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NDA 21-567 Atazanavir

NDA 21-567 Atazanavir. Kendall A. Marcus, M.D. Medical Reviewer Division of Antiviral Drug Products. Presentation Outline. NDA Submission Overview Efficacy Summary - Tom Hammerstrom, Ph.D. Clinical Virology - Lisa Naeger, Ph.D. Safety Issues Hyperbilirubinemia Lipid Profiles

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NDA 21-567 Atazanavir

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  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 3 Different Strains of HIV-1 were serially selected with ATV for 4-5 months (200 - 500 nM) Virus strain: mutations RF:V32I, L33F, M46I, A71V, I84V, N88S LAI:L10Y/F, I50L, L63P, A71V, N88S NL4-3: V32I, M46I, I84V, L89M 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. 74% 56% 20%

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

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

  23. Response Based on Baseline Genotype

  24. Cross-Resistance

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

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

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

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

  29. 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

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

  31. 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

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

  33. Results in Trials with ART Naïve Subjects

  34. Percent Sustained <400 copies/mL to Week 48 TrialArm%<40095% Interval ATV - Con 34 EFV 251 / 405 62% ATV 271 / 405 67% -1.5%, 11.6% 7 NFV 62 / 103 60% ATV 62 / 103 60% -13.8%, 13.0% 8 NFV 54 / 91 63% ATV 121 / 181 69% -5.0%, 19.4%

  35. Results in Trial with ART Experienced Subjects

  36. Trial 43, ATV vs Kaletrafor 24 Weeks EndpointArmEstimate95% Interval %<400 KAL 98 / 150 = 65% ATV 70/150 = 47% -30%, -7.9% TAD KAL -1.65 ATV -1.39 .078, .44

  37. 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

  38. ATV vs Placebo% <400 Source ArmEstimateDIFF SEE Trial 43 ATV 70/150 = 47% KAL 98 / 150 = 65% -19% 5.73% Trial 863KAL 259 / 326 = 79% NFV 233 / 327 = 71%8% 3.36% Trial 511NFV 66/ 99 = 67% PLA 7/ 101 = 7% 60% 5.37% Imputed ATV PLAC 49% 8.54%

  39. ATV vs Placebo% <400 Source ArmEstimateDIFF SEE Trial 43 ATV 70/150 = 47% KAL 98 / 150 = 65% -19% 5.73% Trial 888KAL 84 / 148 = 57% S. PI 46 / 140 = 33% 24% 5.69% Imputed ATV Selected PI 5% 8.07%

  40. ATV vs Control% <400 SourceControlDifference95% Interval Trial 43 KAL -19% -30%, -7.9% Imputed Sel PI 5% -10.8%, 21% Discounted Sel PI 4.5% -12.3%, 23% Imputed PIacebo49%32%, 66%

  41. ATV vs PlaceboTAD, Week 24 Source ArmEstimateDIFF SEE 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 Imputed ATV PLAC -.107 .137

  42. ATV vs PlaceboTAD, Week 24 Source ArmEstimateDIFF SEE Trial 43 ATV -1.39 KAL -1.65 .26 .093 Trial 888KAL -.972 S. PI -.867 -.104 .078 Imputed ATV Selected PI .156 .121

  43. ATV vs ControlTAD, Week 24 SourceControlDifference95% Interval Trial 43 KAL .26 .078, .44 Imputed Sel PI .156 -.081, .393 Imputed Placebo -.107-.376, .162

  44. 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

  45. 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

  46. 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

  47. 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

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