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

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.

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.

TM RAPAMUNE ® O-4 RAPAMUNE ® Mechanism of Action

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

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

TM RAPAMUNE ® O-7 RAPAMUNE ® Rationale for Proposed Indication

TM RAPAMUNE ® O-8 RAPAMUNE + CsA Studies (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 Months Creatinine, µmol/L Placebo Azathioprine RAPAMUNE 2 mg RAPAMUNE 5 mg P < Creatinine, mg/dL 0.5 0

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.

TM RAPAMUNE ® O-10 * P <.05. ** Pooled analyses of studies 207 plus 210. Improved Renal Function in RAPAMUNE Group ** * * * * * * * * * * * * * * * * * * * * * * * *

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 Creatinine, mg/dL n = Study 204* (RAPA Monotherapy) RAPAMUNE Does Not Impair Renal Function in Psoriatic Patients *Duration of therapy 12 weeks.

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