1. US NDA No. 21-272 Remodulin Injection 1 NDA 21-272 Remodulin™ (treprostinil sodium) Injection United Therapeutics Corporation Research Triangle Park, NC

2. US NDA No. 21-272 Remodulin Injection 2 Presentation and Speakers Efficacy of treprostinil Stuart Rich, MD Professor of Medicine Director, Rush Heart Institute Center for Pulmonary Heart Disease Rush Presbyterian-St. Lukes Medical Center Safety of treprostinil Robyn Barst, MD & P rofessor of Pediatric Cardiology Benefit to Risk Director, Pulmonary Hypertension Center Columbia Presbyterian Medical Center

3. US NDA No. 21-272 Remodulin Injection 3 Gary Koch, Ph.D. Professor, Department of Biostatistics University of North Carolina Tom Wenger, M.D. Consultant Cardiologist Allen Lai, Ph.D. Pharmacokinetic Consultant Shelley Ching, D.V.M., Ph.D. Toxicology Consultant Additional Representatives for Treprostinil

4. US NDA No. 21-272 Remodulin Injection 4 Pulmonary Arterial Hypertension Primary Pulmonary Hypertension (PPH) –Sporadic –Familial Pulmonary Hypertension Associated with: –Collagen Vascular Disease –Congenital Systemic to Pulmonary Shunts –Drugs/Toxins –Portal Hypertension –HIV Infection

5. US NDA No. 21-272 Remodulin Injection 5 Symptoms of PAH Initial (%)Eventual (%) Dyspnea6098 Fatigue1973 Chest Pain747 Near Syncope541 Syncope836 Edema337

6. US NDA No. 21-272 Remodulin Injection 6 Commonly Used Treatments for PAH Digitalis Diuretics Vasodilators Anticoagulants Epoprostenol

7. US NDA No. 21-272 Remodulin Injection 7 Epoprostenol Indication Intravenous treatment of NYHA Class III/IV PPH and PAH associated with scleroderma Risks Trauma and pneumothorax with catheter placement Local site infection & sepsis Thromboembolic events related to catheter Cardiovascular collapse

8. US NDA No. 21-272 Remodulin Injection 8 Treprostinil Sodium Generic Name:Treprostinil Sodium Brand Name:Remodulin TM Other Names:UT-15, Uniprost, treprostinol OCH 2 CO 2 H H OH OH Na

9. US NDA No. 21-272 Remodulin Injection 9 Development Rationale Prostaglandin family –Potent vasodilator –Inhibitor of platelet aggregation Clinical Pharmacology –Acute hemodynamic effects in PPH similar to those of epoprostenol Chemically Stable at Neutral pH/Room Temp Apparent Plasma Half-Life –IV: 45 minutes –SC: 3 hours

10. US NDA No. 21-272 Remodulin Injection 10 Epoprostenol Delivery System

11. US NDA No. 21-272 Remodulin Injection 11 Treprostinil Delivery System

12. US NDA No. 21-272 Remodulin Injection 12 Epoprostenol vs. Treprostinil CharacteristicEpoprostenolTreprostinil Delivery of Drug IntravenousSubcutaneous Implant of catheter SurgicalPatient Thrombus YesNo Sterile conditions for frequent drug constitution required YesNo Risk of cardiovascular collapse HighLow Risk of serious infections, including sepsis HighNone Bulky pump YesNo

13. US NDA No. 21-272 Remodulin Injection 13 Clinical Development Controlled Trials Open Label Studies P01:03 (n=26) P01:04 P01:05 (n=470) Pivotal Studies P01:06 (n= 631) Pilot Direct Enrollment (n=208)

14. US NDA No. 21-272 Remodulin Injection 14 Pilot Study P01:03 Efficacy Results - Change from Baseline Assessment Treprostinil (n=17) Placebo (n=9) Median 6-min Walk (m) +24-6 Borg Dyspnea Score 0.00+0.97 Dyspnea-Fatigue Rating +0.57-0.25 Hemodynamics CI ( L/min/m 2 ) PAPm ( mmHg ) PVRI ( mmHg/L/min/m 2 ) +0.42 0.0 -4.8 -0.03 -2.4 +0.2

15. US NDA No. 21-272 Remodulin Injection 15 P01:04 and P01:05 International, Multicenter, Double-Blind, Placebo-Controlled Trial Program (40 Centers)

16. US NDA No. 21-272 Remodulin Injection 16 Entry Criteria Age: 8 to 75 years Etiology: Primary pulmonary hypertension Collagen vascular disease Congenital heart disease NYHA class:II, III and IV Hemodynamics:PAPm  25 mmHg PVR > 3 Wood units PCWP  15 mmHg Walk distance: 50 to 450 meters

17. US NDA No. 21-272 Remodulin Injection 17 Study Design Phase: Screen/Baseline Treatment Week 1 Week 6 Week 12 Treprostinil Placebo Randomization (1:1) Exercise Symptoms QOL Clinical Labs Catheterization Initiate Study Drug Exercise Symptoms Exercise Symptoms QOL Exercise Symptoms QOL Clinical Labs Catheterization Assessments:

18. US NDA No. 21-272 Remodulin Injection 18 Efficacy Measures Exercise tolerance (6-minute walk) Signs and symptoms of PAH Dyspnea-fatigue rating Clinical deterioration –Death, transplant or worsening requiring IV therapy Borg dyspnea score Hemodynamics Quality of life

19. US NDA No. 21-272 Remodulin Injection 19 6-Minute Walk Test Unencouraged test Practice test (within 6 weeks) Independent assessor –No involvement in study or patient care –Blinded to patient treatment –Was not aware of clinical course –Results not communicated to study staff –Separate CRFs kept in locked & secure files Borg dyspnea score at end of test

20. US NDA No. 21-272 Remodulin Injection 20 Symptoms and Signs 8 symptoms and 8 signs of PAH Symptoms and Signs were noted by the physician as either being “present” or “absent” A change score thus represented either first development of a new symptom/sign or complete resolution of a pre-existing symptom/sign

21. US NDA No. 21-272 Remodulin Injection 21 Symptoms and Signs SymptomsSigns DyspneaLoud P2 sound FatigueRV S3 sound Chest PainRV S4 sound DizzinessRV heave SyncopeTricuspid murmur EdemaPulmonic murmur OrthopneaHepatomegaly PalpitationsJVD at 45 degrees

22. US NDA No. 21-272 Remodulin Injection 22 Dyspnea-Fatigue Rating Physician-based assessment Rated symptoms and their clinical impact Consisted of three components, each rated 0-4: –Magnitude of task (at normal pace) –Magnitude of pace –Functional impairment in general activities Composite score was derived Lower scores reflected more symptomatic patient

23. US NDA No. 21-272 Remodulin Injection 23 Dyspnea Fatigue Rating Magnitude of Task Symptomatic with: 4 = Extraordinary activity 3 = Major activities 2 = Moderate or average tasks 1 = Light activities 0 = At rest

24. US NDA No. 21-272 Remodulin Injection 24 Hemodynamic Measurements Hemodynamic measurements were measured by right heart catheterization at baseline and after 12 weeks. To minimize bias, other efficacy parameters were completed prior to invasive measurements

25. US NDA No. 21-272 Remodulin Injection 25 Quality of Life (Minnesota Questionnaire) Added at the request of the FDA after start of the study and thus assessed only in subgroup Included evaluation of physical, emotional, and global dimensions 21 questions were answered using a 0-5 response scale (a lower score was “better”)

26. US NDA No. 21-272 Remodulin Injection 26 Prespecified Endpoints Primary endpoints –Exercise tolerance (6-minute walk distance) Secondary endpoints –Signs and symptoms of disease* –Dyspnea-fatigue rating* –Clinical deterioration (deaths, transplants or worsening of the underlying disease necessitating intravenous rescue therapy)* –Borg dyspnea score –Hemodynamics

27. US NDA No. 21-272 Remodulin Injection 27 Statistical Analysis Prespecified and finalized with the FDA prior to randomization code-break Efficacy population– 469 of 470 randomized patients –Excluded 1 placebo patient who did not receive study drug Analysis of non-completers (primary endpoint) –Death, transplant, worsening disease: worst rank –Adverse effects: last value carried forward Nonparametric analysis of primary endpoint

28. US NDA No. 21-272 Remodulin Injection 28 Pre-specified Primary Analysis Plan Combined studies P  0.01 and one study P  0.049 Supported by effects on principal reinforcing and secondary endpoints Individual studies both P  0.049 OR Treatment effect demonstrated if

29. US NDA No. 21-272 Remodulin Injection 29 Baseline Characteristics Study 04/05 Treprostinil n=233 Placebo n=236 AgeYears (mean±SE)45 ± 144 ± 1 RaceCaucasian85%84% GenderFemale85%78% PAH EtiologyPPH Connective Tissue Congenital Heart 58% 17% 25% 58% 20% 22% NYHAClass II Class III Class IV 11% 82% 8% 12% 81% 7%

30. US NDA No. 21-272 Remodulin Injection 30 Treprostinil n=233 Placebo n=236 Six-Minute Walk (m)326 ± 5327 ± 6 Borg Scale 4.3 ± 0.134.4 ± 0.13 Dyspnea–Fatigue Rating 4.3 ± 0.154.4 ± 0.17 Signs and Symptoms Score 7.6 ± 2.57.5 ± 2.4 Quality of Life Global Physical Emotional 54 ± 1.6 25 ± 0.7 12 ± 0.6 55 ± 1.6 25 ± 0.7 12 ± 0.5 Baseline Characteristics Study 04/05 Mean ± SEM

31. US NDA No. 21-272 Remodulin Injection 31 Baseline Hemodynamics Study 04/05 Treprostinil n=233 Placebo n=236 RAPm (mmHg)10 ± 0.4 PAPm (mmHg)62 ± 160 ± 1 PCWPm (mmHg)10 ± 0.29 ± 0.2 CI (L/min/m 2 )2.4 ± 0.12.2 ± 0.1 PVRI (mmHg/L/min/m 2 ) 27 ± 1.025 ± 0.9 SBP (mmHg)119 ± 2123 ± 2 SvO 2 (%)62 ± 160 ± 1 HR (bpm)82 ± 1 Mean ± SEM

32. US NDA No. 21-272 Remodulin Injection 32 Baseline Treatment Study 04/05 Treprostinil n (%) Placebo n (%) Anticoagulants 149 (64)160 (68) Ca ++ Channel Blockers 97 (42)99 (42) Other Vasodilators 33 (14)35 (15) Digoxin 56 (24)59 (25) Diuretics 136 (58)129 (55)

33. US NDA No. 21-272 Remodulin Injection 33 Dosing Principles Study 04/05  Initiate at 1.25 ng/kg/min  Increase dose if symptoms persist or worsen  Reduce dose if side effects unacceptable Week 123456789101112 Dose 1.252.53.755.07.510.012.515.017.520.022.5

34. US NDA No. 21-272 Remodulin Injection 34 Patient Disposition Study 04/05 Treprostinil n (%) Placebo n (%) Randomized 233 (100)237 (100) Received drug 233 (100)236 (>99) Completed 12 weeks 200 (86)221 (93) Withdrawn consent 2 (1)1 (< 1) Withdrawn due to death, transplant, rescue 13 (6)14 (6) Withdrawn due to AE 18 (8)1 (< 1)

35. US NDA No. 21-272 Remodulin Injection 35 Effect of Treprostinil on 6-Minute Walk Distance at Weeks 1, 6, 12 (Placebo-Corrected; Study 04/05 ) Treatment Effect (meters) P=0.03 P=0.0064 P=0.3

36. US NDA No. 21-272 Remodulin Injection 36 Change in 6-Minute Walk Distance Week 12 Median Change From Baseline (m) Median Difference Between Groups (m)* P-value Study P01:04 Treprostinil (n=113)3.0 13.00.0607 Placebo (n=111)1.0 Study P01:05 Treprostinil (n=119)16.0 18.50.0550 Placebo (n=125)-3.0 Pooled 04/05 Treprostinil (n=232)10.0 16.00.0064 Placebo (n=236)0.0 *Hodges Lehmann estimate

37. US NDA No. 21-272 Remodulin Injection 37 FDA Review of Primary Endpoint Agreement that data supported the finding of a treatment effect, but FDA has questioned the Robustness of the finding Clinical meaningfulness of the treatment effect

38. US NDA No. 21-272 Remodulin Injection 38 Patient Disposition Study 04/05 Treprostinil n (%) Placebo n (%) Randomized 233 (100)237 (100) Received Drug 233 (100)236 (>99) Completed 12 Weeks 200 (86)221 (93) Withdrawn Consent 2 (1)1 (< 1) Withdrawn due to death, transplant, rescue 13 (6)14 (6) Withdrawn due to AE 18 (8)1 (< 1)

39. US NDA No. 21-272 Remodulin Injection 39 020406080100120140160180 Time to Initiation of epoprostenol Discontinuation due to AE vs Deterioration Since discontinuation 100 90 80 70 60 50 40 30 20 10 0 AE Deterioration Type of Discontinuation Days since Discontinuations % of Patients Not on Flolan

40. US NDA No. 21-272 Remodulin Injection 40 Survival Distribution Since Discontinuation % of Patients Days since Discontinuations AE Deterioration Type of Discontinuation 01002003004005006007008009001000 100 90 80 70 60 50 40 30 20 10 0

41. US NDA No. 21-272 Remodulin Injection 41 Three Alternate Approaches Suggested by the FDA Approach #1 –Patients who died or were transplanted after withdrawal but within 100 days of randomization were reassigned to the deterioration group 2 active + 1 placebo patients reclassified to worst rank Approach #2 –Patients who died or were transplanted after withdrawal but within 100 days of randomization plus patients who received epoprostenol within 30 days of discontinuation were reassigned to the deterioration group 8 active + 1 placebo patients reclassified to worst rank Approach #3 –Patients who died, were transplanted or received epoprostenol after withdrawal but within 100 days of randomization were reassigned to the deterioration group 10 active + 1 placebo reclassified to worst rank

42. US NDA No. 21-272 Remodulin Injection 42 P-Values for Analyses of Prespecified Endpoints (FDA-Requested Post Hoc Reassignment of Patients Who Discontinued Treatment) Pre- specified Approach #1 Approach #2 Approach #3 6-Min Walk 0.00640.00750.0380.047 Borg Score 0.0000070.000020.00010.0002 Signs & Symptoms 0.000020.000030.00004 0.0005 Dyspnea-Fatigue Rating <0.000001

43. US NDA No. 21-272 Remodulin Injection 43 FDA Review of Primary Endpoint Agreement that data supported the finding of a treatment effect, but FDA has questioned the Robustness of the finding Clinical meaningfulness of the treatment effect

44. US NDA No. 21-272 Remodulin Injection 44 Distribution of Exercise Responses at Week 12 Study 04/05 Change from Baseline (meters) Trepnl Placebo Treatment 90 80 70 60 50 40 30 20 10 -50-40-30-20-10 0+10+20 +30 +40+50 % Achieving at Least Outcome

45. US NDA No. 21-272 Remodulin Injection 45 Influence of Baseline Walk on 6-Minute Walk Distance at Week 12 Study 04/05 Covariate AnalysisTreatment Effect* Baseline Walk 150m+51 m 250m+33 m 350m+16 m 450m-2 m *Mean change predicted from linear regression model

46. US NDA No. 21-272 Remodulin Injection 46 Influence of NYHA Class on 6-Minute Walk Distance Study 04/05 Covariate AnalysisTreatment Effect* NYHA Classification IV (n=34)+54 m III (n=382)+17 m II (n=53)+2 m *Hodges-Lehmann estimate at Week 12

47. US NDA No. 21-272 Remodulin Injection 47 Severity of Dyspnea During Exercise Borg Dyspnea Score Baseline (m) Change at Week 12 * (m) P-value Study P01:04 Treprostinil (n=97)4.4 ± 0.2-0.89 ± 0.180.0006 Placebo (n=100)4.3 ± 0.2+0.10 ± 0.22 Study P01:05 Treprostinil (n=104)4.2 ± 0.2-0.88 ± 0.22 0.0010 Placebo (n=112)4.4 ± 0.2+0.13 ± 0.27 Pooled 04/05 Treprostinil (n=201)4.3 ± 0.1-0.88 ± 0.14 <0.0001 Placebo (n=212)4.4 ± 0.1+0.11 ± 0.17 Mean ± SEM *Lower is improved

48. US NDA No. 21-272 Remodulin Injection 48 Effect of Treprostinil on Distance and Symptoms During 6-Minute Walk Test (Placebo-Corrected, Study 04/05) -20 -15 -10 -5 0 +5 +10 +15 +20 -1.2 -0.8 -0.4 +0.0 +0.4 +0.8 +1.2 Week 1 Week 6 Week 12 P=0.0002 P<0.0001 P=0.3 P=0.0064 P=0.03 P=0.11 Borg Walk (m)

49. US NDA No. 21-272 Remodulin Injection 49 Cumulative Frequency Distribution Analysis of Distance and Symptoms During 6-Minute Walk Test (Study 04/05, Week 1)

50. US NDA No. 21-272 Remodulin Injection 50 Cumulative Frequency Distribution Analysis of Distance and Symptoms During 6-Minute Walk Test (Study 04/05, Week 6)

51. US NDA No. 21-272 Remodulin Injection 51 Cumulative Frequency Distribution Analysis of Distance and Symptoms During 6-Minute Walk Test (Study 04/05, Week 12)

52. US NDA No. 21-272 Remodulin Injection 52 Prespecified Endpoints Primary endpoints –Exercise tolerance (6-minute walk distance) Secondary endpoints –Signs and symptoms of disease* –Dyspnea-fatigue rating* –Clinical deterioration (deaths, transplants or worsening of the underlying disease necessitating intravenous rescue therapy)* –Hemodynamics Other assessments –Quality of life

53. US NDA No. 21-272 Remodulin Injection 53 Signs and Symptoms of PAH Composite Score Baseline (m) Change at Week 12 * (m) P-value Study P01:04 Treprostinil (n=97)4.3 ±0.20.9 ±0.26 0.0107 Placebo (n=103)4.7 ±0.2-0.1 ±0.22 Study P01:05 Treprostinil (n=104)4.2 ±0.21.0 ±0.20 <0.0001 Placebo (n=114)4.2 ±0.20.0 ±0.20 Pooled 04/05 Treprostinil (n=201)4.3 ±0.20.9 ±0.16 <0.0001 Placebo (n=217)4.4 ±0.2-0.1 ±0.15 Mean ± SEM *Higher is improved

54. US NDA No. 21-272 Remodulin Injection 54 Individual Symptoms Any Time During Double-Blind Therapy Compared With 4 Weeks Prior to Randomization # Resolved Completely # Newly Developed TrepnlPlaceboTrepnlPlacebo Dyspnea1 202 Fatigue021217 Chest Pain25172450 Dizziness18103850 Syncope13839 Orthopnea863147 Palpitations2084634 Edema13123441

55. US NDA No. 21-272 Remodulin Injection 55 Individual Symptoms Last 6 Weeks of Double-Blind Therapy Compared With 4 Weeks Prior to Randomization # Resolved Completely # Newly Developed TrepnlPlaceboTrepnlPlacebo Dyspnea 8 401 Fatigue17125 Chest Pain4837830 Dizziness55352733 Syncope151117 Orthopnea29141730 Palpitations46252722 Edema36251829

56. US NDA No. 21-272 Remodulin Injection 56 Syncope # Resolved Completely # Newly Developed Last 6 weeks of double-blind therapy compared with 4 weeks prior to randomization Treprostinil 15 Placebo 11 Treprostinil 1 Placebo 7 P Value 0.062 Any time during double-blind therapy compared with 4 weeks prior to randomization Treprostinil 13 Placebo 8 Treprostinil 3 Placebo 9 P Value 0.047 Any time during double-blind therapy compared with any time in the past Treprostinil 57 Placebo 49 Treprostinil 2 Placebo 4 P Value 0.121

57. US NDA No. 21-272 Remodulin Injection 57 Dyspnea Fatigue Score Baseline (m) Change at Week 12 * (m)P-value Study P01:04 Treprostinil (n=97)4.3 ±0.21.15 ±0.18 <0.0001 Placebo (n=102)4.7 ±0.2-0.24 ±0.21 Study P01:05 Treprostinil (n=104)4.2 ±0.21.30 ±0.19 <0.0001 Placebo (n=114)4.2 ±0.2-0.06 ±0.15 Pooled 04/05 Treprostinil (n=201)4.3 ±0.21.23 ±0.13 <0.0001 Placebo (n=216)4.4 ±0.2-0.14 ±0.13 Mean ±SEM *Higher is better

58. US NDA No. 21-272 Remodulin Injection 58 Magnitude of Task Change from Baseline Percent of Patients Study 04/05 Change in Magnitude of Task Scale

59. US NDA No. 21-272 Remodulin Injection 59 Patients Experiencing Clinical Deterioration (Prespecified Analysis) Study 04/05 Treprostinil (n=233) Placebo (n=236) Death within 12 weeks or discontinuation due to transplant or clinical worsening requiring rescue therapy 13 (6%) 16 (7%) Death 7 9 Transplant 0 1 Clinical worsening requiring rescue 6 6

60. US NDA No. 21-272 Remodulin Injection 60 Patients Experiencing Clinical Deterioration (Expanded Analysis) Study 04/05 Treprostinil (n=233) Placebo (n=236) Odds Ratio (CI) Death within 12 weeks or discontinuation due to transplant or clinical worsening requiring rescue therapy 1316 0.81 (0.38-1.73) Clinical worsening (PH/RHF) leading to hospitalization* 16 Clinical worsening (too ill to walk)*26 Total1628 0.55 (0.29-1.04) *Not included in the first row

61. US NDA No. 21-272 Remodulin Injection 61 Hospitalizations Study 04/05 Number of PatientsNumber of Events Treprostinil (n=233) Placebo (n=236) Treprostinil (n=233) Placebo (n=236) Any hospitalization 37405356 Due to worsening pulmonary hypertension or right heart failure 718822 Other reason 33264534

62. US NDA No. 21-272 Remodulin Injection 62 Hemodynamic Effect Week 12 Study 04/05 Treprostinil (n=163-199) Placebo (n=182-215) P-value RAPm (mmHg) -0.5 ± 0.4+1.4 ± 0.30.0002 PAPm (mmHg) -2.3 ± 0.5+0.7 ± 0.60.0004 CI (L/min/m 2 ) +0.12 ± 0.04-0.06 ± 0.04<0.0001 PVRI ( mmHg/L/min/m 2 ) -3.5 ± 0.6+1.2 ± 0.6<0.0001 SvO 2 (%) +2.0 ± 0.8-1.4 ± 0.7<0.0001 SBP (mmHg) -2.3 ± 1.1-0.2 ± 1.20.08 HR (bpm) -0.5 ± 0.8-0.8 ± 0.70.6 Mean ± SEM

63. US NDA No. 21-272 Remodulin Injection 63 Quality of Life (Minnesota Scale) Study 04/05 BaselineChange at Week 12*P-value Global Treprostinil a Placebo b 54 ± 2 55 ± 2 -6.6 ± 1.6 -1.9 ± 1.4 0.17 Physical Treprostinil Placebo 25 ± 1 -4.5 ± 0.7 -1.8 ± 0.6 0.006 Emotional Treprostinil Placebo 12 ± 1 -1.3 ± 0.5 -0.3 ± 0.5 0.37 Mean ± SEM a n=157 b n=173 *Lower is improved

64. US NDA No. 21-272 Remodulin Injection 64 Study 06 Controlled Trials Open Label Studies P01:03 (n=26) P01:04 P01:05 (n=470) Pivotal Studies P01:06 (n= 631) Pilot Direct Enrollment (n=208)

65. US NDA No. 21-272 Remodulin Injection 65 Long-term Effects on 6-minute Walk (Study P01:06) Months No. Patients (% of patients with specified duration of exposure) Dose (ng/kg/min) Exercise Change from Baseline (meters) 3235 (47)10 ± 0.4+15 ± 4 6156 (38)16 ± 0.7+34 ± 6 9112 (34)19 ± 1.3+34 ± 8 12102 (37)25 ± 1.7+33 ± 7 1563 (35)24 ± 2.1+37 ± 12 1846 (43)31 ± 3.1+46 ± 13 2115 (38)38 ± 7.1+55 ± 17 Mean ± SEM

66. US NDA No. 21-272 Remodulin Injection 66 Efficacy Conclusions In patients with PAH, treprostinil produced clinically meaningful improvements in: exercise tolerance (distance and symptoms) symptoms of PAH dyspnea-fatigue rating hemodynamic variables quality of life (physical domain)

67. US NDA No. 21-272 Remodulin Injection 67 Treprostinil Safety Experience/Exposure Overall Experience 843 Subjects PAH Trial Experience 743 Patients Controlled Trials Studies 03/04/05 496 Patients Open Label Study 06 Direct Enrollment 208 Patients Open-Label Study Study 06 631 Patients 423 of 445 eligible (95%) Acute Trials Studies 01/02 39 Patients Treprostinil Exposure 679 Patients

68. US NDA No. 21-272 Remodulin Injection 68 Duration of Exposure (As of Oct. 1, 2000) Time (months) Number of Patients

69. US NDA No. 21-272 Remodulin Injection 69 Doses of Treprostinil Used During Long-term Treatment Dose (ng/kg/min) 0 1 2 36 9 121518 Months

70. US NDA No. 21-272 Remodulin Injection 70 Adverse Events Reported by >10% of Patients Percent of Patients 03/04/05 Placebo (n=242) 03/04/05 Treprostinil (n=253) P01:06 Treprostinil (n=631) Infusion Site Pain268583 Infusion Site Reaction268476 Infusion Site Bleed/Bruise433326 Diarrhea152729 Headache243121 Nausea172523 Jaw Pain51516 Vasodilatation5139 Pain101415 Dizziness8911 Rash111311 Pharyngitis9612

71. US NDA No. 21-272 Remodulin Injection 71 Adverse Events Reported by >10% of Patients Percent of Patients 03/04/05 Placebo (n=242) 03/04/05 Treprostinil (n=253) P01:06 Treprostinil (n=631) Infusion Site Pain268583 Infusion Site Reaction268476 Infusion Site Bleed/Bruise433326 Diarrhea152729 Headache243121 Nausea172523 Jaw Pain51516 Vasodilatation5139 Pain101415 Dizziness8911 Rash111311 Pharyngitis9612

72. US NDA No. 21-272 Remodulin Injection 72 Adverse Events Reported by >10% of Patients Percent of Patients 03/04/05 Placebo (n=242) 03/04/05 Treprostinil (n=253) P01:06 Treprostinil (n=631) Infusion Site Pain268583 Infusion Site Reaction268476 Infusion Site Bleed/Bruise433326 Diarrhea152729 Headache243121 Nausea172523 Jaw Pain51516 Vasodilatation5139 Pain101415 Dizziness8911 Rash111311 Pharyngitis9612

73. US NDA No. 21-272 Remodulin Injection 73 Adverse Events by Dose at First Onset Doses (ng/kg/min) 2.5 >2.5- 5.0 >5.0- 10.0 >10.0- 20.0 >20.0- 40.0 >40.0- 60.0 Infusion Site Pain 521517142<1 Infusion Site Reaction 481519144<1 Diarrhea 20112130153 Nausea 2712272373 Headache 39171220103 Jaw Pain 14112925173 Vasodilatation 16182326133 Numbers denote percent of patients who reported a specific adverse event who experienced that event for the first time at a specific dose. All rows add up to 100%.

74. US NDA No. 21-272 Remodulin Injection 74 Adverse Events by Duration of Treatment Percent of Patients Day 1 Day 2- Week 12 Weeks 13-24 Weeks 25-48 Weeks 48-72 Infusion Site Pain1288544339 Infusion Site Reaction1083574743 Diarrhea218151612 Headache62110127 Nausea31511 7 Jaw Pain111996 Pain113776 Infusion Site Bleed/Bruise616775 Vasodilatation211645 Rash211443 Data expressed as percent of the 254 patients treated for at least 72 weeks (May 01)

75. US NDA No. 21-272 Remodulin Injection 75 Serious Adverse Events 03/04/05 Placebo (n=242) n (%) 03/04/05 Treprostinil (n=253) n (%) P01:06 Treprostinil (n=631) n (%) Serious adverse event38 (16)44 (17)170 (27) Deaths during study10 (4)9 (4)36 (6)

76. US NDA No. 21-272 Remodulin Injection 76 Adverse Events Leading to Discontinuation Number of Patients (%) 03/04/05 Placebo (n=242) 03/04/05 Treprostinil (n=253) P01:06 Treprostinil (n=631) Any Event 7 (3)26 (10)96 (15) Infusion Site Pain 0 (0)18 (7)88 (14) Infusion Site Reaction 0 (0)8 (3)22 (3) Heart Failure 0 (0)2 (1)11 (2) Pulmonary Hypertension 4 (2)1 (<1)6 (<1) Infusion Site Bleed/Bruise 0 (0)2 (1)1 (<1) Chest Pain 1 (<1)2 (1)1 (<1) Pain 0 (0) 2 (<1) Shock 1 (<1)2 (1)0 (0) Anxiety 0 (0)2 (1)0 (0)

77. US NDA No. 21-272 Remodulin Injection 77 Local Infusion Site Pain and Reaction Characterized by pain, erythema, induration Varies from patient to patient and infusion site to infusion site Primarily related to initiation of infusion Improves after several months Generally not dose-limiting Manageable in majority of patients –By relocation of the infusion site –By use of hot/cold compresses –By OTC and/or prescription meds, if needed

78. US NDA No. 21-272 Remodulin Injection 78 Infusion Site Treatments Prescribed to >20% Patients Study 04/05 Prescribed Medications 236 Patients n (%) Other Analgesics and Antipyretics96 (41) Anti-inflammatory/Antirheumatic (non steroid)83 (35) Topicals (non steroid)76 (32) Corticosteroids, topical67 (29) Narcotic Analgesics64 (27) Antiinflammatory60 (25) Antihemorrhoidals51 (22) Antipruritics48 (20)

79. US NDA No. 21-272 Remodulin Injection 79 Prescribing of Narcotic Analgesics Prescribed for PRN use –Actual use not captured Center-specific –Approximately 40% of centers did not prescribe for treatment of infusion site pain Prescription rate lower in long-term study

80. US NDA No. 21-272 Remodulin Injection 80 Infusion Site Pain Treatment Prescribed Narcotic Analgesics Percent of Patients Study 04/05 n=236 Study 06 n=631 All Opioids 2721 Schedule IV86 Schedule III1311 Schedule II65 Schedule I0<1* *Tilidine/Naloxone used in non-US center

81. US NDA No. 21-272 Remodulin Injection 81 Use of Narcotic Analgesics Study 06 Survey (535 of 545 patients) Percent of Patients with Use in: Past DayPast Week All Opioids 815 Schedule IV 35 Schedule III 48 Schedule II 12 Schedule I 00

82. US NDA No. 21-272 Remodulin Injection 82 Other Safety Considerations Treprostinil was not associated with adverse changes in: –serum electrolytes –renal and hepatic function –hemoglobin/hematocrit –platelet count –coagulation parameters –ECG intervals There were no clinically important drug interactions or idiosyncratic events

83. US NDA No. 21-272 Remodulin Injection 83 Safety Conclusions The adverse effects of treprostinil were related to its pharmacologic properties and were generally not serious. Serious AEs occurred with similar frequency in the placebo and treprostinil groups. Localized infusion site pain and reactions were common, but generally were manageable and did not limit increases in dose or require the withdrawal of treatment. Treprostinil was not associated with any significant changes in laboratory parameters or end-organ toxicity.

84. US NDA No. 21-272 Remodulin Injection 84 Risks of Epoprostenol Therapy Risk of sepsis Risk of thrombosis Risk of stroke Risk of trauma and pneumothorax Risk of cardiovascular collapse

85. US NDA No. 21-272 Remodulin Injection 85 Treprostinil Microinfusion delivery device Self-insertion of subcutaneous catheter at home No reconstitution; ready for infusion Stable at ambient temperature; no cold packs Addresses unmet medical need

86. US NDA No. 21-272 Remodulin Injection 86 Benefits of Treprostinil In patients with pulmonary arterial hypertension, treprostinil produced clinically meaningful improvements in: exercise tolerance (distance and symptoms) symptoms of PAH hemodynamics

87. US NDA No. 21-272 Remodulin Injection 87 Relation of Benefits to Risks of Treprostinil Since treprostinil produces clinically meaningful effects without potentially life- threatening risks, both patients and physicians can weigh on an ongoing and individual basis the severity of infusion site pain against the magnitude of improvement in symptoms. As a result, the benefits of treprostinil can be expected to outweigh the risks of treatment in each patient who continues to receive treatment with the drug.

88. US NDA No. 21-272 Remodulin Injection 88 Proposed Indication Treprostinil is indicated for the treatment of symptoms in patients with pulmonary arterial hypertension.