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

2. 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. 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. 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. 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. 6 Study WV15376 Primary 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. 7 Study WV15376

8. 8

9. 9

10. 10 Study WV15376

11. 11 Study WV15376 FDA 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. 12 Study WV15376 Patient Accountability

13. 13 Study WV15376 Intent to Treat Analysis

14. 14 WV15376 Intent to Treat Analysis *Asymptotic approximation with continuity adjustment

15. 15 Study WV15376 Death = Progression

16. 16 WV15376: FDA Efficacy Analyses *Asymptotic approximation with continuity adjustment

17. 17 Study WV15376 Applicant’s Analysis

18. 18 Summary of Endpoint Evaluation *Asymptotic approximation with continuity adjustment

19. 19 WV15376 Dropouts Weeks 4 to 12

20. 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. 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. 22 Study WV15376 Treatment of Zone 1 Retinitis Previous registrational trials have excluded patients with Zone 1 Similar outcomes to overall population Week 4 OutcomeIV GCV N=22 Valgan N=19 Progressor22 Non-progressor1714 Discontinued33

23. 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. 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. 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. 26 Number of Patients Contributing to the Safety Database

27. 27 Study WV15376 Comparative induction phase

28. 28 Study WV15376 Comparative induction phase

29. 29 Study WV15376 Comparative induction phase

30. 30 Study WV15376 Deaths 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. 31 Studies WV15376 WV15705 Adverse Events GastrointestinalDiarrhea 41% Nausea/vomiting 30% Abdominal pain 15% HematologicNeutropenia/anemia 27% OtherFever 31% Candidiasis 24% Rash 22% Headache 22% Retinal Detachment 15% Abnormal LFT’s 9%

32. 32 PV16000: CMV Prevention Oral Ganciclovir vs. Valganciclovir Total number of patients enrolled: N=121 Patients completed the 100 day course: N=39 Masked data, 41 patients reported 60 SAE’s Hematologic4% Gastrointestinal3% Infectious complications6% Increased creatinine3% Graft rejection4%

33. 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. 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.