1 / 88

NDA 21-272 Remodulin™ (treprostinil sodium) Injection

NDA 21-272 Remodulin™ (treprostinil sodium) Injection. United Therapeutics Corporation Research Triangle Park, NC. Presentation and Speakers . Efficacy of treprostinil Stuart Rich, MD Professor of Medicine Director, Rush Heart Institute

alda
Download Presentation

NDA 21-272 Remodulin™ (treprostinil sodium) Injection

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. NDA 21-272Remodulin™ (treprostinil sodium) Injection United Therapeutics Corporation Research Triangle Park, NC 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 • & Professor of Pediatric CardiologyBenefit to Risk Director, Pulmonary Hypertension Center Columbia Presbyterian Medical Center US NDA No. 21-272 Remodulin Injection

  3. Additional Representatives for Treprostinil • 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 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 US NDA No. 21-272 Remodulin Injection

  5. Symptoms of PAH US NDA No. 21-272 Remodulin Injection

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

  8. Treprostinil Sodium • Generic Name: Treprostinil Sodium • Brand Name: RemodulinTM • Other Names: UT-15, Uniprost, treprostinol O H H O H H O C H C O 2 2 N a 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 US NDA No. 21-272 Remodulin Injection

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

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

  12. Epoprostenol vs. Treprostinil US NDA No. 21-272 Remodulin Injection

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

  14. Pilot Study P01:03 Efficacy Results - Change from Baseline US NDA No. 21-272 Remodulin Injection

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

  17. Study Design Phase:Screen/Baseline Treatment Week 1 Week 6 Week 12 Treprostinil Randomization(1:1) Placebo Assessments: 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 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 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 US NDA No. 21-272 Remodulin Injection

  21. Symptoms and Signs 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 US NDA No. 21-272 Remodulin Injection

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

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

  29. Baseline CharacteristicsStudy 04/05 US NDA No. 21-272 Remodulin Injection

  30. Baseline CharacteristicsStudy 04/05 Mean ± SEM US NDA No. 21-272 Remodulin Injection

  31. Baseline HemodynamicsStudy 04/05 Mean ± SEM US NDA No. 21-272 Remodulin Injection

  32. Baseline TreatmentStudy 04/05 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 US NDA No. 21-272 Remodulin Injection

  34. Patient DispositionStudy 04/05 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) P=0.0064 P=0.03 Treatment Effect (meters) P=0.3 US NDA No. 21-272 Remodulin Injection

  36. Change in 6-Minute Walk DistanceWeek 12 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 US NDA No. 21-272 Remodulin Injection

  38. Patient DispositionStudy 04/05 US NDA No. 21-272 Remodulin Injection

  39. Type of Discontinuation AE Deterioration Time to Initiation of epoprostenolDiscontinuation due to AE vs DeteriorationSince discontinuation 100 90 80 70 60 50 40 30 20 10 0 % of Patients Not on Flolan 0 20 40 60 80 100 120 140 160 180 Days since Discontinuations US NDA No. 21-272 Remodulin Injection

  40. Type of Discontinuation AE Deterioration Survival DistributionSince Discontinuation 100 90 80 70 60 50 40 30 20 10 0 % of Patients 0 100 200 300 400 500 600 700 800 900 1000 Days since Discontinuations 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 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) 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 US NDA No. 21-272 Remodulin Injection

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

  45. Influence of Baseline Walk on 6-Minute Walk Distance at Week 12 Study 04/05 *Mean change predicted from linear regression model US NDA No. 21-272 Remodulin Injection

  46. Influence of NYHA Class on 6-Minute Walk DistanceStudy 04/05 *Hodges-Lehmann estimate at Week 12 US NDA No. 21-272 Remodulin Injection

  47. Severity of Dyspnea During ExerciseBorg Dyspnea Score Mean ± SEM *Lower is improved 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 +1.2 P=0.0064 +15 +0.8 P=0.03 +10 +0.4 P=0.3 Borg +5 0 +0.0 Walk (m) -5 -0.4 P=0.11 -10 -0.8 P=0.0002 -15 P<0.0001 -20 -1.2 Week 1 Week 6 Week 12 US NDA No. 21-272 Remodulin Injection

  49. 100 90 80 70 60 50 40 30 20 10 0 Treatment Trepnl Placebo % Achieving at Least this Rank 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Standardized Combined Rank Cumulative Frequency Distribution Analysis of Distance and Symptoms During 6-Minute Walk Test (Study 04/05, Week 1) US NDA No. 21-272 Remodulin Injection

  50. 100 90 80 70 60 50 40 30 20 10 0 Treatment Trepnl Placebo % Achieving at Least this Rank 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Standardized Combined Rank Cumulative Frequency Distribution Analysis of Distance and Symptoms During 6-Minute Walk Test (Study 04/05, Week 6) US NDA No. 21-272 Remodulin Injection

More Related