S-1

1
CsA Elimination Studies
RAPAMUNE

• Safety

2
Summary of Safety Assessments

• Etiologies of graft loss and death
• Adverse events, including those related to
  immunosuppression (infection and malignancy)
• Blood pressure measurements
• Laboratory parameters

3
Study 310Equivalent 12 Month Graft Survival
RAPA CsA RAPA All Patients (n 215) (n
215) (N 525) Overall rate ()
95.8 97.2 89.1 95 CI
1.4 ( 4.9, 2.1) Graft loss 2.3 lt
1 6.7 Death with functioning graft 1.9 1.9 4.0 L
ost to follow-up 0 0 lt 1
Death censored physical or functional loss of
graft. Intent-to-treat population.
4
Study 310Etiologies of Graft Loss

• RAPA CsA RAPA (n 215) (n 215)
• Infection (sepsis) 2 (0.9) 0
• Renal fibrosis 1 (0.5) 0
• Graft ischemia 1 (0.5) 1 (0.5)
• Graft vascularthrombosis 1 (0.5) 0
• Recurrent disease 0 1 (0.5)

Intent-to-treat analysis at 12 months.
5
Study 310 Equivalent 12 Month Patient Survival
RAPA CsA RAPA All Patients (n 215) (n
215) (N 525) Survival () 97.2 98.1 94.9
95 CI 0.9 ( 3.8, 1.9)
Intent-to-treat analysis.
6
Study 310Etiologies of Patient Death

• RAPA CsA RAPA (n 215) (n 215)
• Cardiac arrest 3 (1.4) 1 (0.5)
• Infection Sepsis 2 (0.9) 2 (0.9) Aspergillosis 1
  (0.5) 1 (0.5)

Intent-to-treat analysis at 12 months.
7
Summary of Safety Assessments

• Etiologies of graft loss and death
• Adverse events, including those related to
  immunosuppression (infection and malignancy)
• Blood pressure measurements
• Laboratory parameters

8
Study 310 Incidence () of Significantly
Different Treatment-Emergent Adverse Events
RAPA CsA RAPA (n 215) (n 215) P
value
CsA toxicity 8.8 2.8 .012 Creatinine
increase 26.5 15.3 .006 Edema 7.4 2.8 .047 Hypert
ension 20.0 7.0 lt.001 Hyperuricemia 13.5 4.7 .002
Hypokalemia 2.3 8.8 .005 SGOT (AST)
increased 3.3 9.8 .010 SGPT (ALT)
increased 4.7 14.9 lt.001 Thrombocytopenia 4.2 11.2
.010

Post-randomization.

9
Study 310Incidence () of Infections
RAPA CsA RAPAInfection type (n 215) (n
215) Sepsis 4.2 3.3 Cytomegalovirus Syndrome 4.7
5.1 Tissue-invasive 1.4 0.9 Pneumonia 5.6 9.3 Her
pes simplex 5.6 6.5 Herpes zoster 6.0 0.5 Urinary
tract infection 20.5 26.5
P .002
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Study 310Similar Incidence () of Neoplasia

• RAPA CsA RAPA (n 215) (n 215)
• Total, n () 14 (6.5) 8 (3.7)
• Skin Non-melanomatous 6 (2.8) 5
  (2.3) Melanoma 1 (0.5) 0
• B-cell lymphoma 1 (0.5) 1 (0.5)
• Acute myeloid leukemia 1 (0.5) 0
• Other Lung 1 (0.5) 0 Oropharynx 1
  (0.5) 0 Renal 2 (0.9) 0 Prostate 1
  (0.5) 0 Cervix 0 1 (0.5) Colon 0 1 (0.5)

2 cases (RAPA CsA) and 1 case (RAPA) - onset
prerandomization. Adenomatoid polyp not
malignant.
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Summary of Safety Assessments

• Etiologies of graft loss and death
• Adverse events, including those related to
  immunosuppression (infection and malignancy)
• Blood pressure measurements
• Laboratory parameters

12
Study 310Improved Mean Blood Pressure (mmHg)
n 189 182 119 25

n 188 182 119 25








mmHg
n 178 163 106 20
n 179 163 107 21
Randomization
Randomization
P lt .05
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Study 310 Reduced Requirement for Combination
Anti-Hypertensive Regimens Percent of Patients
at 12 Months
Drugs (n) RAPA CsA RAPA 0 8.0 10.9
1 25.1 32.1 2 28.9 34.5 3 24.1 17.0
4 9.1 3.6 5 4.3 1.8 6 0.5 0
CMH P .013 (row mean score difference).
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Summary of Safety Assessments

• Etiologies of graft loss and death
• Adverse events, including those related to
  immunosuppression (infection and malignancy)
• Blood pressure measurements
• Laboratory parameters

15
Study 310 Similar Use of Lipid-Lowering Agents
Pre-Treatment
On-Therapy
n
41 32 7 39 35 3 179 156 51 180 158 53
P N.S. Cumulative data.
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Study 310 Similar Fasting Cholesterol Values
14
RAPA CsA
RAPA
450
(n 156)
(n 143)
12
400
10
350
300
8
Mean Fasting Cholesterol, mg/dL
250
Mean Fasting Cholesterol, mmol/L
6
200
150
4
100
2
50
0
0
Month 12
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Study 310 Similar Mean FastingHDL- and
LDL-Cholesterol Values

ULN
n 137 136 85 19

n 125 121 102 80
ULN
n 132 141 83 17
n 141 144 85 18
Randomization
Randomization
P lt .05ULN upper limit of normal.
18
Study 310 Similar Fasting Triglyceride Values
19
Study 310 Mean ALT/SGPT and AST/SGOT Values
ULN
n 175 158 110 22
ULN
n 175 157 106 22







n 178 175 118 25
n 177 175 119 25
Randomization
Randomization
P lt .05ULN upper limit of normal.
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Study 310 Randomized Patients With at Least 1
SGPT Value Greater Than 5 Times the Upper Limit
of Normal (SGPT ? 275 IU/L)
TABLE 10.4.2.4C
Therapy GroupPatient No. Time Slot Value
(IU/L) Cause of Elevated Liver Enzymes RAPA CsA
(12 Months) 3505 Month 4 670 Hepatitis
B 3814 Months 4-7 347 - 804 Hepatitis B
reactivation 5807 Month 3 301 Etiology
undetermined 6110 Months 3-5, 7 323 -
770 Increased liver enzymes since d7 6912 Month
5 555 Hepatitis B core antigen
positive 7202 Month 8 332 Etiology
undetermined RAPA (12 Months) 3821 Month
5 297 Hepatitis B 4102 Month 5 377 Etiology
undetermined 8506 Month 4 460 CMV
Hepatitis 8512 Month 12 539 - 680 Hepatitis
(drug-induced) 8708 Months 4, 5 297 -
322 Hepatitis (drug-induced)
Values greater than 10 times the normal values
(ALT/SGPT ? 550 IU/L).
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Study 310 Mean WhiteBlood Cell and Platelet
Counts
ULN
ULN
n 183 182 122 25
n 183 181 120 25





n 180 163 111 22
n 180 163 111 22
LLN
LLN
Randomization
Randomization
P lt .05ULN upper limit of normal.LLN
lower limit of normal.
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Study 310 Safety Summary

• Equivalent patient and graft survival
• RAPA CsA group increased incidence of CsA
  toxicity, increased creatinine, edema,
  hypertension, hyperuricemia
• RAPA group increased incidence of hypokalemia,
  increased SGOT/SGPT, thrombocytopenia
• Similar rates of infection and malignancy
• Improved blood pressure following CsA elimination
• Comparable lipid profiles, WBCs and platelet
  counts

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Study 212 Similar 12 Month Graft Survival
RAPA CsA RAPA Nonrandomized (n 97) (n
100) (N 49) Overall rate () 92.8 95.0 75.5
95 CI 2.2 (
8.9, 4.5) Graft loss 4.1 1.0 14.3 Death with
a functioning graft 3.1 4.0 8.2 Lost to
follow-up 0 0 2.0
Death censored physical or functional loss of
graft.
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Study 212Etiologies of Graft Loss

• RAPA CsA RAPA (n 97) (n 100)
• Acute rejection 1 (1.0) 1 (1.0)
• ATN/DGF 1 (1.0) 0
• HUS 2 (2.1) 0

Intent-to-treat analysis at 12 Months death
censored. HUS Hemolytic uremic syndrome.
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Study 212 Similar 12 Month Patient Survival
RAPA CsA RAPA Nonrandomized (n 97) (n
100) (n 49) Survival () 96.9 96.0 89.8 95
CI 0.9 ( 4.3, 6.1)
Intent-to-treat population.
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Study 212Etiologies of Patient Death

• RAPA CsA RAPA (n 97) (n 100)
• Cardiovascular cardiac arrest 2 (2.1) 1
  (1.0) heart failure 0 1 (1.0) unspecified 0 1
  (1.0)
• Infection (encephalitis) 1 (1.0) 0
• Pulmonary edema 0 1 (1.0)

Intent-to-treat population.
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Study 212 Treatment Emergent Adverse Events ()
RAPA CsA RAPA Adverse Event, (n 97) (n
99) P value Hypertension 46.4 30.3 .027 Dyspnea
20.6 9.1 .027 Edema 14.4 3.0 .005 Hypervole
mia 12.4 4.0 .039 Hypomagnesemia 12.4
4.0 .039 Thrombocytopenia 14.4 28.3 .023
Hypokalemia 13.4 25.3 .046 Diarrhea 11.3 25.3 .
016 Liver function tests abnormal
7.2 17.2 .048 Atrial fibrillation 1.0
8.1 .035
1 patient did not receive drug.
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Atrial Fibrillation Incidence in Study 212 Not
Observed in Other Studies
Study 212
Treatment Incidence () Comments Study 212
(N246)RAPA CsA 1.0 Age 49y Duration 1
d(n1) Outcome resolved with
treatment Relationship not related RAPA 8.1 Age
51 to 68y Duration 1 to 58d(n8)
Outcome resolved with treatment P
.035 Relationship not related Study 310
(N525)RAPA CsA 1.9 P N.S.RAPA 3.7 Studies
301/302 (N1296)RAPA 2mg/CsA 3.6 P N.S.RAPA
5mg/CsA 3.1AZA/CsA 3.1Placebo/CsA 1.6
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Study 212 Similar Incidence ()of Infections at
Month 12
RAPA CsA RAPAInfection Type (n 97) (n
100) Sepsis 7.2 6.0 Cytomegalovirus syndrome 4.1
5.0 tissue-invasive 1.0 2.0 Pneumonia
9.3 7.0 Pneumocystis carinii pneumonia 0 1.0 Herp
es simplex 13.4 11.0 Herpes zoster 5.2 4.0 Urinary
tract infection 33.0 36.0 Wound
infection 7.2 7.0 Epstein-Barr virus 0 2.0
P N.S. Intent-to-treat population at 12
months.
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Study 212 Incidence () ofMalignancy at Month 12
RAPA CsA RAPA (n 97) (n
100) Total 0 4.0 Non-melanomatous skin
cancer 0 2.0 PTLD (presumed) 0 1.0 Renal cell
carcinoma (native kidney) 0 1.0
PTLD Post-transplant lymphoproliferative
disease.
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Study 212 Safety Summary

• Equivalent patient and graft survival
• RAPA CsA group increased incidence of
  hypertension, dyspnea, edema, hypervolemia,
  hypomagnesemia
• RAPA group increased incidence of
  thrombocytopenia, hypokalemia, diarrhea,
  increased SGOT/SGPT, atrial fibrillation
• Similar rates of infection and malignancy
• Similar lipid profiles, WBCs and platelet counts

32
Study 310Patient Disposition by Month 12
d/c
Enrolled (N525)
Nonrandomized (n95)
Randomized 11 at Month 3 (n430)
18.1
3
RAPA CsA (n215)
RAPA (n215)
d/c (n58)
d/c (n38)
Primary Endpoint at Month 12
36.4
12
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Study 310 Similar Incidence of Discontinuations
() at ? Month 15
Nonrandomized
Randomized Reason for RAPA CsA RAPADiscontinu
ation (Month 12) (n/n 95/95) (n/n
38/215) (n/n 58/215) Adverse
event 74.0 14.0 17.0 Acute rejection 13.0 2.0 5.0
Other 13.0 2.0 6.0 Total 100.0 18.0 27.0
Discontinuations (? Month 15) (n/n
59/215) (n/n 65/215) Adverse
event 20.0 20.0 Acute rejection 4.0 5.0 Other 3.
0 5.0 Total 27.0 30.0
P .027 (RAPA CsA vs RAPA). P N.S.
(RAPA CsA vs RAPA).
34
Study 310 Treatment of Patients Discontinued
from the RAPAMUNE Group
Converted Therapy n 58 () Corticosteroids 43
(81)CsA 29 (55)Tacrolimus 14 (26)MMF 16
(30)RAPAMUNE 10 (19)

• No acute rejections
• 3 Deaths
• 2 Graft losses

Each patient may be receiving gt 1 therapy.MMF
mycophenolate mofetil.
35
Study 310 Successful Elimination of Cyclosporine
in 92.6 of Patients
50 90
Intent-to-treat analysis.
36
Study 212Patient Disposition by Month 12
d/c
Enrolled (N246) Randomized 11 within 7 Days
(n197)
Nonrandomized (n49)
RAPA CsA (n97)
RAPA (n100)
d/c (n25)
d/c (n20)
Patient Survival Graft Survival at Month 12
29.7
12
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Study 212 Discontinuations () by Month 12
Nonrandomized
Postrandomization Reason for RAPA
CsA RAPADiscontinuation (n/n 28/49) (n/n
20/97) (n/n 25/99) Adverse event 41.0 12.0 12.0
Acute rejection 6.0 5.0 4.0 Other 10.0 3.0 10
.0 Total 57.0 20.0 26.0
P N.S. 49 patients not randomized (48
ATN/DGF 1 acute rejection).
38
Study 212Successful Elimination of Cyclosporine
RAPAMUNEPatients Eligible for CsA Withdrawalby
Month 2 (n82)
RAPAMUNEAll Randomized Patients (n100)
93
76
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Safety Summary (I)

• Studies 310 and 212 confirm the beneficial safety
  profile of RAPAMUNE-based therapy following CsA
  elimination
• Excellent patient and graft survival
• Similar rates of infection and malignancy
• Significantly lower rates of CsA-related adverse
  events
• Significant and sustained improvement in blood
  pressure in patients in Study 310
• The overall RAPAMUNE safety profile is similar to
  that observed when it is administered as a fixed
  2 mg dose in combination with CsA

40
Safety Summary (II)

• Rates of discontinuation from study medication
  were similar to other recent immunosuppressive
  registration trials
• Reasons for early discontinuation were typical,
  with few due to acute rejection
• Alternate maintenance therapies were utilized for
  patients discontinued from the studies
• Cyclosporine was successfully eliminated in the
  majority of patients in the RAPAMUNE group