1 FDA Review of NDA 21-304 Valganciclovir for the Treatment of CMV Retinitis in AIDS Joseph Toerner, MD Medical Officer DAVDP.

1

FDA Review of NDA 21-304Valganciclovir for the

Treatment of CMV Retinitis in AIDS

Joseph Toerner, MDMedical Officer

DAVDP

2

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

3

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

4

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

5

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

6

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

7

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)

8

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%)

9

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%)

10

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%)

11

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

12

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

13

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

14

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

15

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

16

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

17

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

18

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

19

WV15376Dropouts Weeks 4 to 12

Week 4 endpointIV GCV

N=4Valgan N=14

CMV Progression 1 3

Discontinuations Adverse event No photos/No CMV

10

22

Non-Progressors 2 7

20

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

21

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

22

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

23

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

24

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

25

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

26

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

27

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%

28

Study WV15376 Comparative induction phase

IV GCV ValganHematologic AdverseEvents- all grades % %

Neutropenia 13% 11%

Anemia 9% 6%

Thrombocytopenia 0 1%

29

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%

30

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

31

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%

32

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%

33

Safety Conclusions

Patients completing at least 6 months of therapy: N=293

Hematologic and Gastrointestinal Adverse Events predominate

Similar adverse event profile to ganciclovir

34

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.