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TM RAPAMUNE ® O-1 RAPAMUNE ® Overview John F. Neylan, MD Vice President, Transplantation Immunology Clinical Research and Development Wyeth-Ayerst Research John F. Neylan, MD Vice President, Transplantation Immunology Clinical Research and Development Wyeth-Ayerst Research
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TM RAPAMUNE ® O-2 Renal Transplantation: Present Status Graft survival –Short-term (85% to 95% at 1 year) –Long-term (40% at 10 years) Renal function –Progressive dysfunction results in reduced graft survival Graft survival –Short-term (85% to 95% at 1 year) –Long-term (40% at 10 years) Renal function –Progressive dysfunction results in reduced graft survival UNOS OPTN Data, September 2000.
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TM RAPAMUNE ® O-3 Clinical Impact of Nephrotoxicity Calcineurin Inhibition –Effective immunosuppression –Toxicity contributes to chronic allograft nephropathy Prevalence of Nephrotoxicity * –Up to 65% of renal, liver, heart, and bone marrow transplant recipients –End-stage renal disease in up to 10% of non-renal solid organ transplant recipients Calcineurin Inhibition –Effective immunosuppression –Toxicity contributes to chronic allograft nephropathy Prevalence of Nephrotoxicity * –Up to 65% of renal, liver, heart, and bone marrow transplant recipients –End-stage renal disease in up to 10% of non-renal solid organ transplant recipients * Fisher et al, Transplantation 1998; 66:59.
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TM RAPAMUNE ® O-4 RAPAMUNE ® Mechanism of Action
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TM RAPAMUNE ® O-5 RAPAMUNE Binds/inhibits the mammalian Target of Rapamycin (mTOR) –Not a calcineurin inhibitor –Not an antimetabolite –Inhibits cytokine-mediated proliferative responses T cells B cells Mesenchymal cells Binds/inhibits the mammalian Target of Rapamycin (mTOR) –Not a calcineurin inhibitor –Not an antimetabolite –Inhibits cytokine-mediated proliferative responses T cells B cells Mesenchymal cells
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TM RAPAMUNE ® O-6 p70 S6 kinase p70 S6 kinase Ribosome Protein synthesis S6 DNA synthesis Cyclin E cdk2 cdk2 P27 P P Translation activation eIF-4E phas-1 mTOR Is a Critical Kinase in Cell Cycle Progression mTOR IL-2, IL-15 Co-stimulatory pathwayFKBP12 RAPA
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TM RAPAMUNE ® O-7 RAPAMUNE ® Rationale for Proposed Indication
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TM RAPAMUNE ® O-8 RAPAMUNE + CsA Studies 301 + 302 (Integrated Data) N = 1300 Low incidence of acute rejection Excellent 12 month patient and graft survival Higher creatinine than comparators N = 1300 Low incidence of acute rejection Excellent 12 month patient and graft survival Higher creatinine than comparators 0 50 100 150 200 250 3612 Months Creatinine, µmol/L Placebo Azathioprine RAPAMUNE 2 mg RAPAMUNE 5 mg P <.001 2.5 2.0 1.5 1.0 Creatinine, mg/dL 0.5 0
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TM RAPAMUNE ® O-9 Study 207* N = 83 Combined with azathioprine and corticosteroids Study 207* N = 83 Combined with azathioprine and corticosteroids Study 210 † N = 78 Combined with mycophenolate mofetil and corticosteroids Study 210 † N = 78 Combined with mycophenolate mofetil and corticosteroids Open-label, randomized studies RAPAMUNE versus CsA Open-label, randomized studies RAPAMUNE versus CsA RAPAMUNE as Primary Therapy in De Novo Renal Transplantation *Groth et al, Transplantation 1999; 67:1036. † Kreis et al, Transplantation 2000; 69:1252.
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TM RAPAMUNE ® O-10 * P <.05. ** Pooled analyses of studies 207 plus 210. Improved Renal Function in RAPAMUNE Group ** * * * * * * * * * * * * * * * * * * * * * * * *
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TM RAPAMUNE ® O-11 RAPA 1 mg/m 2 /day (~ 2 mg/d) RAPA 3 mg/m 2 /day (~ 6 mg/d) RAPA 5 mg/m 2 /day (~ 10 mg/d) Placebo Creatinine, µmol/L 1.0 0.9 0.8 0.7 0.6 0.5 Creatinine, mg/dL 30273027 n = 30273027 Study 204* (RAPA Monotherapy) RAPAMUNE Does Not Impair Renal Function in Psoriatic Patients *Duration of therapy 12 weeks.
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TM RAPAMUNE ® O-12 RAPAMUNE and Renal Function in Clinical Trials - Normal renal function RAPAMUNE Monotherapy Up to for 12 weeks Up to ~ 10 mg/day for 12 weeks Psoriasis RAPAMUNE Monotherapy Up to for 12 weeks Up to ~ 10 mg/day for 12 weeks Psoriasis - Similar patient and graft survival - Improved renal function RAPAMUNE Primary Therapy (RAPAMUNE vs CsA) 6 to 9 mg/day for 24 months Renal transplant RAPAMUNE Primary Therapy (RAPAMUNE vs CsA) 6 to 9 mg/day for 24 months Renal transplant - Low rate of acute rejection - Higher creatinine than comparators comparators - Low rate of acute rejection - Higher creatinine than comparators comparators RAPAMUNE Plus CsA 2 and 5 mg/day for 12 months Renal transplant RAPAMUNE Plus CsA 2 and 5 mg/day for 12 months Renal transplant
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