# Presentation: 282239

## Overview

***RAPAMUNE******®***

**Overview**

**John F. Neylan, MD**
**Vice President, Transplantation Immunology****Clinical Research and Development****Wyeth-Ayerst Research**

## 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.**

## 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; 66:59.**

## Mechanism of Action

***RAPAMUNE******®***

**Mechanism of Action**

## 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**

## mTOR Is a Critical Kinase in Cell Cycle Progression

**mTOR Is a Critical Kinase in ****Cell Cycle Progression**

## Rationale for Proposed Indication

***RAPAMUNE******®***

**Rationale for Proposed Indication**

## 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**

**0**

**50**

**100**

**150**

**200**

**250**

**3**

**6**

**12**

**Months**

**Creatinine, μmol/L**

**Placebo**

**Azathioprine**

**RAPAMUNE 2 mg**

**RAPAMUNE 5 mg**

***P *****< .001**

***P < *****.001**

***P *****< .001**

**2.5**
**2.0**
**1.5**
**1.0**

**Creatinine, mg/dL**

**0.5**

**0**

## RAPAMUNE as Primary Therapy in De Novo Renal Transplantation

**Combined with *****azathioprine***** and corticosteroids**

**Study 210****†****N = 78**
**Combined with *****mycophenolate mofetil***** and corticosteroids**

**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.**

## Improved Renal Function in RAPAMUNE Group**

*** *****P *****< .05.**
**** Pooled analyses of studies 207 plus 210.**

**Improved Renal Function in RAPAMUNE Group********

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## RAPAMUNE Does Not Impair Renal Function in Psoriatic Patients

**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**

**n =****	****30****	****27****	****30****	****27**

**Study 204* (RAPA Monotherapy)**

**RAPAMUNE Does Not Impair Renal Function in Psoriatic Patients**

***Duration of therapy 12 weeks.**

## RAPAMUNE and Renal Function in Clinical Trials

**RAPAMUNE and Renal Function in Clinical Trials**

**	****- Normal renal function**

**RAPAMUNE Monotherapy**
**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**

**	****- Low rate of acute rejection****- Higher creatinine than**
**      ****comparators**

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