development program & study results
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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DEVELOPMENT PROGRAM & STUDY RESULTS
Slide # 31
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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
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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
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Slide # 34
MECHANISM OF ACTION
ExtracellularIntracellular
GCV GCV-MP GCV-DP GCV-TP
CellularEnzymes
ViralProtein Kinase
(UL97)
Inhibits Viral DNA Polymerase (UL54)
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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
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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
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COMPARATIVE GANCICLOVIR PK PROFILES
0.01
0.1
1
10
0 5 10 15 20 25 30
Time (h)
Gan
cicl
ovir
Con
cent
ratio
n(ug
/mL)
GCV from VGCV(900mg) Oral GCV(1g t.i.d)i.v GCV(5mg/kg) Val-GCV from VGCV (900mg)
GANS2230
Slide # 37
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COMPARATIVE GANCICLOVIR PK PROFILES
0.01
0.1
1
10
0 5 10 15 20 25 30
Time (h)
Gan
cicl
ovir
Con
cent
ratio
n(ug
/mL)
GCV from VGCV(900mg) Oral GCV(1g t.i.d)i.v GCV(5mg/kg) Val-GCV from VGCV (900mg)
GANS2230
Slide # 38
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COMPARATIVE GANCICLOVIR PK PROFILES
0.01
0.1
1
10
0 5 10 15 20 25 30
Time (h)
Gan
cicl
ovir
Con
cent
ratio
n(ug
/mL)
GCV from VGCV(900mg) Oral GCV(1g t.i.d)i.v GCV(5mg/kg) Val-GCV from VGCV (900mg)
GANS2230 (IV & Oral GCV)WP15509 (GCV from Val-GCV)
Slide # 39
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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
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COMPARATIVE PK: MEAN (%CV)
Dose AUC0-24(µg•h/mL)
Cmax(µg/mL)
Cmin(µg/mL)
Bioavail.
IV GCVGANS2230
n=165mg/kg
q.d. 26.8 (23) 9.03 (16) 0.027*(181)(n=15)
NA
Oral GCVGANS2230
n=241g
t.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
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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
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BASIS OF DOSE SELECTION
0
10
20
30
40
50
60
70
80
90
0 1000 2000 3000
Valganciclovir Dose (mg)
Gan
cicl
ovir
AU
C0-
24 (m
g.h/
mL)
900 mg Val-GCV achieves target AUC ( 26 mg•h/mL)
maintenance
induction
Slide # 43
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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
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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
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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
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From Kovacs JA and Masur H. N Engl J Med. 2000342: 1415-1429
IMPACT OF HAART
Slide # 47
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DEVELOPMENT PROGRAMOverallN = 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
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BrazilAustralia
Mexico
Canada
FranceItaly
United States Germany
United Kingdom
Spain
PARTICIPATING COUNTRIES372 patients in 26 months (50 sites)
Slide # 49
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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
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EFFICACY
Slide # 51
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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
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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
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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
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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
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ASSESSING NON-INFERIORITY
0Val-GCV No Worse than IV GCV
Treatment difference (Pg-Pv) - 0.25
d
Slide # 56
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ASSESSING NON-INFERIORITY (cont’d)
0
Treatment difference (Pg-Pv) - 0.25
d
(Hypothetical)
Slide # 57
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0Val-GCV No Worse than IV GCV
Treatment difference (Pg-Pv) - 0.25
d
ASSESSING NON-INFERIORITY (cont’d)
(Hypothetical)
Slide # 58
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ASSESSING NON-INFERIORITY (cont’d)
0Val-GCV No Worse than IV GCV
Treatment difference (Pg-Pv) - 0.25
d (WV15376 Results)
(Hypothetical)
Slide # 59
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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%)
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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)
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BASELINE - HIV THERAPY
PI Use - ongoing/priorPI-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%)
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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
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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%)
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PRIMARY ENDPOINT(COMPARABLE EFFICACY AT WEEK 4)
IV GCVn=73
Val-GCVn=73
Photo Progression 7 7No Photo Progression 63 64Unevaluable 3 2
Proportion progressed 0.100 (10%) 0.099 (9.9%)
Difference 0.001 (0.1%)95% Confidence Interval (-0.097, 0.100)
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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
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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)
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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
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CMV CULTURES
% of patients withIV GCV Val-GCVCMV-positive culture
Baseline
Week 4
65% (46/71)
6% ( 4/64)
46% (33/71)
7% ( 4/58)
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CMV PCR
% of patients withCMV viremia (plasma)
Baseline
Week 4
51% (39/76)
3% ( 2/70)
40% (31/77)
4% ( 3/71)
IV GCV Val-GCV
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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
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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
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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
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WV15376 MEAN STEADY-STATE CONC. OF GCV AFTER IV GCV & VAL-GCV
0.01
0.1
1
10
0 5 10 15 20 25Time (h)
Con
cent
ratio
n ug
/mL
i.v GCV wk1 GCV from Val-GCV wk1
Week 1
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WV15376 MEAN STEADY-STATE CONC. OF GCV AFTER IV GCV & VAL-GCV
0.01
0.1
1
10
0 5 10 15 20 25Time (h)
Con
cent
ratio
n ug
/mL
i.v GCV wk4 GCV from Val-GCV wk4
Week 4
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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 25Time (h)
Con
cent
ratio
n ug
/mL
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
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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.
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WV15376 MEAN GCV PK PARAMETERS
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
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WV15376 MEAN GCV PK PARAMETERS
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
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SAFETY
Slide # 80
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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)
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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%)VomitingCatheter-Related 9 (11%) 2 ( 3%)
Adverse Event
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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)
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POOLED SAFETYWV15376 & WV15705
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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
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VAL-GCV TREATMENT (DAYS)(To Clinical Cut off)
WV15376 WV15705IV GCV
n=79Val-GCV
n=79Val-GCV
n=212Mean 322 281 333
Median 287 248 372
Range 0-875 2-847 12-513
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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
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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)
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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%)
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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
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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)
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CONCLUSION
Valganciclovir, an oral prodrug of ganciclovir with high bioavailability, provides an effective and convenient treatment for CMV retinitis
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