R DEVELOPMENT PROGRAM & STUDY RESULTS Slide # 31

DEVELOPMENT PROGRAM & STUDY RESULTS

Slide # 31

IV GANCICLOVIR

IV GCV is a first-line treatment for CMVR Approved in US in 1989 Current Indications

– treatment of CMVR in immunocompromised patients

– prevention of CMV disease in transplant patients at risk

Well-described efficacy and safety profile

Slide # 32

ORAL GANCICLOVIR

Oral GCV approved in US in 1994

Current Indications:– maintenance treatment of CMVR in

immunocompromised patients– prevention of CMV disease in SOT

patients & in HIV patients at risk

Limited by bioavailability (6%) and t.i.d. dosing regimen

Slide # 33

Slide # 34

MECHANISM OF ACTION

ExtracellularIntracellular

GCV GCV-MP GCV-DP GCV-TP

CellularEnzymes

ViralProtein Kinase

(UL97)

Inhibits Viral DNA Polymerase (UL54)

PRO-DRUG OF GANCICLOVIR

valganciclovir HCl ganciclovir

HN

N

O

H2N

N

NO

HO O

O

H2N

HCl HN

N

O

H2N

N

NO

HO OH

Slide # 35

VALGANCICLOVIR KEY CHARACTERISTICS

GCV exposure (AUC) following 900 mg Val-GCV similar to IV GCV (5 mg/kg)

Bioavailability approx. 60% (10X higher than oral GCV)

< 2% of absorbed dose appears as valganciclovir in plasma (t1/2 1 hour)

450 mg film-coated tablet

Slide # 36

COMPARATIVE GANCICLOVIR PK PROFILES

0.01

0.1

1

10

0 5 10 15 20 25 30

Time (h)

Ga

nc

iclo

vir

Co

nc

en

tra

tio

n(u

g/m

L)

GCV from VGCV(900mg) Oral GCV(1g t.i.d)

i.v GCV(5mg/kg) Val-GCV from VGCV (900mg)

GANS2230

Slide # 37


0.01

0.1

1

10

0 5 10 15 20 25 30

Time (h)

Ga

nc

iclo

vir

Co

nc

en

tra

tio

n(u

g/m

L)



GANS2230

Slide # 38


0.01

0.1

1

10

0 5 10 15 20 25 30

Time (h)

Ga

nc

iclo

vir

Co

nc

en

tra

tio

n(u

g/m

L)



GANS2230 (IV & Oral GCV)WP15509 (GCV from Val-GCV)

Slide # 39

COMPARATIVE PK: MEAN (%CV)

Dose AUC0-24(µg•h/mL)

Cmax(µg/mL)

Cmin(µg/mL)

Bioavail.

IV GCVGANS2230

n=16

5mg/kgq.d.

26.8 (23) 9.03 (16) 0.027*(181)(n=15)

NA

Oral GCVGANS2230

n=24

1gt.i.d.

13.0 (25) 0.975 (21) 0.2 (39) 6%

* Concentrations at 24h after single doseSlide # 40

COMPARATIVE PK: MEAN (%CV)

Dose AUC0-24(µg•h/mL)

Cmax(µg/mL)

Cmin(µg/mL)

Bioavail.

IV GCVGANS2230

n=16

5mg/kgq.d. 26.8 (23) 9.03 (16) 0.027*(181)

(n=15)NA

Oral GCVGANS2230

n=24

1gt.i.d.

13.0 (25) 0.975 (21) 0.2 (39) 6%

Val-GCVWP15509

n=17

900mgq.d.

24.9 (18) 5.15 (22) 0.085*(56) 59%

* Concentrations at 24h after single doseSlide # 41

PK/PD SUPPORTS GCV AUC AS CORRELATE OF EFFICACY

PK/PD explored in GANS2226- dose-ranging maintenance study- included IV and three oral GCV doses

Population PK approach (NONMEM)

AUC0-24 significantly correlated with efficacy (time to progression)

Slide # 42

BASIS OF DOSE SELECTION

0

10

20

30

40

50

60

70

80

90

0 1000 2000 3000

Valganciclovir Dose (mg)

Gan

cicl

ovi

r A

UC

0-24

(m

g.h

/mL

)

900 mg Val-GCV achieves target AUC ( 26 mg•h/mL)

maintenance

induction

Slide # 43

METABOLISM AND ELIMINATION

Rapid hydrolysis to GCV

Intestinal and hepatic esterases represent a high-capacity system

No other metabolites detected

GCV drug interactions applicable to Val-GCV

Renal impairment requires dose adjustment

Slide # 44

DEVELOPMENT RATIONALE

Therapeutic alternative to IV GCV treatment of CMVR (induction and maintenance)

Avoidance of risks associated with IV access required for IV GCV therapy

Simple oral regimen that could improve patient adherence during maintenance treatment

The PK profile of GCV from Val-GCVprovided the potential for:

Slide # 45

EARLY CHALLENGE

Pilot Study: potential efficacy in induction treatment

– Enrollment initiated Jan,1997

– Impact of HAART

– 11/70 patients enrolled in 4 months (17 sites)

Slide # 46

From Kovacs JA and Masur H. N Engl J Med. 2000342: 1415-1429

IMPACT OF HAART

Slide # 47

DEVELOPMENT PROGRAM

OverallN = 491

Therapeutic Studiesin AIDS Patients

N=372

Clinical PharmacologyStudiesN=119

Controlled StudyWV15376

N=160

Uncontrolled StudyWV15705

N=212

Multiple Dose StudyWP15347

N=39

Single-Dose andSpecial Population Studies

GANS2661, WP15509WP15511

N= 80

Transplant: PV16000 (n=121 as of Aug 31, 2000); WP15711 (n=28) Slide # 48

BrazilAustralia

Mexico

Canada

FranceItaly

United States Germany

United Kingdom

Spain

PARTICIPATING COUNTRIES372 patients in 26 months (50 sites)

Slide # 49

DEVELOPMENT PROGRAM

Built on the proven efficacy of GCV

Primary interest: Comparison of Val-GCV and IV GCV efficacy & safety

Induction setting - highest efficacy hurdle for CMVR treatment

Slide # 50

EFFICACY

Slide # 51

WV15376 STUDY DESIGN

900 mg bid 3 weeks900 mg qd 1 week

Week 4Baseline

5 mg/kg bid 3 weeks5 mg/kg qd 1 week

Randomize

IV Ganciclovir

Valganciclovir

RANDOMIZED PHASE EXTENSION

Valganciclovir

900 mg qdN = 160

Slide # 52

WV15376 PRIMARY ENDPOINT

Progression defined as movement 750 mm (along a 750 mm front ) or new retinitis lesion 750 mm diameter

Assessed by retinal photography

Proportion of Patients DemonstratingProgression of CMV Retinitis by Week 4

Slide # 53

PHOTO ASSESSMENT METHODS

Full-field, bilateral photographs

Central retinal photograph reading center (independent)

Scored by experienced grader (masked)

Scored: progression, distance of border movement, border activity

Slide # 54

WV15376: ANALYSIS CONSIDERATIONS

Non-inferiority is a standard statistical approach to address this

Non-inferiority test utilizes only the lower bound of confidence interval

Non-inferiority limit (d = -0.25) chosen to represent the limit of a clinically acceptable treatment group difference

Is efficacy of Val-GCV similar to (no worse than)

IV GCV for induction therapy?

Slide # 55

ASSESSING NON-INFERIORITY

0

Val-GCV No Worse than IV GCV

Treatment difference (Pg-Pv)

- 0.25

d

Slide # 56

ASSESSING NON-INFERIORITY (cont’d)

0


- 0.25

d

(Hypothetical)

Slide # 57

0



- 0.25

d


(Hypothetical)

Slide # 58


0



- 0.25

d (WV15376 Results)

(Hypothetical)

Slide # 59

BASELINE STATUS [1]

IV GCVn=80

Val-GCVn=80

Gender (M/F)

Age Median (yr)

73 / 7 72 / 8

37 39

EthnicityCaucasianHispanicBlackAsianOther

42 (53%)25 (30%) 9 (11%) 1 ( 1%) 3 ( 4%)

43 (54%)25 (30%) 9 (11%) 1 ( 1%) 2 ( 3%)

Slide # 60

BASELINE STATUS [2]

IV GCVn=80

Val-GCVn=80

CD4 median (cells/mL)(range)

26(2-365)

20(2-390)

HIV Load, median (log) (range)

4.9(1.7-5.9)

4.8(1.7-5.9)

CMV Load, median (log) (range)

3.4(2.5-5.5)

3.6(2.6-4.8)

CMV-Positive Culture 65% (n = 46/71)

46% (n = 33/71)

CMV-Positive Plasma PCR 51% (n =39/76)

40% (n = 31/77)

Slide # 61

BASELINE - HIV THERAPY

PI Use - ongoing/prior

PI-Naïve 16 (20%) 16 (20%)

IV GCVn=80

Val-GCVn=80

No Anti-Retrovirals at entry 18 (23%) 17 (21%)

Anti-Retroviral-Naïve 7 ( 9%) 5 ( 6%)

Protease Inhibitors (PI) at entry 47 (59%) 53 (66%)

64 (80%) 64 (80%)

Slide # 62

BASELINE RETINITIS

IV GCVn=80

Val-GCVn=80

19 (24%)Zone 1 19 (24%)

Zone 2/3 55 (69%) 53 (66%)

Bilateral 20 (25%) 20 (25%)Unilateral 54 (68%) 52 (65%)

71 (89%) 68 (85%)Active Lesion Border

Slide # 63

STUDY POPULATIONS

IV GCV Val-GCV

ITT - All Randomized 80 (100%) 80 (100%)

EFFICACY (STD) Population 73 ( 91%) 73 ( 91%)

- Subjects excluded 7 ( 9%) 7 ( 9%)

Slide # 64

PRIMARY ENDPOINT(COMPARABLE EFFICACY AT WEEK 4)

IV GCVn=73

Val-GCVn=73

Photo Progression 7 7

No Photo Progression 63 64

Unevaluable 3 2

Proportion progressed 0.100 (10%) 0.099 (9.9%)

Difference 0.001 (0.1%)

95% Confidence Interval (-0.097, 0.100)

Slide # 65

PROGRESSION AT WEEK 4 BY CMVR ZONE AT BASELINE (PHOTO)

IV-GCV Val-GCV

Zone 1

Zone 2/3

Uneval.

Prog n=7

Non-Prog n=64

14 (88%)

48 (91%)

1

2 (13%)

5 ( 9%)

0

16 (89%)

45 (90%)

3

2 (11%)

5 (10%)

0

Prog n=7

Non-Prog n=63

Slide # 66

VISUAL ACUITY & FUNCTIONAL VISION

25/79 (32%)24/77 (31%)Decreased Functional Vision By 1 Category

13/77 (17%)11/77 (14%)Decreased Acuity By 2 Categories

12/77 (16%)10/77 (13%)Decreased Acuity By 1 Category

Val-GCVIV GCV

(To Clinical Cut-Off)

Slide # 67

K-M: TIME TO PROGRESSION (PHOTOGRAPHY)

72/74 65/62 39/49 33/34 25/32 21/26 18/22 17/18 15/16 14/14 *

Median Time To ProgressionIV GCV/Val-GCV 125 daysVal-GCV/Val-GCV 160 days

* IV GCV/Val-GCV Pts still at riskSlide # 68

CMV CULTURES

% of patients with

IV GCV Val-GCVCMV-positive culture

Baseline

Week 4

65% (46/71)

6% ( 4/64)

46% (33/71)

7% ( 4/58)

Slide # 69

CMV PCR

% of patients with

CMV viremia (plasma)

Baseline

Week 4

51% (39/76)

3% ( 2/70)

40% (31/77)

4% ( 3/71)

IV GCV Val-GCV

Slide # 70

K-M : TIME TO WITHDRAWAL

* IV GCV/Val-GCV Pts still at risk

80/80 77/74 74/65 68/61 64/58 58/51 53/46 46/39 39/35 36/33 *

Median Time To WithdrawalIV GCV/Val-GCV 419 daysVal-GCV/Val-GCV 376 days

Slide # 71

WITHDRAWALS BETWEEN WEEKS 4 & 12

Adverse Events: IV GCV - Pneumocystis carinii pneumonia Val-GCV - hypoaesthesia & pain in limb; neutropenia; lymphoma; dehydration; pancytopenia

DeathAdverse EventRefused TreatmentFailed to ReturnInsufficient ResponseTotal

211004

1 5 2 2 414

IV GCV Val-GCV

Slide # 72

K-M: TIME TO PROGRESSION OR WITHDRAWAL

* IV GCV/Val-GCV Pts still at risk

77/80 67/66 43/52 35/36 27/33 22/28 19/23 17/19 15/16 14/14 *

Median Time To Progression or WithdrawalIV GCV/Val-GCV 102 daysVal-GCV/Val-GCV 112 days

Slide # 73

WV15376 MEAN STEADY-STATE CONC. OF GCV AFTER IV GCV & VAL-GCV

0.01

0.1

1

10

0 5 10 15 20 25

Time (h)

Co

nce

ntr

atio

n u

g/m

L

i.v GCV wk1 GCV from Val-GCV wk1

Week 1

Slide # 74

WV15376 MEAN STEADY-STATE CONC. OF GCV AFTER IV GCV & VAL-GCV

0.01

0.1

1

10

0 5 10 15 20 25

Time (h)

Co

nce

ntr

atio

n u

g/m

L

i.v GCV wk4 GCV from Val-GCV wk4

Week 4

Slide # 75

WV15376 MEAN STEADY-STATE CONC. OF GCV & VAL-GCV AFTER IV GCV & VAL-GCV

0.01

0.1

1

10

0 5 10 15 20 25

Time (h)

Co

nce

ntr

atio

n u

g/m

L

i.v GCV wk1 i.v GCV wk4GCV from Val-GCV wk1 GCV from Val-GCV wk4Val-GCV wk1 Val-GCV wk4

Weeks 1 & 4

Slide # 76

WV15376 MEAN GCV PK PARAMETERS

IV GCVn=18

Val-GCVn=25

IV GCVn=18

Val-GCVn=20

Dose

WEEK 1 WEEK 4

5 mg/kgb.i.d.

5 mg/kgq.d.

900 mgb.i.d.

900 mgq.d.

Slide # 77


IV GCVn=18

Val-GCVn=25

IV GCVn=18

Val-GCVn=20

12 hr AUC

(CV%)

24 hr AUC28.6

(31.6)

32.8

(30.7)

30.7

(25)

34.9

(38.1)

Dose

WEEK 1 WEEK 4

5 mg/kgb.i.d.

5 mg/kgq.d.

900 mgb.i.d.

900 mgq.d.

AUC: µg•h/mL Slide # 78


IV GCVn=18

Val-GCVn=25

IV GCVn=18

Val-GCVn=20

12 hr AUC

(CV%)

24 hr AUC28.6

(31.6)

32.8

(30.7)

30.7

(25)

34.9

(38.1)

Cmax 10.4 6.71 9.86 5.87(n=21)

Dose

WEEK 1 WEEK 4

5 mg/kgb.i.d.

5 mg/kgq.d.

900 mgb.i.d.

900 mgq.d.

AUC: µg•h/mL; Cmax: µg/mL Slide # 79

SAFETY

Slide # 80

SAFETY-RELATED STUDY WITHDRAWALS RANDOMIZED PHASE

IV GCVn=80

Val-GCVn=80

Total Safety-Related Withdrawals

2 (3%) 1 (1%)

Adverse Event OrIntercurrent Illness

1 (1%) (ANC)

0

Death 1 (1%)(lymphoma)

1 (1%)(PCP)

Slide # 81

SAFETY RANDOMIZED PHASE (10%)

IV GCVn=79

Val-GCVn=79

Diarrhea 8 (10%) 13 (16%)

Pyrexia 9 (11%) 10 (13%)

Neutropenia 10 (13%) 9 (11%)

11 (14%)Nausea 6 ( 8%)

Oral Candidiasis 5 ( 6%) 9 (11%)

8 (10%) 6 ( 8%)Vomiting

Catheter-Related 9 (11%) 2 ( 3%)

Adverse Event

Slide # 82

LABORATORY ABNORMALITIESRANDOMIZED PHASE

IV GCVn=79

Val-GCVn=79

5 ( 6%)10 (13%)

5 ( 6%)12 (15%)

< 500500 to < 750

ANC (cells/µL)

0 2 ( 3%)

04 ( 5%)

< 6.56.5 to < 8.0

Hemoglobin (g/dL)

0 0

01 ( 1%)

< 2500025000 to < 50000

Platelets (/µL)

Slide # 83

POOLED SAFETYWV15376 & WV15705

Slide # 84

STUDY WV15705 DESIGN (SAFETY & TOLERANCE)

Patients with CMV Retinitisn=212 Val-GCV

900 mg bid21 days

Val-GCV 900 mg qd

CMVR Progression

CMVR Progression

CMVR Stable CMVR Stable

Slide # 85

VAL-GCV TREATMENT (DAYS)

(To Clinical Cut off)

WV15376 WV15705IV GCV

n=79Val-GCV

n=79Val-GCV

n=212

Mean 322 281 333

Median 287 248 372

Range 0-875 2-847 12-513

Slide # 86

SAFETYMAINTENANCE TREATMENT PHASE

Adverse Event (%)Val-GCVN= 370

GCV 3gN= 536

IV GCVN=412

PLAN=119

Diarrhea 34 31 27 24Pyrexia 24 35 36 35

Neutropenia 21 23 26 12Nausea 22 25 19 22Fatigue 18 17 18 23

20Anemia 17 20 17Vomiting 17 13 12 13

Historical(To Clinical Cut-off)

Oral Candidiasis 17 9 6 13

Slide # 87

LABORATORY ABNORMALITIESMAINTENANCE TREATMENT PHASE

< 500500 to < 750

ANC (cells/µL)

< 6.56.5 to < 8.0

Hemoglobin (g/dL)

< 2500025000 to < 50000

Platelets (/µL)

N = 370

55 (15%)54 (15%)

25 ( 7%)34 ( 9%)

10 ( 3%)17 ( 5%)

(To Clinical Cut-off)

Slide # 88

VALGANCICLOVIR COMPARABLE SAFETY TO GCV

Safety profile comparable to GCV experience

No unexpected toxicities observed

Most frequent severe or serious events:neutropenia, anemia

Frequency of pancytopenia similar to IV GCV (1-2%)

Slide # 89

CMVR progression rates were equal

Clear and comparable anti-viral effect

Significantly fewer IV catheter-related & serious adverse events in Val-GCV group

Other adverse event rates were similar

During Randomized Treatment (IV GCV or Val-GCV):

SUMMARY

Slide # 90

SUMMARY

Val-GCV provides:

Systemic exposures comparable to

IV GCV (induction and maintenance)

Similar long-term rates of CMVR

progression and adverse events,

regardless of randomized induction

regimen (IV GCV or Val-GCV)

Slide # 91

CONCLUSION

Valganciclovir, an oral prodrug of ganciclovir with high bioavailability, provides an effective and convenient treatment for CMV retinitis

Slide # 92

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R DEVELOPMENT PROGRAM & STUDY RESULTS Slide # 31