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

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

Tipranavir Trough Concentrations *Study day 11 (prior to coadministration of RTV) † BLQ = below the limit of quantitation TPV morning C min ( min median max µM) after 21 days exposure to TPV/RTV BLQ BLQ n= 11 to BLQ BLQ BLQ BLQ † n= 10 to * n=12 to TPV (mg BID) RTV (mg BID)

TPV 300 RTV 200 (1182.3) TPV 500 RTV 100 (1182.2) TPV 500 RTV 100 (1182.4) TPV 1000 RTV 100 (1182.2) TPV 1200 RTV 200 (1182.3) TPV 1250 RTV 100 (1182.4) Duration 14 days48 weeks16 weeks48 weeks14 days16 weeks N Patient Population NaïveMultiple PI Failure Single PI Failure Multiple PI Failure NaïveSingle PI Failure Diarrhea (any Grade) 30%42%33%73%64%43% Nausea 026%19%36%55%43% Vomiting 10%11%023%18%33% All AEs 80%100%71%100%81.8%81% Tipranavir Adverse Event Data Trials ,.3, and.4

Tipranavir Efficacy Data Trials ,.3, and.4 TPV 300 RTV 200 (1182.3) TPV 500 RTV 100 (1182.4) TPV 1200 RTV 200 (1182.3) AnalysisAT/OCITTAT/OC Duration14 days16 weeks14 days N Patient Population NaïveSingle PI Failure Naïve Mean VL Reduction 1.43 log1.30 log1.64 log % BLQ %20.0 % BLQ %0.0 CD4 Count Change TPV 500 RTV 100 (1182.2) TPV 1000 RTV 100 (1182.2) TPV 1250 RTV 100 (1182.4) FAS ITT 48 weeks 16 weeks Multiple PI Failure Multiple PI Failure Single PI Failure 2.34 log1.71 log 1.40 log 78.9%50.0%55.0% 68.4%40.9%35.0%

Phase IIB Trial--Dose Optimization BI 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 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

Phase IIB Trial--Dose Optimization BI 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 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

Phase IIB Trial--Dose Optimization BI 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 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

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

Phase III Trial--Registrational Study RESIST-1 (BI ) 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 log 10 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 log 10 reduction in viral load at 24 weeks. 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 log 10 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 log 10 reduction in viral load at 24 weeks.

Phase III Trial--Registrational Study RESIST-1 (BI ) 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 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

Phase III Trial--Registrational Study RESIST-1 (BI ) 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) 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)

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

Phase III Trial--Registrational Study RESIST-2 (BI ) 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 log 10 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 log 10 reduction in viral load at 16 weeks. 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 log 10 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 log 10 reduction in viral load at 16 weeks.

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

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

Phase I-II Trial--1st Companion Study BI 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 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

Phase I-II Trial--1st Companion Study BI 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 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

Phase I-II Trial--1st Companion Study BI 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 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

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

Phase III Trial--2nd Companion Study RESIST-3 (BI ) 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 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

Phase III Trial--2nd Companion Study RESIST-3 (BI ) 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 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

Phase III Trial--2nd Companion Study RESIST-3 (BI ) 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 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

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

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

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

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