Change in 6-Minute Walk Distance (meters)

36. 36 Issues in Selection of First PDE-5 Inhibitor SildenafilTadalafil DosingThree times a dayOnce-daily TitratabilityYes * No Important Drug- Drug Interactions Nitrates, alpha blockers SafetyEpistaxis, headache, dyspepsia Headache * Dose adjustments performed in clinical practice, not approved FDA. Sildenafil full prescribing information. 2006. Tadalafil full prescribing information. 2009.

37. 37 SUPER-1: 6-Minute Walk Distance Improvements Through 12 Weeks of Therapy With Sildenafil Galie N, et al. N Engl J Med. 2005;353:2148-2157. N=266. P<0.001 versus placebo for all sildenafil doses. 70 60 30 10 50 40 20 0 -10 -20 04812 Placebo Sildenafil 20 mg 40 mg 80 mg Change in 6-Minute Walk Distance (meters) Weeks

38. 38 Long-term Tadalafil: 6MWD by Initial Treatment Assignment 2009 ATS Abstract. Oudiz RJ, et al. Am J Respir Crit Care Med. 179;2009:A1042. Open-label extension of 16 week blinded study. Most patients titrated to 40 mg qd in open-label phase. 420 400 380 360 340 320 0 4 8 1013 16 Months Extension Study 16-Week Study Abbreviation: 6MWD = 6-minute walk distance Mean 6MWD (m) Placebo:40mg 20mg:20mg 2.5-20mg:40mg 40mg:40mg ^

39. 39 Prostanoid Use Varies in US by Region Use of any prostacyclin in WHO class III/IV by geographic region Frantz RP. Am J Respir Crit Care Med. 179;2009:A3350. N=2732. NH 40% 51% AK and Hi are part of west region VT MA RI CT NJ DE MD DC West Midwest Northeast South ^

40. 40 Inhaled Iloprost for Severe PAH N=203. NYHA Class III or IV at baseline. Olschewski H, et al. N Engl J Med. 2002;347:322-329. Iloprost Placebo P=0.004 40 20 0 -20 -40 Base Line4 Wk8 Wk12 Wk Mean Change in Distance Walked (m)

41. 41 Long-term Inhaled Treprostinil Plus Oral Therapy: Change in NYHA Functional Class Over Time *P<0.05. NYHA Unchanged (%) NYHA Worsened (%) NYHA Improved (%) Month 12 n=93 Month 9 n=121 Month 6 n=160 Month 3 N=197 Change from Baseline 80 70 60 50 40 30 20 10 0 * * * * Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. ^

42. 42 Intravenous Treprostinil: Impact on 6-Minute Walk Distance Baseline N=16. *P=0.008 and † P=0.001 versus baseline. Week 6Week 12 Tapson VF, et al. Chest. 2006;129:683-688. 319 378* 400 † Total 6-Minute Walk Distance (meters)

43. 43 Epoprostenol for Severe PAH: 3-Year Survival vs Historical Controls N=162 consecutive patients with IPAH in NYHA Class III or IV. 3-year survival with IV epoprostenol compared with expected survival from historical controls. *P<0.001 at all time points. McLaughlin VV, et al. Circulation. 2002;106(12):1477-1482. 061218243036 Months 20 40 60 80 100 Survival (%) * * * Observed Expected

44. 44 Does Patient Preference Matter? Some patients unwilling to accept parenteral therapy, even when seriously ill Dosing interval for inhaled iloprost may limit its usefulness Adverse-effect profiles of various agents may impact patient tolerability and acceptance

45. Controversy #4 De Novo Combination Therapy in Class III/IV PAH

46. 46 Options for Patients Failing to Improve or Deteriorating Under Initial Therapy Badesch DB, et al. Chest. 2007;131:1917-1928. Functional Class III or IV Atrial septostomy and/or Lung transplantation Combination Therapy(?) Prostanoids Endothelin Receptor Antagonists PDE5 Inhibitors

47. 47 Predictors of PAH Mortality Odds ratio: death within 2 years versus >5 year survival Batal O. Am J Respir Crit Care Med. 179;2009:A4863. Comparison of baseline characteristics of PAH patients with 5 years survival (n=61). 0510301520 0 Age > 60 NYHA=4 6MWD<320 Scleroderma Pericardial effusion BNP > 100 No epoprostenol therapy 253540 ^

48. 48 Issue: Add-on Therapy Versus Sequential Monotherapy Little data available to support either approach Add-on therapy is common in clinical practice Triple-class therapy (ERA, PDE5, prostacyclin) is maintained in substantial proportion of patients without clinical trial data Is an induction/maintenance model possible?

49. 49 REVEAL Database: Therapy Choices at Enrollment PDE5 InhibitorERA 305 417 452 290 190 224 At-enrollment therapy of first 2438 patients in REVEAL. Excludes patients enrolled in blinded controlled trials. Prostacyclin (IV, IM and Inhaled) 295 No PAH Therapy = 266 Badesch DB, et al. Chest. 2009; DOI 10.1378/chest.09-1140. Epub ahead of print.

50. 50 Add-on Oral Therapy: Bosentan and Sildenafil 9 patients with IPAH initially responsive to bosentan monotherapy — Sildenafil added when 6-minute walk distance declined — Mean interval of 11 months Addition of sildenafil improved 6-minute walk distance at 3 months — Improvement was sustained for 6 to 12 months Hoeper MM, et al. Eur Respir J. 2004;24:1007-1010. 3 150 200 250 300 350 400 450 BaselineBosentan Monotherapy 3 Months Baseline Add Sildenafil Distance (meters) 6-12 Combination Therapy (months) 6-Minute Walk Distance

51. 51 Sildenafil Added to Stable Epoprostenol Therapy: Clinical Worsening Events 16-week study (N=267) — Patients on stable epoprostenol for >3 months — 80% of patients provided with sildenafil 80 mg tid Deaths at 16 weeks — Placebo (n=7) — Sildenafil (n=0) Clinical Worsening Event at Week 16 Patients (%) PlaceboSildenafil Simonneau G, et al. Ann Intern Med. 2008;149:521-530. 0 2 4 6 8 10 12 14 16 18 20

52. 52 Sildenafil Added to Epoprostenol: Change From Baseline in 6-Minute Walk Distance N=267; *P<0.0009 versus placebo (ITT population). Mean Change From Baseline (m) Weeks 0 48 12 16 * Placebo Sildenafil -10 0 10 20 30 40 50 Simonneau G, et al. Ann Intern Med. 2008;149:521-530.

53. 53 Add-on Inhaled Iloprost to Stable Bosentan Monotherapy (STEP Study) Patients (%) Improved 1 Class 34.4% Clinical Deterioration 6.0% 62.5% N=67. Inhaled iloprost added to stable bosentan monotherapy for a mean of 17.6 to 18.8 months. 94% of patients were NYHA class III at baseline. Iloprost Placebo McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174(11):1257-1263. 0% 15.2% No Change Change From Baseline in NYHA Class 91.0% Worsened 1 Class 3% 0%

54. 54 Failure of Add-on Inhaled Iloprost to Bosentan Monotherapy 12-Week Change in 6-Minute Walk Distance Trial was terminated early after a futility analysis predicted failure with full sample size. Hoeper MM, et al. Eur Respir J. 2006;28:691-694. 500 400 300 200 100 0 6-Minute Walk Distance (meters) Control (n=21)Iloprost (n=19)

55. 55 Short-term Delay Initiating Ambrisentan Associated with Poorer Long-term 6MWD but Not Survival Waxman AB. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8573 6-Minute Walk Distance Survival 00.250.51.01.52.0 Mean Change in 6MWD (m) -10 0 10 20 30 40 50 Placebo group starts ABS Time (years) ABS/ABS n=195 PLB/ABS n=97 Improvement Mean ± SEM Placebo group starts ABS 40 ABS/ABS n=195 PLB/ABS n=97 Survival (%) Time (years) 00.250.51.02.0 0 20 60 80 100 1-Year 93% (88% to 96%) 92% (84% to 96%) 2-Year 88% (83% to 92%) 86% (77% to 91%) Kaplan-Meier estimate (95% Cl) At Riskn=197n=186n=173n=158 At Riskn=100n=89n=84n=79n=64 ^

56. 56 2-year Ambrisentan Outcomes: Monotherapy vs Combination Therapy Groups Key Baseline Variables Monotherapy (n = 302) Combination (n = 81) 6MWD (m)356 + 83329 + 91 Borg Dyspnea Index3.7 + 2.34.4 + 2.5 WHO Class II (%)4726 WHO Class III (%)4165 Torres F. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8525 Survival, Monotherapy vs Combination Therapy Years ABS-M ABS-C Survival (%) 2.00.00.51.01.5 100 0 80 60 40 91% (87% to 94%) 76% (63% to 84%) At Risk n=302n=264n=250n=237n=209 At Risk n=81n=70n=65n=61n=45 ^

57. 57 Prognostic Factors for Risk of PAH Disease Progression McLaughlin VV, et al. Circulation. 2006;114(13):1417-1431. Lower RiskHigher Risk Evidence of RV failureNoYes ProgressionGradualRapid WHO ClassII, IIIIV 6-minute walk distance>380 m<325 m Brain natriuretic peptide<180 pg/mL>180 pg/mL Echo findingsMinimal right ventricular dysfunction Pericardial effusion; significant right ventricular dysfunction HemodynamicsNormal/near normal RAP ( 2.5 L/min/m 2 ) High RAP, Low CI

58. 58 Composite Scoring System Predicts Disease Progression in PAH Anderson A, et al. Am J Respir Crit Care Med. 2008;177:A922. Time (years) Composite Score 3-year Survival 0-6 Survival (%) 100 0 75 50 0 1 2 3 25 6-9 9-12 Points0123 Walk (m)340260-340190-260<190 FC1234 NT-proBNP<2000>2000 QOL (CAMPHOR)<12>12 Activity<11>11 Symptoms<16>16 ^

59. 59 Survival in PAH by Etiology: Does CTD-PAH Require A More Aggressive Approach? McLaughlin VV, et al. Chest. 2004;126:78S-92S. 012345 Years 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Percent Survival Congenital Heart Disease Portopulmonary IPAH Connective Tissue Disease HIV

60. 60 Systemic Sclerosis Progresses More Rapidly When PAH is Diagnosed Koh ET, et al. Br J Rheumatol. 1996;35:989-993.

61. 61 Goal-directed Combination Therapy: Suggested Treatment Algorithm Baseline and 2- to 6-Month Evaluation for Treatment Goals 6-Minute Walk Distance >380 meters; Peak VO 2 >10.4 mL/min/kg Peak systolic BP >120 mm Hg during exercise Oral Monotherapy Dual-Class Oral Combination Therapy Addition of Inhaled Prostanoid Transition to Intravenous Prostanoid Refer for Lung Transplantation Hoeper MM, et al. Eur Respir J. 2005;26(5):858-863.

62. 62 Should PAH Therapy Follow a Different Model? Current guidelines suggest monotherapy, followed by add-on therapy In HIV, cancer, coronary disease, and other common diseases, de novo combination therapy is the norm Is there potential to stabilize disease with multi- modal therapy, then peel away to minimum required?

63. 63 Theoretical Advantages of De Novo Combination Therapy More rapid improvement in clinical symptoms Potential to alter the pathophysiologic processes — Disease modification vs symptom management Attack the disease through multiple pathways Larger improvements in hemodynamics Reduced risk of disease progression

64. 64 Theoretical Disadvantages of De Novo Combination Therapy Additive adverse effects make adherence difficult Additive cost with unknown benefit De novo combination therapy eliminates the role of monotherapy when it might be effective in certain patients Potential unwillingness to remove therapy in patients doing well Reduced choices in the event of disease progression, lack of tolerability

65. 65 Low-dose Treprostinil Added to Existing Oral Therapy: Change in 6-Minute Walk Distance Mean Improvement in 6-Minute Walk Distance (m) Overall 12 Weeks N=20. PDE5i: phosphodiesterase type 5 inhibitor; ERA: endothelin receptor antagonist. Mean treprostinil dose at 12 weeks was 24 ng/kg/min. ERAPDE5i + ERA PDE5i 35 5 36 63 Feldman JP, et al. Chest. 2007;132(4 suppl):474S. ^

66. 66 “Class Switching” Usually done only when all agents within a class are intolerable In event of single-agent class, trial transition to investigational agent may be preferable

67. 67 Role of Investigational Therapies/ New Classes of Agents Investigational therapies should be utilized — In context of clinical trials — In compassionate use settings where no other option exists

68. 68 Upcoming/Ongoing Clinical Trials A wide range of clinical trials are currently enrolling patients — Investigational agents and approaches — Combination therapy trials of approved agents Complete list of approved studies is available at www.clinicaltrials.gov