1. 1 Antiviral Drug Products Advisory Committee Meeting NDA 21-266voriconazole tablets NDA 21-267voriconazole for injection Rosemary Tiernan, MD, MPH

2. 2 Division of Special Pathogen and Immunologic Drug Products Voriconazole Review Team Jouhayna Saliba, RPh Marc Cavaillé-Coll, MD, PhD Gene W. Holbert, PhD Norman R. Schmuff, PhD Owen G. McMaster, PhD Kenneth L. Hastings, PhD Linda L. Gosey, MS Shukal Bala, PhD Philip M.Colangelo, PharmD, PhD Funmi O. Ajayi, PhD Joette M. Meyer,PharmD Wiley A. Chambers, MD Cheryl A. Dixon, PhD Karen M. Higgins, ScD M. Regina Alivisatos, MD Edward M. Cox, MD, MPH Rosemary Johann-Liang, MD Rigoberto A. Roca, MD John H. Powers III, MD Rosemary Tiernan, MD, MPH

3. 3 Indications Requested in the NDA Treatment of invasive aspergillosis Empiric antifungal therapy of febrile neutropenic patients Treatment of: -candida esophagitis -serious candida infections -serious fungal infections due to Fusarium and Scedosporium spp. -serious fungal infections in patients refractory or intolerant to other therapy

4. 4 FDA Presentation Treatment of Invasive Aspergillosis Empiric Antifungal Therapy of Febrile Neutropenic Patients Clinical Safety Questions to the Advisory Committee

5. 5 Treatment of Invasive Aspergillosis Study 307/602 Study 304 and Historical Control Study 1003

6. 6 Treatment of Invasive Aspergillosis Study 307/602 –Randomized, controlled, open-label, initial therapy –Blinded Data Review Committee –voriconazole vs. amphotericin B followed by other licensed antifungal therapy (OLAT) Study 304 –Uncontrolled study of primary and salvage cases –Expert Panel –Retrospectively designed historical control

7. 7 Study 307/602 MITT –voriconazole (N = 144) –amphotericin B (N = 133) Patient Characteristics –White male, hematologic malignancies, pulmonary site Switch to OLAT –voriconazole 36.1% –amphotericin B80.5%

8. 8 Study 307/602 Primary Efficacy Endpoint Satisfactory Response at Week 12 (MITT) –voriconazole76/14452.8% –ampho B42/13331.6% 95% CI stratified by protocol (9.6, 33.6)

9. 9 Study 307/602 Additional Efficacy Analyses Not allowing DRC to upgrade investigator assessment –vori 46.5% vs. ampho B 29.3% Modified Week 12 –vori 45.1% vs. ampho B 31.6% Week 16 follow-up –vori 45.8% vs ampho B 33.1%

10. 10 Study 307/602 Survival Probability of Survival at Day 84 vori 0.708 ampho B 0.579

11. 11 Study 304 Expert Evaluable Population –Overall N = 112 Primary therapy N = 58 Salvage therapy N = 54 Patient Characteristics –White male, hematologic malignancies, pulmonary site, European population

12. 12 Study 304 Expert Global Response at EOT (expert evaluable population) –Overall55/11249.1% Primary35/5860.3% Salvage20/5437.0%

13. 13 Historical Control (HC) Study 1003 Substantial effort to provide the most comparable population to primary therapy patients in Study 304 –primary therapy was <5 days prior antifungal therapy Matched on certainty of diagnosis, underlying disease, and site of infection

14. 14 Study 304/ Historical Control Study 1003 Global Response –Study 304 vori26/50 52.0% –Historical Control23/9225.0% Probability of Survival at Day 90 –Study 304 vori0.554 –Historical Control0.417

15. 15 Historical Control Issues Patient populations –Study 304 only in Europe –Historical Control both in Europe and US –Global Response –US HC11/5121.6% –EU HC12/4129.3% –Study 304 vori26/5052.0% –Probability of Survival at Day 90 –US HC0.290 –EU HC0.573 –Study 304 vori0.554

16. 16 Historical Control Issues (cont.) Duration of treatment –longer for voriconazole treated patients Difference in inclusion/exclusion criteria –which could possibly allow for sicker patients in the HC

17. 17 Aspergillosis Summary HC good effort but still concerns about comparability of the study populations Study 304 results are used to support the randomized controlled study Study 307/602 showed –Non-inferior Global Response Statistically superior –Survival Benefit

18. 18 Clinical Safety Rosemary Tiernan, MD, MPH

19. 19 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

20. 20 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

21. 21 Ocular Safety Pre-clinical studies Incidence in clinical studies is 1 out of every 3 subjects Symptoms Decreased vision, photophobia, altered color perception and ocular discomfort Unknown Mechanism No human histopathology Ocular biomicroscopy has not detected ocular lesions

22. 22 Ocular safety Results from study 150-1004 –Effects noted in ERG Farnsworth-Munsell 100 hue test (color vision) Humphrey Perimetry (visual field) –Drug effect on both rod and cone function –Decreased vision on day 1 and continued through 28 days of therapy –Testing 2 weeks after the end of treatment demonstrated return to normal function

23. 23 Ocular Safety Additional issues regarding use of this drug -re-challenge or re-treatments -ocular development in pediatric patients -patients with underlying eye disease -treatment beyond 28 days

24. 24 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

25. 25 Cardiac Safety In vitro data In vivo data Clinical data –One sudden death

26. 26 Cardiac Safety Clinical data –Adverse Events Cardiac arrhthymias, CHF, cardiac arrests –Discontinuations

27. 27 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

28. 28 Hepatic Safety Summary Phase I/II Studies –Positive dose (exposure) response with ALT and AST Phase III Comparative Studies –Hepatic adverse events and ALT & AST abnormalities were more frequent with voriconazole than fluconazole –Frequency of hepatic adverse effects similar between voriconazole and amphotericin B formulations studied –Serious hepatic adverse events reported more frequently in voriconazole treated patients.

29. 29 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

30. 30 Rash Difficulties in assessment of rash include: –Concomitant medications that can also cause rash –Concomitant medications can affect the type or severity of skin exanthem observed –Underlying conditions such as GVHD

31. 31 Rash Observed in 18.6% of patients on voriconazole in therapeutic studies program Most rashes mild to moderate No major differences in discontinuations for rash 4 non-fatal cases of Stevens-Johnson

32. 32 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

33. 33 Drug Interactions with Voriconazole In Vitro Metabolism Voriconazole is a substrate and inhibitor of CYP2C19, CYP2C9, CYP3A4 Substrate affinity and inhibition potency of voriconazole is greater for CYP2C19 and CYP2C9 compared to CYP3A4 – CYP3A4 inhibition potency of voriconazole weaker than ketoconazole and itraconazole Potency of voriconazole to inhibit CYP3A4 metabolism varies among several CYP3A4 substrates (and vice-versa) –HIV-PI, NNRTI, and Immunosuppressant Drugs

34. 34 Drug Interactions with Voriconazole In Vivo Metabolism Representative substrates / inhibitors / inducers of the three CYP enzymes were studied, since it is not possible to evaluate every potential drug interaction –Example: HIV-PI and NNRTI drugs not studied in vivo CYP3A4 inhibitors and/or inducers Exception: Indinavir no significant interaction The potential for drug interactions with voriconazole presents a therapeutic challenge for the prescriber

35. 35 Clinical Safety Rosemary Tiernan, MD, MPH

36. 36 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

37. 37 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

38. 38 Ocular Safety Pre-clinical studies Incidence in clinical studies is 1 out of every 3 subjects Symptoms Decreased vision, photophobia, altered color perception and ocular discomfort Unknown Mechanism No human histopathology Ocular biomicroscopy has not detected ocular lesions

39. 39 Ocular safety Results from study 150-1004 –Effects noted in ERG Farnsworth-Munsell 100 hue test (color vision) Humphrey Perimetry (visual field) –Drug effect on both rod and cone function –Decreased vision on day 1 and continued through 28 days of therapy –Testing 2 weeks after the end of treatment demonstrated return to normal function

40. 40 Ocular Safety Additional issues regarding use of this drug -re-challenge or re-treatments -ocular development in pediatric patients -patients with underlying eye disease -treatment beyond 28 days

41. 41 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

42. 42 Cardiac Safety In vitro data In vivo data Clinical data –One sudden death

43. 43 Cardiac Safety Clinical data –Adverse Events Cardiac arrhthymias, CHF, cardiac arrests –Discontinuations

44. 44 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

45. 45 Hepatic Safety Summary Phase I/II Studies –Positive dose (exposure) response with ALT and AST Phase III Comparative Studies –Hepatic adverse events and ALT & AST abnormalities were more frequent with voriconazole than fluconazole –Frequency of hepatic adverse effects similar between voriconazole and amphotericin B formulations studied –Serious hepatic adverse events reported more frequently in voriconazole treated patients.

46. 46 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

47. 47 Rash Difficulties in assessment of rash include: –Concomitant medications that can also cause rash –Concomitant medications can affect the type or severity of skin exanthem observed –Underlying conditions such as GVHD

48. 48 Rash Observed in 18.6% of patients on voriconazole in therapeutic studies program Most rashes mild to moderate No major differences in discontinuations for rash 4 non-fatal cases of Stevens-Johnson

49. 49 Clinical Safety Focus on 5 specific areas: –Ocular safety –Cardiac safety –Hepatic safety –Rash –Drug interactions

50. 50 Drug Interactions with Voriconazole In Vitro Metabolism Voriconazole is a substrate and inhibitor of CYP2C19, CYP2C9, CYP3A4 Substrate affinity and inhibition potency of voriconazole is greater for CYP2C19 and CYP2C9 compared to CYP3A4 – CYP3A4 inhibition potency of voriconazole weaker than ketoconazole and itraconazole Potency of voriconazole to inhibit CYP3A4 metabolism varies among several CYP3A4 substrates (and vice-versa) –HIV-PI, NNRTI, and Immunosuppressant Drugs

51. 51 Drug Interactions with Voriconazole In Vivo Metabolism Representative substrates / inhibitors / inducers of the three CYP enzymes were studied, since it is not possible to evaluate every potential drug interaction –Example: HIV-PI and NNRTI drugs not studied in vivo CYP3A4 inhibitors and/or inducers Exception: Indinavir no significant interaction The potential for drug interactions with voriconazole presents a therapeutic challenge for the prescriber