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FDA Review of NDA 21-304Valganciclovir for the
Treatment of CMV Retinitis in AIDS
Joseph Toerner, MDMedical Officer
DAVDP
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Valganciclovir NDA
EFFICACY• Induction therapy
– W V15376
• Maintenance therapy– Pharmacokinetic
data
SAFETY• Study W V15376• Study W V15705
– Single-arm safety study
• Study PV16000– Prevention of CMV in
SOT
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Valganciclovir Development for CMV Retinitis
• An adequately powered study for equivalence– 200 patients per arm
• A feasible study in the current epidemiological climate– 75 patients per arm, under-powered to demonstrate equiv.
• Ongoing phase 2 study (W V 15376) was expanded into a phase 3 trial
• Academic consultants and FDA concur with the 4 week endpoint
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Study WV15376 (Induction)
Newly diagnosed CMV retinitis
Open-label, 21 day induction therapy– IV ganciclovir 5 mg/kg BID– Oral valganciclovir 900 mg BID
Followed by maintenance therapy– IV ganciclovir 5 mg/kg daily– Valganciclovir 900 mg daily
All received valganciclovir after week 4
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Study WV15376 Primary Endpoint
• Photographic assessment of CMV retinitis at week 4 compared to baseline
• Standardized retinal photography
• Used in previous registrational trials
• Performed by the University of Wisconsin Fundus Photograph Reading Center
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Study WV15376Primary Endpoint Analysis
• Potential limitations: small sample size
• Agreement was not reached on -25% as the lower limit of the 95% CI
• The analysis of the primary endpoint was not pre-specified
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Study WV15376DemographicCharacteristics
IV GCVN=80
ValganN=80
Race Black White Hispanic Other
9 (11%)42 (53%)24 (30%)5 (6%)
9 (11%)43 (54%)25 (31%)3 (4%)
Male 73 (91%) 72 (90%)
Age, mean(median)
38 (37) 40 (39)
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Study WV 15376
Baseline HIVDiseaseCharacteristics
IV GCVN=80
ValganN=80
HIV RNA, median 4.9 log10 4.8 log10
CD4 cell countmedian (cells/mm3)
26 20
History of PI use 64/80 (80%) 64/80 (80%)
Ongoing PI use 47/80 (59%) 53/80 (66%)
Other OI’s 57/80 (71%) 63/80 (79%)
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Study WV15376IV GCV ValganAIDS-defining Conditions
at Baseline N=80 (%) N=80 (%)
MAC 12 (15%) 20 (25%)
Esophageal Candidiasis 8 (10%) 15 (19%)
PCP 35 (43%) 32 (40%)
Kaposi’s Sarcoma 12 (15%) 13 (16%)
Cryptococcal Meningitis 5 (6%) 1 (1%)
CNS Toxoplasmosis 1 (1%) 3 (4%)
Cryptosporidium 4 (5%) 2 (3%)
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Study WV15376
IV GCV ValganCharacteristics of CMVretinitis at baseline N=80 (%) N=80 (%)
Zone 1 retinitis 22 (28%) 19 (24%)
Bilateral retinitis 20 (25%) 20 (25%)
> 50% border activity 65 (81%) 59 (74%)
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Study WV15376FDA Analysis of Efficacy
• FDA confirmation of the retinal photography– masked review: complete agreement with
exception of one patient
• Applicant’s primary analysis is based on evaluable subjects, which excluded deaths and lost to follow-ups.
• FDA conducted sensitivity analyses– per protocol to intent to treat
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Study WV15376Patient Accountability
IV GCV ValganWeek 4 Primary Endpoint
N=80 N=80
Progressor 7
26
7
Non-progressor 63
54
64
59Death 2
20
1
16AE before week 4 1 2
Failed to return 1 1
No photos or CMVretinitis at baseline
6 5
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Study WV15376Intent to Treat Analysis
IV GCV ValganWeek 4 Primary Endpoint
N=80 N=80
Progressor 7
26
7
Non-progressor 63
54
64
59Death 2
20
1
16AE before week 4 1 2
Failed to return 1 1
No photos or CMVretinitis at baseline
6 5
FDA Intent to Treat N=74 N=75
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WV15376Intent to Treat Analysis
Analysis IV GCV Valgan Diff 95% CI*
ITT, missing =progression
11/74
14.9%
11/75
14.7%0.2% (-13%, 13%)
*Asymptotic approximation with continuity adjustment
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Study WV15376Death = Progression
IV GCV ValganWeek 4 Primary Endpoint
N=80 N=80
Progressor 7
26
7
Non-progressor 63
54
64
59Death 2
20
1
16AE before week 4 1 2
Failed to return 1 1
No photos or CMVretinitis at baseline
6 5
Death = Progression N=72 N=72
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WV15376: FDA Efficacy Analyses
Analysis IV GCV Valgan Diff 95% CI*
ITT,missing=progression
11/74
14.9%
11/75
14.7%0.2% (-13%, 13%)
Deaths=progression
9/72=12% 8/72=11% 1% (-11%, 13%)
*Asymptotic approximation with continuity adjustment
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Study WV15376Applicant’s Analysis
IV GCV ValganWeek 4 Primary Endpoint
N=80 N=80
Progressor 7
26
7
Non-progressor 63
54
64
59Death 2
20
1
16AE before week 4 1 2
Failed to return 1 1
No photos or CMVretinitis at baseline
6 5
Applicant’s analysis N=70 N=71
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Summary of Endpoint EvaluationAnalysis IV GCV Valgan Diff 95% CI*
ITT, Missing =progression
11/74
14.9%
11/75
14.7%0.2% (-13%, 13%)
Deaths =progression
9/72=12% 8/72=11% 1% (-11%, 13%)
Applicant’sAnalysis
7/70=10% 7/71=9.9% 0.1% (-11%, 11%)
*Asymptotic approximation with continuity adjustment
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WV15376Dropouts Weeks 4 to 12
Week 4 endpointIV GCV
N=4Valgan N=14
CMV Progression 1 3
Discontinuations Adverse event No photos/No CMV
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22
Non-Progressors 2 7
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Are Disproportionate Dropouts Failures of Induction?
• Disproportionate dropouts persisted after accounting for week 4 progressors or dropouts
• Evaluation of CMV progression during weeks 4 and 12 by retinal photography
• Evaluation of reasons for discontinuation• Ophthalmologist clinical diagnosis examined
– On-study treatment decisions, photographic scoring not provided in real-time
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Are Disproportionate Dropouts Failures of Induction?
• Only 1 had photographic evidence of CMV progression between weeks 4 and 12
• Reasons for discontinuation: 4 deaths, 3 voluntary withdrawals, 2 requested GCV implant
• Treating ophthalmologists more likely to classify a patients in Valgan as CMV progressors regardless of the photographic determination
• Disproportionate dropouts driven by open-label study design
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Study WV15376Treatment of Zone 1 Retinitis
Previous registrational trials have excluded patients with Zone 1
Similar outcomes to overall population
Week 4 Outcome IV GCV
N=22
Valgan
N=19
Progressor 2 2
Non-progressor 17 14
Discontinued 3 3
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Study WV15376 Impact of Protease Inhibitors
• Few changed HAART during induction – Valganciclovir: 4 patients IV ganciclovir: 5 patients
• Majority changed HAART at week 4 visit
• Time to CMV retinitis progression much longer in comparison to historical studies
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Summary of FDA Analysis of Efficacy
• Proportion with CMV progression is similar
• Maximum lower bound of 95% CI is approximately -13%
• Results of primary endpoint confirmed by FDA masked review of the retinal photographs
• Visual acuity scores similar
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Valganciclovir Safety
WV15376: N = 158
Open label valganciclovir after week 4
WV15705: N = 212
Single-arm, open-label valganciclovir for maintenance therapy
PV16000: N = 121
Prevention of CMV disease in SOT Oral GCV vs. Valgan, still masked
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Number of Patients Contributing to the Safety
Database
Duration ofvalganciclovirtherapy
WV15376
N
WV15705
N
Total
N
6 months 115 178 293
12 months 86 152 238
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Study WV15376 Comparative induction phase
IV GCV ValganGastrointestinalAdverse Events-all
grades%
%
Diarrhea 14% 20%
Nausea 18% 10%
Vomiting 11% 10%
Nausea/vomiting 6% 5%
Abdominal pain 8% 4%
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Study WV15376 Comparative induction phase
IV GCV ValganHematologic AdverseEvents- all grades % %
Neutropenia 13% 11%
Anemia 9% 6%
Thrombocytopenia 0 1%
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Study WV15376 Comparative induction phase
IV GCV ValganOther Adverse Events in>5% of study participants % %
Fever 11% 11%
Oral Candidiasis 6% 10%
Cough 5% 10%
Headache 5% 10%
Rash 8% 5%
Retinal Detachment 6% 1%
Catheter-associatedinfection
13% 3%
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Study WV15376Deaths
• 4 weeks:– 3 deaths, 2 in IV GCV, 1 in Valgan
• 12 weeks:– 10 deaths, 5 in each arm
• primarily due to underlying AIDS
• One year:– 28 deaths, 18 in IV GCV, 10 in Valgan
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Studies WV15376 WV15705Adverse Events
Gastrointestinal Diarrhea 41%
Nausea/vomiting 30%
Abdominal pain 15%
Hematologic Neutropenia/anemia 27%
Other Fever 31%
Candidiasis 24%
Rash 22%
Headache 22%
Retinal Detachment 15%
Abnormal LFT’s 9%
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PV16000: CMV Prevention Oral Ganciclovir vs.
ValganciclovirTotal number of patients enrolled: N=121
Patients completed the 100 day course: N=39
Masked data, 41 patients reported 60 SAE’s
Hematologic 4%
Gastrointestinal 3%
Infectious complications 6%
Increased creatinine 3%
Graft rejection 4%
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Safety Conclusions
Patients completing at least 6 months of therapy: N=293
Hematologic and Gastrointestinal Adverse Events predominate
Similar adverse event profile to ganciclovir
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Valganciclovir Review Team Acknowledgements
Medical Officer Team Leader
Therese Cvetkovich, M.D.
Biometrics
Andrei Breazna, Ph.D.
Greg Soon, Ph.D.
Medical Officer, DAAODP
William Boyd, M.D.
Biopharmaceutics
Robert Kumi, Ph.D.
Kellie Reynolds, Pharm.D.