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Design of the RESIST Study Program

Design of the RESIST Study Program. Dr Kevin Curry Boehringer Ingelheim, Bracknell, UK. Tipranavir Clinical Development Plan - Phase II-III Program. RESIST-1 N=500, 24W TPV/RTV vs. PI/RTV +OBR NA, AUS. 1182.52 Phase IIB 500/100 500/200 750/200. Analysis, choose optimal dose.

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Design of the RESIST Study Program

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  1. Design of the RESIST Study Program Dr Kevin Curry Boehringer Ingelheim, Bracknell, UK

  2. Tipranavir Clinical Development Plan - Phase II-III Program RESIST-1N=500, 24W TPV/RTV vs. PI/RTV +OBR NA, AUS 1182.52Phase IIB 500/100 500/200 750/200 Analysis, choose optimal dose RESIST-2N=800, 16W TPV/RTV vs. PI/RTV +OBR EU, SA 1182.51 3-PI, PK/Safety RESIST-33-PI, Efficacy 1182.17/.57 Rollover Studies

  3. Tipranavir Trough Concentrations TPV morning Cmin (minmedianmax µM) after 21 days exposure to TPV/RTV RTV (mg BID) TPV (mg BID) 250 500 750 1000 1250 0* n=12 to 25 0.28 0.06 0.48 0.63 0.25 1.32 0.69 0.06 3.13 0.95 0.11 4.74 1.81 0.13 5.88 100 n= 10 to 14 ------ 23 BLQ† 66 25 BLQ 80 76 BLQ 143 38 BLQ 173 200 n= 11 to 12 15 0.1 47 32 0.7 71 60 BLQ 102 59 BLQ 173 ----- *Study day 11 (prior to coadministration of RTV) † BLQ = below the limit of quantitation

  4. Tipranavir Adverse Event DataTrials 1182.2, .3, and .4 TPV 300 TPV 500 TPV 500 TPV 1000 TPV 1200 TPV 1250 RTV 200 RTV 100 RTV 100 RTV 100 RTV 200 RTV 100 (1182.3) (1182.2) (1182.4) (1182.2) (1182.3) (1182.4) 14 days 48 weeks 16 weeks 48 weeks 14 days 16 weeks Duration 10 19 21 22 11 21 N Naïve Multiple PI Single PI Multiple PI Naïve Single PI Patient Failure Failure Failure Failure Population 30% 42% 33% 73% 64% 43% Diarrhea (any Grade) 0 26% 19% 36% 55% 43% Nausea 10% 11% 0 23% 18% 33% Vomiting 80% 100% 71% 100% 81.8% 81% All AEs

  5. Tipranavir Efficacy DataTrials 1182.2, .3, and .4 TPV 300 TPV 500 TPV 500 TPV 1000 TPV 1200 TPV 1250 RTV 200 RTV 100 RTV 100 RTV 100 RTV 200 RTV 100 (1182.3) (1182.2) (1182.4) (1182.2) (1182.3) (1182.4) Analysis AT/OC FAS ITT FAS AT/OC ITT Duration 14 days 48 weeks 16 weeks 48 weeks 14 days 16 weeks N 10 19 20 22 11 21 Patient Naïve Multiple PI Single PI Multiple PI Naïve Single PI Population Failure Failure Failure Failure 1.40 log Mean VL 1.43 log 2.34 log 1.30 log 1.71 log 1.64 log Reduction % BLQ 400 0.0 78.9% 38.9% 50.0% 20.0 55.0% % BLQ 50 0.0 68.4% 22.2% 40.9% 0.0 35.0% CD4 Count +41.5 +184 +80 +149 +83 -6 Change

  6. Phase IIB Trial--Dose OptimizationBI 1182.52 DESIGN Objective: define “maximum tolerated dose” Primary endpoints Viral load reduction (efficacy) at 14 days Incidence of GI adverse events (safety) at 28 days Patient population HIV+ adults with >2 PI regimen experience & 3-class experience >1 major PI mutation & <1 of 82T, 84V, 90M Duration: up to 32 weeks before rollover

  7. Phase IIB Trial--Dose OptimizationBI 1182.52 TREATMENT All patients receive TPV/RTV + optimized background regimen (OBR) 3 doses of TPV/RTV: 750mg/200mg 500mg/200mg 500mg/100mg OBR is individually determined for each patient from baseline genotyping and treatment history

  8. Phase IIB Trial--Dose OptimizationBI 1182.52 STATUS UPDATE Trial initiated 29 April 2002 in 9 countries 406 patients screened; 206 enrolled and receiving treatment Final patient will complete 4 weeks on 31 July Rapid data collection and analysis to follow Discussions with regulatory authorities planned for fall 2002 Phase III program to begin following regulatory approval

  9. Tipranavir Clinical Development Plan - Phase II-III Program RESIST-1N=500, 24W TPV/RTV vs. PI/RTV +OBR NA, AUS 1182.52Phase IIB 500/100 500/200 750/200 Analysis, choose optimal dose RESIST-2N=800, 16W TPV/RTV vs. PI/RTV +OBR EU, SA 1182.51 3-PI, PK/Safety RESIST-33-PI, Efficacy 1182.17/.57 Rollover Studies

  10. Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12) DESIGN Objective Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults Primary endpoints Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48. An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in viral load at 24 weeks.

  11. Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12) DESIGN Patient population HIV+ adults with >2 PI regimen experience & 3-class experience >1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M) <1 of 82L, 82T, 84V, 90M Duration 48 weeks Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment

  12. Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12) TREATMENT Investigators must pre-declare preferred comparator PI and OBR from baseline genotyping and treatment history Once randomized, patients will receive TPV/RTV + OBR, or Comparator PI/RTV +OBR N= 247 patients per arm PARTICIPATING COUNTRIES Canada, USA, Australia (~100 sites)

  13. Tipranavir Clinical Development Plan - Phase II-III Program RESIST-1N=500, 24W TPV/RTV vs. PI/RTV +OBR NA, AUS 1182.52Phase IIB 500/100 500/200 750/200 Analysis, choose optimal dose RESIST-2N=800, 16W TPV/RTV vs. PI/RTV +OBR EU, SA 1182.51 3-PI, PK/Safety RESIST-33-PI, Efficacy 1182.17/.57 Rollover Studies

  14. Phase III Trial--Registrational StudyRESIST-2 (BI 1182.48) DESIGN Objective Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults Primary endpoints Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48. An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in viral load at 16 weeks.

  15. Phase III Trial--Registrational StudyRESIST-2 (BI 1182.48) DESIGN N= 404 patients per arm PARTICIPATING COUNTRIES France, Germany, Spain, United Kingdom, Sweden, Italy, Portugal, Greece, Denmark, Belgium, Netherlands Argentina, Mexico

  16. Tipranavir Clinical Development PlanPhase II-III Program RESIST-1N=500, 24W TPV/RTV vs. PI/RTV +OBR NA, AUS 1182.52Phase IIB 500/100 500/200 750/200 Analysis, choose optimal dose RESIST-2N=800, 16W TPV/RTV vs. PI/RTV +OBR EU, SA 1182.51 3-PI, PK/Safety RESIST-33-PI, Efficacy 1182.17/.57 Rollover Studies

  17. Phase I-II Trial--1st Companion StudyBI 1182.51 DESIGN Objective PK drug interaction between TPV/RTV and APV, LPV, and SQV Primary endpoints APV, LPV, SQV Cmin ratio between week 8 and baseline Safety

  18. Phase I-II Trial--1st Companion StudyBI 1182.51 DESIGN Patient population HIV+ adults with >2 PI regimen experience & 3-class experience >1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M) >2 of 82L, 82T, 84V, 90M Duration 48 weeks Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment

  19. Phase I-II Trial--1st Companion StudyBI 1182.51 TREATMENT Patients will be randomized to one of four arms TPV/RTV + OBR TPV/RTV/APV +OBR TPV/RTV/LPV +OBR TPV/RTV/SQV + OBR N= 50 patients per arm PARTICIPATING COUNTRIES ALL in either RESIST-1 and RESIST-2

  20. Tipranavir Clinical Development Plan - Phase II-III Program RESIST-1N=500, 24W TPV/RTV vs. PI/RTV +OBR NA, AUS 1182.52Phase IIB 500/100 500/200 750/200 Analysis, choose optimal dose RESIST-2N=800, 16W TPV/RTV vs. PI/RTV +OBR EU, SA 1182.51 3-PI, PK/Safety RESIST-33-PI, Efficacy 1182.17/.57 Rollover Studies

  21. Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13) DESIGN Objective Safety and efficacy of a 3-PI regimen in very highly treatment experienced HIV+ adults Primary endpoints Viral load reduction at 24/48 weeks Timing Will follow analysis of 8-week data from trial 1182.51

  22. Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13) DESIGN Patient population HIV+ adults with >2 PI regimen experience & 3-class experience >1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M) >2 of 82L, 82T, 84V, 90M Duration 48 weeks

  23. Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13) TREATMENT Patients will be randomized to one of four arms TPV/RTV/APV +OBR TPV/RTV/LPV +OBR TPV/RTV/SQV + OBR N= ~50 patients per arm PARTICIPATING COUNTRIES ALL in either RESIST-1 and RESIST-2

  24. Tipranavir Clinical Development PlanPhase III, Peds, Naïve, & EA Program Pediatric PK Trial .14 Phase III Program 1182.52Phase IIB Dose Selection, PK Analysis Naïve Trial .33 EXPANDED ACCESS

  25. Tipranavir PK Development Program Completed or ongoing studies Grid study Antivirals: Multiple ARV regimens NRTIs: ZDV, ddI NTRTI: tenofovir NNRTIs: EFV Oral contraceptive, loperamide

  26. Tipranavir PK Development Program Planned studies Other drugs: clarithromycin, fluconazole, rifampin, methadone, rifabutin, atorvastatin PK/PD: ADME, bioequivalence, GI transit, high fat/antacid Special populations: hepatic/renal insufficiency

  27. Tipranavir Clinical Development Plan - Phase II-III Program RESIST-1N=500, 24W TPV/RTV vs. PI/RTV +OBR NA, AUS 1182.52Phase IIB 500/100 500/200 750/200 Analysis, choose optimal dose RESIST-2N=800, 16W TPV/RTV vs. PI/RTV +OBR EU, SA 1182.51 3-PI, PK/Safety RESIST-33-PI, Efficacy 1182.17/.57 Rollover Studies

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