# Presentation: 787413

## 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

## MECHANISM OF ACTION

**MECHANISM OF ACTION**

## PRO-DRUG OF GANCICLOVIR

- valganciclovir HCl

- ganciclovir

- HN

- N

- O

- H2N

- N

- N

- O

- HO

- O

**O**

**H****2****N**

- HCl

- 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 (t****1/2**** **** 1 hour) **
**450 mg film-coated tablet**

- Slide # 36

## COMPARATIVE GANCICLOVIR PK PROFILES

**GANS2230 **

- Slide # 37

## COMPARATIVE GANCICLOVIR PK PROFILES

**GANS2230**

- Slide # 38

## COMPARATIVE GANCICLOVIR PK PROFILES

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

- Slide # 39

## COMPARATIVE PK: MEAN (%CV)

** **Concentrations at 24h after single dose*

- Slide # 40

## COMPARATIVE PK: MEAN (%CV)

** **Concentrations at 24h after single dose*

- Slide # 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) **
**AUC****0-24**** significantly correlated with efficacy (time to progression)**

- Slide # 42

## BASIS OF DOSE SELECTION

**900 mg Val-GCV achieves target AUC (******** 26 ********g****•****h/mL)**

- maintenance

- induction

- Slide # 43

**Notes:**
Dose proprtionality demonstrated for dosing valganciclovir in the fed state.

Previous experience with I.v ganciclovir indicates that AUC24 values in the region of 26 are efficacious and therefore a 900mg dose was selected which achieves that exposure.

At the chosen therapeutic dose 900mg the 24h AUC is around 26ug.h/ml

In range of doses up to 900mg there is little divergence between the curves describing the fed vs fasted states.

## 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-GCV**
**provided 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

## IMPACT OF HAART

- 

*From Kovacs JA and Masur H. N Engl J Med. 2000*
*342: 1415-1429*

**IMPACT OF HAART**

- Slide # 47

## DEVELOPMENT PROGRAM

**Overall**
**N = 491**

- Therapeutic Studies
- in AIDS Patients
- N=372

- Clinical Pharmacology
- Studies
- N=119

- Controlled Study
- WV15376
- N=160

- Uncontrolled Study
- WV15705
- N=212

- Multiple Dose Study
- WP15347
- N=39

- Single-Dose and
- Special Population Studies
- GANS2661, WP15509
- WP15511
- N= 80

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

- Slide # 48

## PARTICIPATING COUNTRIES

**PARTICIPATING COUNTRIES**

**372 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 weeks**
**900 mg qd 1 week**

**Week 4**

**Baseline**

**5 mg/kg bid 3 weeks**
**5 mg/kg qd 1 week**

**Randomize**

**IV Ganciclovir**

**Valganciclovir**

- RANDOMIZED PHASE

- EXTENSION

**Valganciclovir**

**900 mg qd**

- N = 160

- Slide # 52

## WV15376 PRIMARY ENDPOINT

**Progression defined as movement ******** 750 ********m (along a ******** 750 ********m front ) or ****new retinitis lesion ******** 750 ********m diameter**
**Assessed by retinal photography**

**Proportion of Patients Demonstrating**
**Progression 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

- Treatment
- difference
-  (Pg-Pv)

-  - 0.25

- d

- (Hypothetical)

- Slide # 57

## ASSESSING NON-INFERIORITY (cont’d)

- 0

**Val-GCV No Worse than IV GCV**

- Treatment
- difference
-  (Pg-Pv)

-  - 0.25

- d

**ASSESSING NON-INFERIORITY ****(cont’d)**

- (Hypothetical)

- Slide # 58

## ASSESSING NON-INFERIORITY (cont’d)

- 0

**Val-GCV No Worse than IV GCV**

- Treatment
- difference
-  (Pg-Pv)

-  - 0.25

- d

- (WV15376 Results)

- (Hypothetical)

- Slide # 59

## BASELINE STATUS [1]

- IV GCV
- n=80

- Val-GCV
- n=80

- Gender (M/F)

- Age Median (yr)

- 73 / 7

- 72 / 8

- 37

-  39

- Ethnicity

- Caucasian
- Hispanic
- Black
- Asian
- Other

- 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 GCV
- n=80

- Val-GCV
- n=80

- CMV Load, median (log) (range)

-  3.4(2.5-5.5)

- 3.6
- (2.6-4.8)

- Slide # 61

**Notes:**
 3.4(n = 38/39)

## BASELINE - HIV THERAPY

- PI Use - ongoing/prior

- PI-Naïve

- 16 (20%)

- 16 (20%)

- IV GCV
- n=80

- Val-GCV
- n=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 GCV
- n=80

- Val-GCV
- n=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 GCV
- n=73

- Val-GCV
- n=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

**Notes:**
Speak: types of progression 1 in IV GCV arm is new lesion, others movement
Note: mention that this is the efficacy population analysis; also have done ITT pop analysis, and the confidence interval is ??

## 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

**Notes:**
Checked with zoneprogT54

## 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-GCV

- IV GCV

- (To Clinical Cut-Off)

- Slide # 67

**Notes:**
I have checked all numbers and they are correct. Rows 2 and 3 checked with Table 27 in module V and Row 3 checked with Appendix 84 in 			Module V (last section). 
		Change in functional vision was calculated by looking at the baseline results of subject vision assessment for the final 	question (in general, the 		subjects eyesight is: Excellent / Very Good / Good / Fair / Poor) and comparing the change from baseline to the last post-baseline assessment 		before data cut-off. So for example, an 'improvement by 2 grades' could mean poor -> good or fair -> very good and 'worsening by 3 grades' 			could mean excellent->fair or very good->poor.

## 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 *

- Slide # 68

## CMV CULTURES

- % of patients with

- IV GCV

- Val-GCV

- CMV-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 

- Median Time To Withdrawal
- IV GCV/Val-GCV   419 days
- Val-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

- Death
- Adverse Event
- Refused Treatment
- Failed to Return
- Insufficient Response
- Total

- 2
- 1
- 1
- 0
- 0
- 4

-   1
-   5
-   2
-   2
-   4
- 14

- IV GCV

- Val-GCV

- Slide # 72

## K-M: TIME TO PROGRESSION OR WITHDRAWAL

- Slide # 73

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

**Week 1**

- Slide # 74

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

**Week 4**

- Slide # 75

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

**Weeks 1 & 4**

- Slide # 76

## WV15376 MEAN GCV PK PARAMETERS 

- IV GCV
- n=18

- Val-GCV
- n=25

- IV GCV
- n=18

- Val-GCV
- n=20

- Dose

**WEEK 1**

**WEEK 4**

- 5 mg/kg
- b.i.d.

- 5 mg/kg
- q.d.

- 900 mg
- b.i.d.

- 900 mg
- q.d.

- Slide # 77

## WV15376 MEAN GCV PK PARAMETERS 

- IV GCV
- n=18

- Val-GCV
- n=25

- IV GCV
- n=18

- Val-GCV
- n=20

_**12 hr**_ AUC
- (CV%)

_**24 hr**_ AUC

**28.6**
- (31.6)

**32.8**** **
- (30.7)

**30.7**
- (25)

**34.9**
- (38.1)

- Dose

**WEEK 1**

**WEEK 4**

- 5 mg/kg
- b.i.d.

- 5 mg/kg
- q.d.

- 900 mg
- b.i.d.

- 900 mg
- q.d.

- AUC: μg**•**h/mL

- Slide # 78

## WV15376 MEAN GCV PK PARAMETERS 

- IV GCV
- n=18

- Val-GCV
- n=25

- IV GCV
- n=18

- Val-GCV
- n=20

_**12 hr**_ AUC
- (CV%)

_**24 hr**_ AUC

**28.6**
- (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/kg
- b.i.d.

- 5 mg/kg
- q.d.

- 900 mg
- b.i.d.

- 900 mg
- q.d.

- AUC: μg**•**h/mL; Cmax: μg/mL

- Slide # 79

## SAFETY

- Slide # 80

## SAFETY-RELATED STUDY WITHDRAWALS RANDOMIZED PHASE

- IV GCV
- n=80

- Val-GCV
- n=80

- Total Safety-Related
- Withdrawals

- 2 (3%)

- 1 (1%)

- Adverse Event  Or
- Intercurrent Illness

- 1 (1%)  (ANC)

- 0

- Death

- 1 (1%)
- (lymphoma)

- 1 (1%)
- (PCP)

- Slide # 81

## SAFETY RANDOMIZED PHASE (10%)

- IV GCV
- n=79

- Val-GCV
- n=79

- Adverse Event

- Slide # 82

**Notes:**
Oral candidiasis: speak to baseline differences

## LABORATORY ABNORMALITIESRANDOMIZED PHASE

- IV GCV
- n=79

- Val-GCV
- n=79

-   5 (  6%)
- 10 (13%)

-   5 (  6%)
- 12 (15%)

- < 500
- 500 to < 750

**ANC (cells/μL)**

-   0
-   2 (  3%)

- 0
- 4 (  5%)

- < 6.5
- 6.5 to < 8.0

**Hemoglobin (g/dL)**

-   0
-   0

- 0
- 1 (  1%)

- < 25000
- 25000 to < 50000

**Platelets (/μL)**

- Slide # 83

## POOLED SAFETYWV15376 & WV15705

- Slide # 84

## STUDY WV15705 DESIGN (SAFETY & TOLERANCE)

- Patients with CMV Retinitis
- n=212

- Val-GCV 900 mg bid
- 21 days

- Val-GCV 900 mg qd

- CMVR Progression

- CMVR Progression

- CMVR Stable

- CMVR Stable

- Slide # 85

## VAL-GCV TREATMENT (DAYS)

- (To Clinical Cut off)

- Slide # 86

## SAFETYMAINTENANCE TREATMENT PHASE

**Adverse Event (%)**

- Val-GCV
- N= 370

- GCV 3g
- N= 536

- IV GCV
- N=412

- PLA
- N=119

**Historical**

- (To Clinical Cut-off)

- Slide # 87

## LABORATORY ABNORMALITIESMAINTENANCE TREATMENT PHASE

- < 500
- 500 to < 750

**ANC (cells/μL)**

- < 6.5
- 6.5 to < 8.0

**Hemoglobin (g/dL)**

- < 25000
- 25000 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

## SUMMARY

**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