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Tipranavir Resistance

Tipranavir Resistance. Lisa K. Naeger, Ph.D. Kimberly Struble, Pharm.D. Division of Antiviral Drug Products Food and Drug Administration. FDA Antiviral Advisory Committee Meeting. May 19, 2005. TPV In Vitro Resistance Profile.

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Tipranavir Resistance

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  1. Tipranavir Resistance Lisa K. Naeger, Ph.D. Kimberly Struble, Pharm.D. Division of Antiviral Drug Products Food and Drug Administration FDA Antiviral Advisory Committee Meeting May 19, 2005

  2. TPV In Vitro Resistance Profile During selection of resistant viruses by serial in vitro passage, breakthrough mutations arose in this sequence: L33F I84V K45I I13V V32I V82L M36I A71V L10F I54V Fold IC50 3X 16X 70X • A valine to isoleucine mutation at the P2 residue in the CA/P2 • protease cleavage site and a serine to proline mutation in the • transframe region were also observed in variants at passage 39

  3. Cross-Resistance In Vitro • TPV showed <4-fold decreased susceptibility against 90% (94/105) of HIV-1 isolates resistant to APV, ATV, IDV, LPV, NFV, RTV, or SQV. • TPV-resistant viral molecular clones showed decreased susceptibility to all currently available protease inhibitors except SQV.

  4. Clinical Resistance • Baseline genotype/phenotype and virologic outcome analyses • Development of resistance on TPV treatment

  5. Clinical Resistance • Baseline genotype/phenotype and virologic outcome analyses • Development of resistance on TPV treatment

  6. Baseline Genotype/Phenotype and Virologic Outcome Analyses

  7. Endpoints • Proportion of Responders (confirmed 1 log10 decrease) • Median DAVG24 • Median change in HIV RNA from Baseline at Week 2, 4, 8, 16, 24

  8. FDA Reasons for Censoring Primary Endpoint Dataset • FDA Censored: • Subjects who discontinued while suppressed • Subjects who discontinued before confirmed suppression due • to an adverse event or other reasons • Subjects with no week 8-24 HIV RNA data (D/C weeks 0-4) • Subjects who added any new ARV or changed PI

  9. FDA Reasons for Censoring DAVG24 Dataset Added back the RESIST 2 subjects who did not have week 24 data but had week 16 data who were censored in the primary endpoint analysis

  10. Baseline Outcome Analyses • Number of Baseline PI Mutations • Type of Baseline PI Mutation • Baseline TPV Phenotype

  11. Response by Number of Baseline PI Mutations Proportion of Responders (confirmed >1 log decrease at Week 24) # Any change at positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90

  12. Response by #Baseline PI MutationsMedian Change from Baseline: Overall 0 2 4 8 16 24 Week

  13. Response by #Baseline PI MutationsMedian Change from Baseline: No T20 0 2 4 8 16 24 Week

  14. Response by #Baseline PI MutationsMedian Change from Baseline: +T20 Use 0 2 4 8 16 24 Week

  15. Baseline Outcome Analyses • Number of Baseline PI Mutations • Type of Baseline PI Mutation • Baseline TPV Phenotype

  16. Effect of Type of Baseline PI Mutation on the Primary Endpoint

  17. Effect of Type of Baseline PI Mutation on the Primary Endpoint

  18. Baseline Outcome Analyses • Number of Baseline PI Mutations • Type of Baseline PI Mutation • Baseline TPV Phenotype

  19. Proportion of Responders by Baseline TPV Phenotype

  20. Baseline TPV Phenotype: DAVG24

  21. Mutations Developing on TPV Treatment

  22. Mutations that Developed on TPV: RESIST 1 and 2

  23. Resistance Summary • TPV is a protease inhibitor with antiviral activity against multi PI-resistant clinical HIV-1 isolates. • The most common protease mutations that developed in >20% of isolates from treatment-experience subjects who failed on TPV/r treatment were L10I/V/S, I13V, L33V/I/F, M36V/I/L, V82T or L, and I84V. • The resistance profile in treatment-naive subjects has not yet been characterized.

  24. Resistance Summary • Virologic response rates in TPV/r-treated subjects were reduced when: • isolates with substitutions at positions I13, V32, M36, I47, Q58, D60 or I84 and substitutions V82S/F/I/L were present at baseline. • the number of baseline PI mutations was 5 or more. • Subjects taking T20 with TPV/r were able to achieve >1.5 log10 reductions in viral load through 24 weeks • the baseline phenotype for TPV was >3. • Consistent observations were made in each of the analyses conducted by multiple endpoints. • 20% more responders in the TPV/r arm compared to CPI/r • Greater reductions in viral load in TPV/r arm vs. CPI/r arm

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