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CARDIO-RENAL Advisory Committee Meeting

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  1. CARDIO-RENALAdvisory Committee Meeting EXTRANEAL™ (7.5% Icodextrin) Peritoneal Dialysis Solution NDA 21-321 Orphan Drug Designation 97-1056 August 9, 2001 Baxter Healthcare Corporation

  2. Baxter Participants • Marsha Wolfson, M.D. • Vice President, Global Clinical Affairs • Salim Mujais, M.D. • Vice President, Global Medical Affairs • Frank Ogrinc, Ph.D. • Clinical Statistician • Leo Martis, Ph.D. • Vice President, Solution Development • James Moberly, Ph.D. • Director, Solutions R&D • Richard Newman, Ph.D. • Vice President, Global Product Development • Mary Kay Rybicki • Associate Director, Regulatory Affairs

  3. John Burkart, M.D. Professor of Internal Medicine/Nephrology, Bowman Gray School of Medicine Allan Collins, M.D. Professor of Medicine, University of Minnesota, Director Nephrology Analytical Services, Minneapolis Medical Research Foundation Marc DeBroe, M.D., Ph.D. Dept. of Nephrology & Hypertension, University Hospital of Antwerp Ram Gokal, M.D. Consultant Nephrologist, University of Manchester Karl Nolph, M.D. Curator Professor Emeritus, University of Missouri, Columbia William Frishman, M.D. Chairman & Professor of Medicine, New York Medical College, Department of Medicine Peter O’Brien, Ph.D. Professor of Biostatistics, Mayo Medical School, Department of Health Sciences Research Robert Stern, M.D. Carl J. Herzog Professor of Dermatology, Beth Israel Deaconess Medical Center Jeff Trotter, M.M. President, Ovation Research Group Consultants

  4. Extraneal Development Milestones • First market approval UK 1992 by ML Labs • Licensed by Baxter 1996 • Marketing approval in 31 countries • ~8200 patients currently treated worldwide • 30% of PD patients in Europe • US clinical trials began 1997 • Orphan Drug designation granted 1997 • NDA submitted December 2000

  5. Proposed Indication Extraneal is indicated for a single daily exchange for the long (8-16 hour) dwell during continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for the management of chronic renal failure.

  6. Topics Identified in FDA Briefing Document & Questions • Dialysis Efficacy • Quality of Life • Size of Database • Safety Profile • Mortality • Rash • Peritonitis • Membrane Transport Characteristics

  7. AGENDACardio-Renal Advisory CommitteeNDA 21-321 Extraneal (7.5% icodextrin) Introduction and Rationale for Extraneal Salim Mujais, M.D., Vice President Global Medical Affairs, Baxter Clinical Trial Experience with Extraneal Marsha Wolfson, M.D., Vice President Global Clinical Affairs, Baxter Frank Ogrinc, Ph.D., Clinical Statistician, Baxter Conclusions Salim Mujais, M.D., Vice President Global Medical Affairs, Baxter

  8. CH2OH CH2OH O O O O CH2OH CH2OH CH2 CH2OH O O O O O O O Main chain 1 4 linkage Icodextrin: A Polymer of Glucose

  9. Composition of Extraneal DIANEAL EXTRANEAL Dextrose (g/dL) 1.5, 2.5, 4.25 --- Icodextrin (g/dL) --- 7.5 Sodium (mEq/L) 132.0 132.0 Chloride (mEq/L) 96.0 96.0 Calcium (mEq/L) 3.5 3.5 Magnesium (mEq/L) 0.5 0.5 Lactate (mEq/L) 40.0 40.0 Osmolality (mOsm/kg) 346-485 282-285 pH 5.2 5.2

  10. Clinical Rationale for Extraneal • Unmet clinical need • Limitations of fluid management in PD • Limitations of current osmotic agents • Necessity of the long dwell • Kinetics of peritoneal ultrafiltration • Extraneal as a new osmotic agent • Kinetics matching clinical requirement

  11. Unmet Clinical NeedLimitations of Current Fluid Management in PD • Symptomatic fluid retention occurs in 25% of all PD patients1. In these patients: • Lower extremity edema 98.6% • Pleural effusions 76.1% • Pulmonary congestion 80.3% • Similar clinical observations have been reported from Japan2, the Netherlands3 and Sweden4 1Tzamaloukas et al. JASN 1995; 2Kawaguchi et al. Kidney Int 1997; 3Ho-dac-Pannekeet et al. Perit Dial Int 1997; 4Heimbürger et al. Perit Dial Int 1999

  12. Limitations of Fluid Management in PD Hampered by Inflexibility • Complexity of dietary counseling • Hampered by compliance issues • May complicate management • Constrained renal excretion1 • Gradual decline to anuria • Diuretic resistance • Peritoneal Ultrafiltration • Challenge of the long dwell 1 Medcalf et al, Kidney International 59:1128, 2001

  13. Extraneal Use Long dwell APD Dwell 1 Dwell 2 Dwell 3 Dwell 4 Extraneal Use Long dwell day dwell day dwell day dwell CAPD nighttime period daytime period The long dwell: an integral component of PD

  14. Rationale for the long dwell in PD: Intersection of two imperatives • Toxin removal imperative: • Small solutes removal fluid flow dependent • Middle and large molecular weight toxins are time dependent • Continuously wet abdomen required for therapy success • Realistic therapy imperative • Logistic burden and compliance

  15. + 2SD Mean -2 SD Limitations of Current Osmotic Agents Dextrose Kinetics in PD: Rapid Dissipation Mujais et al, Peritoneal Dialysis Int. 2001

  16. Removal from peritoneum Limitations of Current Osmotic Agents Balance of opposing forces Mactier et al, J Clinical Invest 80:1311, 1987

  17. 4.25% Dextrose 2.5% Dextrose 1.5% Dextrose Negative Ultrafiltration Ho-Dac-Pannekeet et al, Kid Int 1996; 50:979-86 Douma et al, Kid Int 1998; 53:1014-21 Limitations of Current Osmotic Agents:Temporal Decline

  18. oral i.p. Limitations of Current Osmotic AgentsGlycemic Effect of 4.25% Dextrose Delarue et al, Kidney Int. 45:1147, 1994

  19. oral i.p. Limitations of Current Osmotic AgentsHyperinsulinemic Effect of 4.25% Dextrose Delarue et al, Kidney Int. 45:1147, 1994

  20. Contrasting Dextrose vs. Icodextrin Peritoneal Kinetics Dextrose data from Mujais et al, PDI 2001; Icodextrin data from RD-99-CA-060

  21. Plasma Levels of Total Icodextrin & MaltoseExtraneal 035 Study – APD

  22. 7.5% Icodextrin 4.25% Dextrose 2.5% Dextrose 1.5% Dextrose Negative Ultrafiltration Ho-Dac-Pannekeet et al, Kid Int 1996; 50:979-86 Douma et al, Kid Int 1998; 53:1014-21 Contrasting Dextrose vs. Icodextrin Net UF Profile Temporal Decline vs. Sustained Effect

  23. Plasma Glucose and Insulin During an Extraneal Dwell(060 Study)

  24. Rationale for Extraneal • Fluid management in PD is constrained by the consequences of the underlying disease resulting in a necessary high reliance on peritoneal ultrafiltration. • With dextrose-based solutions a long dwell can compound the difficulties with fluid management • There is an unmet need in fluid management in PD • Extraneal is uniquely suited for successful ultrafiltration during the long dwell, and can contribute significantly to fluid management in these critically ill patients

  25. Clinical Trial Experience with Extraneal Efficacy and Safety Marsha Wolfson, MD, FACP VP, Global Clinical Affairs Francis G. Ogrinc, Ph.D. Clinical Statistician

  26. Presentation Plan • Efficacy of Extraneal • Net Ultrafiltration • Peritoneal Clearance • Special Assessments in Study 131 • Safety Profile of Extraneal • Database • Observational Mortality Data • Adverse Events • Laboratory Values

  27. Key Studies

  28. Supportive Studies

  29. Age, Gender and RaceIntegrated Summary of Safety — Baseline Demographics for All Studies AGE GENDER RACE

  30. Primary Renal DiagnosisIntegrated Summary of Safety — Baseline Demographics for All Studies

  31. Efficacy Endpoints • Primary Endpoint • Net Ultrafiltration • Secondary Endpoints • Peritoneal Creatinine Clearance • Peritoneal Urea Clearance • Special Assessments from Study 131 • Edema • Body weight • QoL

  32. * * Mean Net UF (ml) *significant within (p<0.001) and between (p<0.01) groups Ultrafiltration Extraneal 130 Study — CAPD8-16 hour Dwell, Mean Net UF – Change from Baseline

  33. * * * Mean Net UF (ml) *significant within (p<0.001) and between (p<0.001) groups Ultrafiltration Extraneal 035 Study — APD12-16 Hour Dwell, Mean Net UF – Change from Baseline

  34. 12 HOUR DWELL 8 HOUR DWELL * * * * * * Mean Net UF (ml) Ultrafiltration Extraneal MIDAS Study — CAPD 8 & 12-Hour Dwell 1.5% Dextrose, Mean Net UF – Change from Baseline *significant within (p<0.001) and between (p<0.001) groups

  35. 8 HOUR DWELL 12 HOUR DWELL Mean Net UF(m) * *significantly different from baseline Ultrafiltration Extraneal MIDAS Study — CAPD 8 & 12-Hour Dwell 4.25% Dextrose, Mean Net UF – Change from Baseline

  36. Percentage of Patients with Negative Net UF Extraneal 130 Study — CAPD8-16 Hour Dwell % patients with Negative Net UF * * * significant between treatment groups (p<0.005)

  37. Percentage of Patients with Negative Net UF Extraneal 035 Study — APD12-16 Hour Dwell % Patients with Negative Net UF * * * *significant between treatment groups (p<0.001)

  38. 8-HOUR DWELL 12-HOUR DWELL % Patients with Negative Net UF * * * * * * * significant between treatment groups (p<0.001) Percentage of Patients with Negative Net UF Extraneal MIDAS Study — CAPD 8-Hour Dwell & 12-Hour Dwell 1.5% Dextrose

  39. Percentage of Patients with Negative Net UF Extraneal MIDAS Study — CAPD 8-Hour Dwell & 12-Hour Dwell 4.25% Dextrose 8-HOUR DWELL 12-HOUR DWELL % Patients with Negative Net UF

  40. Efficacy Endpoints • Primary Endpoint • Net Ultrafiltration • Secondary Endpoints • Peritoneal Creatinine Clearance • Peritoneal Urea Clearance • Special Assessments from Study 131 • Edema • Body weight • QoL

  41. CREATININE UREA * * * * Clearance (mL/min) for the Long Dwell Clearance (mL/min) for the Long Dwell p<0.001 p=0.001 p=0.005 p=0.004 Clearance of Creatinine & Urea Extraneal 130 Study — CAPD

  42. Special Assessments from Long-term Study 131 • Edema • Body Weight • Quality of Life

  43. Peripheral Edema Assessment Extraneal 131 Study — CAPD & APD • Usually assessed by same individual • 0 - 3+ - Recorded on CRF • 4+ - Recorded as Adverse Event

  44. Adverse Events for Edema Extraneal 131 Study — CAPD & APD

  45. Special Assessments from Study 131 • Edema • Body Weight • Quality of Life

  46. Body Weight • Important parameter in ESRD • Assesses: • Fluid balance - short term • Body composition - long term

  47. Body Weight – Before Drain Extraneal 131 Study — CAPD & APD (N=47 Control, N=88 Extraneal) • Extraneal patients - maintained body weight at 52 weeks (mean change -0.03 kg) • Control patients - average increase of 2.33 kg at 52 weeks • (p=0.022 at 52 weeks)

  48. Special Assessments from Long-term Study 131 • Edema • Body Weight • Quality of Life

  49. Quality of Life — KDQoL Extraneal 131 Study — CAPD & APD • Patients completing both Baseline and Week 52 (N=25 Control, 41 Extraneal): • Queried on 35 kidney-specific symptoms/problems • Short Form 36

  50. Change in SF-36 Score: Baseline to Week 52 Patients with Baseline and Week 52 Forms PF RP BP GH VT SF RE MH 5 * ** * * * 0 -5 -10 Mean Change in Score -15 Extraneal -20 Control -25 * clinically significant result favoring Extraneal, ** favoring Dianeal Quality of Life — KDQoL Results - SF36