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1
Overview
RAPAMUNE

• John F. Neylan, MD
• Vice President, Transplantation
  ImmunologyClinical Research and
  DevelopmentWyeth-Ayerst Research

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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

UNOS OPTN Data, September 2000.
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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

Fisher et al, Transplantation 1998 6659.
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Mechanism of Action
RAPAMUNE
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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

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mTOR Is a Critical Kinase in Cell Cycle
Progression
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Rationale for Proposed Indication
RAPAMUNE
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RAPAMUNE CsAStudies 301 302 (Integrated Data)
2.5 2.0 1.5 1.0
250

• N 1300
• Low incidence of acute rejection
• Excellent 12 month patient and graft survival
• Higher creatinine than comparators

Placebo
Azathioprine
RAPAMUNE 2 mg
200
RAPAMUNE 5 mg
P lt .001
P lt .001
P lt .001
150
Creatinine, µmol/L
Creatinine, mg/dL
100
0.5
50
0
0
3
6
12
Months
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RAPAMUNE as Primary Therapy in De Novo Renal
Transplantation
Open-label, randomized studies RAPAMUNE versus CsA
Study 207N 83 Combined with azathioprine and
corticosteroids
Study 210N 78 Combined with mycophenolate
mofetil and corticosteroids
Groth et al, Transplantation 1999
671036. Kreis et al, Transplantation 2000
691252.
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Improved Renal Function in RAPAMUNE Group
























P lt .05. Pooled analyses of studies 207 plus
210.
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RAPAMUNE Does Not Impair Renal Function in
Psoriatic Patients
Study 204 (RAPA Monotherapy)
1.0 0.90.8 0.7 0.6 0.5
Creatinine, µmol/L
Creatinine, mg/dL
n 30 27 30 27
RAPA 1 mg/m2/day ( 2 mg/d)
RAPA 3 mg/m2/day ( 6 mg/d)
RAPA 5 mg/m2/day ( 10 mg/d)
Placebo
Duration of therapy 12 weeks.
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RAPAMUNE and Renal Function in Clinical Trials
- Low rate of acute rejection- Higher
creatinine than comparators

• RAPAMUNE Plus CsA
• 2 and 5 mg/day for 12 months
• Renal transplant

• RAPAMUNE Primary Therapy(RAPAMUNE vs CsA)
• 6 to 9 mg/day for 24 months
• Renal transplant

- Similar patient and graft survival- Improved
renal function

• RAPAMUNE Monotherapy
• Up to 10 mg/day for 12 weeks
• Psoriasis

- Normal renal function