1. NDA 21-567 Atazanavir Kendall A. Marcus, M.D. Medical Reviewer Division of Antiviral Drug Products

2. Presentation Outline NDA Submission Overview Efficacy Summary - Tom Hammerstrom, Ph.D. Clinical Virology - Lisa Naeger, Ph.D. Safety Issues –Hyperbilirubinemia –Lipid Profiles –Effects on the QT and PR Interval Conclusions

3. NDA Overview Submission Date: December 20, 2002 Proposed Dosage: Atazanavir 400 mg once daily Proposed Indication: Treatment of HIV infection

4. Phase 2 Dose-Finding Studies Treatment Naïve Patients AI424-007 N=420 ATV: 200 mg, 400 mg, and 500 mg NFV 750 mg tid Each given with d4T/ddI. AI424-008 N=467 ATV: 400 mg and 600 mg NFV 1250 mg bid Each given with d4T/3TC.

5. Phase 3 Studies AI424-034 Treatment-naïve subjects (n=810) ATV 400 mg daily EFV 600 mg daily Each given with AZT/3TC (Combivir  ) AI424-043 Subjects failing PI based regimens (n=300) ATV 400 mg daily LPV/RTV bid Optimized background of 2 NRTIs based on phenotypic testing.

6. Phase 3 Studies AI424-045* Patients failing at least 2 regimens containing drugs from all three classes (n=358) ATV 300 mg/RTV 100 mg once daily ATV 400 mg/SQV 1200 mg once daily LPV/RTV bid Background therapy of tenofovir and one NRTI. *16 week data on roughly 33 patients/arm submitted with initial NDA submission.

7. Other Supportive Studies AI424-041 and AI424-044 –Rollover studies for Phase 2 PACTG 1020-A –PK and safety study in infants, children, and adolescents AI424-900 - Expanded access protocol AI424-009 (N=85) –Small Phase 2 study of treatment experienced patients comparing ATV/SQV to RTV/SQV

8. Atazanavir Resistance Lisa K. Naeger, Ph.D. Antiviral Advisory Committee Meeting May 13, 2003

9. In vitro Selection Virus strain: mutations RF: V32I, L33F, M46I, A71V, I84V, N88S LAI: L10Y/F, I50L, L63P, A71V, N88S NL4-3: V32I, M46I, I84V, L89M 3 Different Strains of HIV-1 were serially selected with ATV for 4-5 months (200 - 500 nM) Fold ATV Resistance 183 93 96

10. I50L Mutation ATV resistance corresponded to the presence of I50L and A71V in the protease of recombinant viruses from 8 clinical isolates. 2- to 17-fold decreases in ATV susceptibility were observed in viruses containing the I50L and A71V mutation

11. I50L Mutation Viruses containing the I50L mutation either alone or in combination with A71V remained susceptible to APV, IDV, NFV, and RTV. Insertion of the I50L substitution into HIV-1 resulted in replication impaired viruses. The addition of the A71V change with I50L restores some viability.

12. ATV Clinical Resistance Analyses Mutations Associated with ATV-Resistance –Phenotypic and genotypic analyses of evaluable clinical isolates from patients on ATV-containing regimens who experienced virologic failure or discontinued before suppression from studies 007, 008, 034, 009 and 043 Baseline Phenotype and Genotype Analysis Cross-Resistance

13. Evaluable Clinical Isolates from Patients on ATV- Containing Regimens who Experienced Virologic Failure or Discontinued before Suppression

14. Mutations Associated with ATV- Resistance in Naïve-trials 14 ATV-resistant clinical isolates –11 (79%) developed the I50L mutation Median 9-fold change in ATV resistance 7 of these 11 also developed the A71V mutation Development ranged from 2 to 80 weeks (mean = 40 weeks)

15. Phenotype of ATV-Resistant Isolates that Developed the I50L Mutation In Naïve Trials * Average fold-change from reference strain

16. Mutations Associated with ATV- Resistance in Experienced trials 32 ATV-resistant clinical isolates –ATV Treatment (21) 5 isolates developed the A71V or T mutation 2 isolates developed the I84V mutation (5-fold change from BL) 2 developed the N88S or D mutation (4-fold change from BL)

17. Mutations Associated with ATV- Resistance in Experienced trials –ATV/SQV Treatment (11) 5 isolates developed the I84V mutation (14-fold change from BL) 4 isolates developed the A71V or T mutation 2 isolates developed the L90M mutation 2 isolates developed the M46I mutation

18. Cross-Resistance of the Virologic Failure Clinical Isolates that were ATV-Resistant from Treatment- Experienced Patients in Trials 009 and 043 (N = 32)

19. Baseline Analysis

20. 56% 74% 20%

21. 24% of the Isolates from 009 and 043 showed ATV- Resistance at Baseline

22. % Resistance 100% 47% 43% 62% 59%

23. Response Based on Baseline Genotype

25. Cross-Resistance

26. Cross-resistance of HIV-1 Clinical Isolates by Phenotype

27. Cross-Resistance of HIV-1 Clinical Isolates by Genotype

28. ATV Resistance Against PI-Resistant Clinical Isolates (n = 551)

29. ATV Susceptibility Against PI- Resistant Clinical Isolates (n = 551)

30. ATV Resistance Summary I50L mutation is specific for ATV resistance and is the predominant mutation developing in antiretroviral therapy-naïve patients Viruses with the I50L mutation remain susceptible to other PIs Mutations L90M, I84V, N88S/D and A71V/T appear to confer ATV resistance and reduce the clinical response to ATV There is a clear trend toward ATV resistance as isolates become resistant to three or more PIs

31. Atazanavir Efficacy Results Thomas Hammerstrom, PhD Division of Antiviral Drug Products

32. Phase II and III Clinical Trials Pivotal Phase III Trial - 34 –Endpoint = Percent Sustained < 400 copies/mL to Week 48, Time Averaged Difference from Baseline (TAD) –ART Naïve Population –Control is Efavirenz Phase II Trials - 7 and 8 –Endpoint = Percent < 400, TAD –ART Naïve Population –Control is Nelfinavir

33. Phase II and III Clinical Trials Pivotal Phase III Trial - 43 –Endpoint = TAD –ART Experienced Population –Control is Kaletra

34. Results in Trials with ART Naïve Subjects

35. Percent Sustained <400 copies/mL to Week 48 TrialArm %<40095% Interval ATV - Con 34EFV251 / 405 62% ATV271 / 40567%-1.5%, 11.6% 7NFV62 / 10360% ATV62 / 10360%-13.8%, 13.0% 8NFV54 / 9163% ATV121 / 18169%-5.0%, 19.4%

36. Results in Trial with ART Experienced Subjects

37. Trial 43, ATV vs Kaletra for 24 Weeks EndpointArmEstimate95% Interval %<400KAL 98 / 150 = 65% ATV70/150 = 47%-30%, -7.9% TADKAL-1.65 ATV-1.39.078,.44

38. Is ATV Better than Placebo ART Experienced Subjects? Two Meta-analysis Methods: 1. Calculate Difference of ATV and Placebo from Trial 43 and Kaletra Trials 2. Compare Confidence Intervals for ATV + 2 NRTI’s in Trial 43 with Confidence Intervals for 2 NRTI’s alone from other NDA’s

39. ATV vs Placebo % <400 SourceArmEstimateDIFFSEE Trial 43ATV70/150 = 47% KAL 98 / 150 = 65%-19%5.73% Trial 863KAL 259 / 326 = 79% NFV233 / 327 = 71%8%3.36% Trial 511NFV66/ 99 = 67% PLA7/ 101 = 7%60%5.37% ImputedATV PLAC49%8.54%

40. ATV vs Placebo % <400 SourceArmEstimateDIFFSEE Trial 43ATV70/150 = 47% KAL 98 / 150 = 65%-19%5.73% Trial 888KAL 84 / 148 = 57% S. PI46 / 140 = 33%24%5.69% ImputedATV Selected PI5%8.07%

41. ATV vs Control % <400 SourceControlDifference95% Interval Trial 43KAL -19%-30%, -7.9% ImputedSel PI 5%-10.8%, 21% DiscountedSel PI 4.5%-12.3%, 23% ImputedPIacebo49%32%, 66%

43. ATV vs Placebo TAD, Week 24 SourceArmEstimateDIFFSEE Trial 43ATV-1.39 KAL -1.65.26.093 Trial 863KAL -1.798 NFV-1.801.003.057 Trial 511NFV-1.77 PLA-1.40-.37.083 ImputedATV PLAC-.107.137

44. ATV vs Placebo TAD, Week 24 SourceArmEstimateDIFFSEE Trial 43ATV-1.39 KAL -1.65.26.093 Trial 888KAL -.972 S. PI-.867-.104.078 ImputedATV Selected PI.156.121

45. ATV vs Control TAD, Week 24 SourceControlDifference95% Interval Trial 43KAL.26.078,.44 ImputedSel PI.156-.081,.393 ImputedPlacebo-.107-.376,.162

47. Efficacy Conclusions 1. Equal or Better than NFV or EFV on %<400 at week 48 in 3 Trials with Naïve Subjects 2. 95% Lower Limits on %<400 no more than 5% worse than NFV or EFV in 2 out of 3 Trials

48. Efficacy Conclusions 3. Equal or Better than NFV or EFV on TAD at week 48 in 2 out of 3 Trials with Naïve Subjects 4. 95% Upper Limits on TAD no more than.28 log copies worse than NFV or EFV in all 3 Trials

49. Efficacy Conclusions 5. Statistically Significantly Worse than Kaletra on both %<400 and TAD at week 24 in 1 Trial with Experienced Subjects 6. Indirect Imputations: Support for Efficacy on Primary Endpoint, Ambiguity on Secondary Endpoint

50. Efficacy Conclusions 6. Indirectly shown at least 33% better than placebo, no more than 10% worse than selected PI on %<400 7. 95% Confidence Limits on %<400 higher than limits seen on all 2 drug combinations in previous NDA’s

51. Efficacy Conclusions 8. Indirectly shown no more than.16 log copies worse than Placebo on TAD at week 24 9. 95% Confidence Limits on TAD comparable to limits seen on several 2 drug combinations in previous NDA’s

52. Safety Issues Hyperbilirubinemia

53. Hyperbilirubinemia Toxicity Grading Scale Total bilirubin toxicity grading scale Grade 1 1.1 – 1.5 x ULN Grade 2 1.6 – 2.5 x ULN Grade 3 2.6 – 5.0 x ULN Grade 4 > 5.0 x ULN Upper limit of normal for total bilirubin  1.0 - 1.5 mg/dL Upper limit of normal for direct bilirubin  0.2 - 0.5 mg/dL

54. Studies 007 & 008 Hyperbilirubinemia Dose Dependence

55. Percentage of Subjects with Hyperbilirubinemia Atazanavir - 400mg

56. Incidence of Jaundice and Scleral Icterus Phase 2 and 3 Clinical Studies Atazanavir - 400 mg Three patients in 034 (1%) and 2 patients in 043 (1%) discontinued for jaundice or scleral icterus without grade 4 hyperbilirubinemia.

57. Grade 4 Hyperbilirubinemia and Dose Reduction Atazanavir - 400 mg

58. Study 034 Mean Total and Direct Bilirubin Atazanavir - 400 mg

59. Total Bilirubin > 10 mg/dL Occurred in 10 patients across clinical trials 4/10: transient, predominantly unconjugated (DB  0.3 mg/dl) 1/10: diagnosed w/SHL, DB - 0.6 mg/dl 5/10: also with other LFT abnormalities –4 with viral hepatitis (A, B, C) –One had a total bilirubin > 10 mg/dl prior to randomization which resolved prior to treatment and then worsened temporarily on study.

60. LFT Abnormalities - ATV versus NFV Background: ddI/d4T

61. LFT Abnormalities: ATV versus EFV Background: AZT/3TC

62. Discontinuations Due to Hepatotoxicity/Abnormal LFTs All Studies Atazanavir - 15/1596 (1%) –Ten had chronic hepatitis B or C –One had acute hepatitis B –One had history of hepatic steatosis –Three subjects with no apparent risk factors Comparators - 8/892 (1%) –Five had chronic hepatitis B or C –One had acute hepatitis B –One was hep B core Ab positive but surface Ab and antigen negative –One on RTV/SQV w/ no apparent risk factors

63. Hyperbilirubinemia Conclusions Inhibition of UGT 1A1 Predominantly unconjugated Reversible upon discontinuation of atazanavir Jaundice/scleral icterus are likely to be common adverse events in clinical practice resulting in more frequent discontinuations than seen in clinical trials. Risk for hepatotoxicity similar to other marketed ARV

64. Lipid Profiles

65. Study 034 Lipid Profiles at Week 48 Percent Change from Baseline Percent Change from Baseline

66. Study 034 Lipid Profiles at Baseline and Week 48 Percentage of Subjects TC>240 LDL>160 TG>400

67. Study 043 Lipid Profiles at Week 24 Percent Change from Baseline Percent Change from Baseline

68. Study 043 Lipid Profiles at Baseline and 24 Weeks mg/dL TC>240 LDL>160 TG>400

70. Lipodystrophy Treatment-Naïve Studies * Includes events of lipoatrophy, lipohypertrophy, and lipodystrophy.

71. CV Events -Myocardial Infarction Three MIs in atazanavir-treated patients and three MIs in patients receiving comparators One subject receiving RTV/SQV underwent three vessel bypass surgery

72. Lipid Profiles Conclusions Lipid effects of atazanavir appeared to persist through 108 weeks of treatment, although data from phase 2 trials is limited by study design. Benefits for treatment-experienced patients less well defined as factors other than current protease inhibitor use appear to contribute at least to hypertriglyceridemia. Lipid effects do not appear to be associated with a reduced incidence of lipodystrophy. Cardiovascular benefit is unknown at this time.

73. Evaluation of the QT Interval

74. In Vitro Evaluation of Potential Cardiac Effects Modest inhibition of IKr (HERG) - 15% at 30 µM Moderate inhibition of Ca channels - IC50 of 10 µM Weak inhibition of Na channels - IC50 > 30 µM In Purkinje fiber studies, a dose-dependent increase in mean action potential duration was observed.

75. Study 076 3-treatment, 3-period crossover study 72 subjects received multiple, once-daily doses of atazanavir Subjects assigned atazanavir 400 mg, 800 mg, and placebo in six different sequences Washout period of  14 days

76. QTc Changes by Correction Formula  QTcB at Tmax from baseline to 800 mg dose is 7.9 msec (95% CI 2.8, 12.9)  QTcF at Tmax from baseline to 800 mg dose is -1.6 msec (95% CI -4.2, 1.1)

77. Studies 034 and 043 Prolonged QTc Intervals Study 034 Incidence of prolonged QTc intervals similar between atazanavir and efavirenz regimens (2%). One subject receiving efavirenz had a QTc interval > 500 msec. Study 043 Nine subjects (ATV, 2 subjects; LPV/RTV, 7 subjects) experienced a post-baseline QTc prolongation.

78. Study 034 and 043 CV Events Potentially Related to Arrhythmia Sudden death or torsades de pointes CV events leading to treatment discontinuation CV events coded as SAEs Grade 3 - 4 CV events All CV events Events reviewed - No events of sudden death, torsades de pointes, events suspicious for TdP, or an imbalance between treatment arms in events potentially attributable to TdP was observed.

79. Effect of Atazanavir on the QT Interval Conclusions Data from placebo-controlled study 076 limited by lack of positive control (e.g. moxifloxacin) Current data indicates that atazanavir has little or no effect on the QT interval; however, the overall risk is unknown No signal for increased risk relative to comparators was identified in clinical trials

80. Evaluation of the PR Interval

81. Causes of PR Interval Prolongation and AV Block Medications - e.g. antihypertensives, digoxin Fibrosis of the conduction system Ischemic heart disease Valvular or congenital heart disease Cardiomyopathy Myocarditis

82. First Degree AV Block Clinical Significance ACC/AHA/NASPE 2002 Guidelines for Implantation of Cardiac Pacemakers and Antiarrythmic Devices Class II B recommendation: First degree AV block greater than 300 msec in patients with LV dysfunction and symptoms of congestive heart failure in whom a shorter AV interval results in hemodynamic improvement

83. Study 076 (Healthy Volunteers) Plot of Mean PR Versus Time Since Dosing

84. Study 034 PR Interval Time Mean PR Interval Post-dose (min, max) msec EFV2-3 hours 153 (101, 251) ATV*2-3 hours 160 (110, 287) * Maximum PR intervals: 265 - 307

85. Study 034 First Degree AV Block Treatment Incidence of First Degree AV Block (%) Males Females Total Efavirenz 3 0 2 Atazanavir 4 6 4.5

86. Study 041 PR Interval TimeMean PR Interval Post-dose (min, max) msec NFV 2-3 hours 158 (97, 203) ATV* 2-3 hours 164 (120, 243) * Maximum PR intervals: 234 - 250

87. Studies 041 and 044 First Degree AV Block Study Dose N 1st Degree AV Block (%) 041 ATV 400148 5 NFV 47 9 044 ATV 400172 9 ATV 600127 14

88. Study 043 PR Interval TimeMean PR Interval Post-dose (min, max) msec LPV/r 2-3 hours 157 (114, 250) ATV* 2-3 hours 157 (114, 209) * Maximum PR Intervals: 194 - 218

89. Study 043 First Degree AV Block Treatment Incidence of First Degree AV Block (%) Males Females Total Lopinavir/r 6 4 6 Atazanavir 7 3 6

90. Case Narratives - Other Conduction Abnormalities Potentially Related to Atazanavir On day 1053 of therapy in study 007/041, a 43 year old male intentionally ingested a large number of ATV/3TC/d4T pills Received activated charcoal Severely prolonged PR interval with bifascicular block was observed on ECG Patient was monitored for 5 days until ECG normalized

91. Case Narratives - Other Conduction Abnormalities Potentially Related to Atazanavir A 50 year old male with HTN was hospitalized on day 11 of ATV/ 3TC/DLV/TDF for angina and SOB On verapamil SR for HTN An ECG showed junctional rhythm with retrograde atrial activation. ARV medications held One day following admission an ECG showed persistence of junctional rhythm Two days following admission the patient was found unresponsive with idioventricular rhythm Autopsy showed 90% LAD without infarct

92. Effects on PR Interval Conclusions Dose dependent prolongation of the PR interval First degree AV block most common abnormality observed Incidence of first degree block appears to be similar to that observed with selected PIs Severe prolongation (> 300 msec) or more serious events appear to be rare

93. Pediatric Protocol PACTG 1020-A Atazanavir + 2 NRTIs 48 enrolled; 29 continuing on study Adverse event profile in these patients appears similar to adults Due to wide variability of pK data in all age cohorts, a dose has not yet been defined for any group

94. Drug-Drug Interactions

95. Potential interaction with ATV –CYP3A inhibitor, inducer, or substrate –drugs that increase pH –drugs that cause PR prolongation –2C9 (e.g. warfarin) or 1A2 (e.g. theophyline) - not studied

96. Drug Interactions - Diltiazem Diltiazem –CYP 3A substrate + inhibitor –PR prolongation –ATV  diltiazem Cmax and AUC ~ 100%

97. Drug Interactions - Oral Contraceptives Co-administration of atazanavir and ethinyl estradiol/norethindrone (Ortho-Novum 7/7/7  ) was evaluated CmaxAUC Ethinyl estradiol1.151.48 Norethindrone1.672.10

98. Atazanavir Overall Conclusions Antiviral activity similar to efavirenz or nelfinavir in treatment-naive patients Inferior to lopinavir/r in treatment-experienced patients, but multiple analyses indicate activity in this population Low pill burden may enhance compliance in selected patients Unique resistance pathway in treatment-naïve subjects

99. Atazanavir Overall Conclusions Hyperbilirubinemia appears to be due to inhibition of UGT 1A1 and reversible with treatment discontinuation Risk for hepatotoxicity appears to fall within the range of that seen with other ARV medications

100. Atazanavir Overall Conclusions Dose-dependent prolongation of the PR interval Incidence of first degree AV block appears to be similar to that observed in lopinavir/ritonavir and nelfinavir treated patients Clinically significant events due to prolongation of the PR interval appear to be rare Effects of atazanavir on the QT interval appear to be minimal

101. Atazanavir Overall Conclusions Favorable lipid profile as compared to selected protease inhibitors and efavirenz Impact on cardiovascular events unknown Does not appear to “reverse” triglyceride elevations seen in treatment-experienced patients Does not appear to result in a decreased incidence of lipodystrophy

102. Questions

103. Question 1 Do the efficacy and safety of atazanavir support its approval for the treatment of HIV infection? As part of your discussion please comment on: »Treatment effects seen in naїve and experienced patients »Hyperbilirubinemia observed in clinical trials »The effect of atazanavir on the PR and QT intervals

104. Question 2 If atazanavir is recommended for approval, does its safety profile warrant additional clinical or laboratory monitoring?

105. Question 3 Does the effect of atazanavir on lipid parameters offer patients a clinically significant advantage over other treatment options?

106. Question 4 Based on the resistance data, what recommendations would you have regarding its use in naïve and experienced patients?

107. Question 5 Please provide recommendations for any Phase 4 studies of atazanavir?