1. 1 May 19, 2005 Antiviral Drugs Advisory Committee APTIVUS ® (tipranavir) Capsules

2. 2 Introduction Burkhard Blank, MD Senior Vice President Medicine and Drug Regulatory Affairs

3. 3 Clinical Need  Growing population of treatment-experienced HIV+ patients with limited treatment options  3% to 5% of newly HIV-infected patients have multidrug resistant HIV-1  Multidrug resistant HIV-1 is associated with increased AIDS progression and death

4. 4 Tipranavir  Shows significant antiviral activity against the majority of multidrug resistant HIV-1  Challenging clinical development program in PI treatment- experienced HIV+ patients  Offers a significant new treatment option for PI treatment- experienced patients

5. 5 Tipranavir – Proposed Indication “Tipranavir, co-administered with low-dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients who are protease inhibitor treatment ‑ experienced.”

6. 6 Presentation Overview Tipranavir DevelopmentDouglas Mayers, MD Efficacy Scott McCallister, MD Drug-Drug Interactions SafetyChristopher Corsico, MD ResistanceDouglas Mayers, MD Clinical UtilityDaniel Kuritzkes, MD ConclusionsBurkhard Blank, MD

7. 7 Consultants Available to the Committee Angela D.M. Kashuba, PharmD University of North Carolina- Chapel Hill Daniel R. Kuritzkes, MD Harvard Medical School Jens D. Lundgren, MD University of Copenhagen Denmark Joel Morganroth, MD University of Pennsylvania Jonathan M. Schapiro, MD Stanford University School of Medicine Mark Sulkowski, MD Johns Hopkins University School of Medicine

8. 8 Tipranavir Development Douglas Mayers, MD International Head, Therapeutic Area Virology

9. 9  Novel nonpeptidic protease inhibitor developed to provide a new treatment option for PI-experienced patients  Potent in vitro activity against both WT HIV-1 and HIV-2, and the majority of multiple PI-resistant HIV-1  Requires co-administration with ritonavir  Available as a soft-gel capsule (250 mg) CH 3 OH NH O O SO 2 N F3CF3C H3CH3C Tipranavir Overview

10. 10 Tipranavir Development  Initial development by P & U; BI acquired in 2000  End of Phase II Meeting with FDA 17 December 2002  Concurrence with TPV/r dose selection of 500mg/200mg BID  Agreement on original clinical trial protocol design for pivotal Phase III trials  Tipranavir NDA for accelerated approval submitted to FDA 22 December 2004  Based on 24-week efficacy/safety data

11. 11 Tipranavir Clinical Development Program  39 clinical trials  25 trials by BI  11 in HIV+ patients  14 in HIV- subjects  Two nearly identical Phase III studies (RESIST) began in early 2003: 1485 patients, more than 270 sites, 21 countries  1411 patients treated with the TPV/r 500/200 dose, 1206 patients treated for at least 24 weeks  Pediatric and treatment-naïve adult studies ongoing

12. 12 Tipranavir Co-Administration with Ritonavir  TPV exposure markedly enhanced with RTV co- administration  Cytochrome P450 3A is the major metabolic pathway  TPV induces CYP 3A  TPV and RTV co- administration results in net inhibition of CYP 3A Mean Plasma Tipranavir Concentration (  M) 125 100 75 50 25 0 Target 024681012 4x Cmax ss 9x greater exposure at steady-state Time (h) 48x Cmin ss TPV/r 500/200mg TPV 500mg alone

13. 13 Tipranavir Combined with Ritonavir ADME In Vitro  Using human microsomes, the inhibition potential for TPV had a rank order of: CYP 2C9 > CYP 3A4 > CYP 2C19 > CYP 2D6 > CYP 1A2 Absorption  Formulated in a “self-emulsifying drug delivery system” (SEDDS) for solubility  Food improves emulsification  TPV/r induces the P-gp efflux transporter system Distribution  Protein binding >99.9% Metabolism  Substrate for and inducer of the cytochrome P450 3A system  Must be taken with RTV to inhibit first pass effect  Predominantly unchanged drug measured in plasma, urine, and feces Excretion  Half-life of 6 hours (TPV/r 500/200) in HIV+ patients  Majority excreted in feces  Less than 5% excreted in urine

14. 14 Dose Finding BI 1182.52 NA, EU, AUS N=216 RESIST-1 BI 1182.12 North America Australia RESIST-2 BI 1182.48 Europe Latin America Companion Study BI 1182.51 All RESIST Countries Pediatrics, Naïve Adults Emergency Use Expanded Access Tipranavir Phase II-III Study Program Rollover Study, BI 1182.17, All RESIST Countries Optimal Dose TPV/r 500/200

15. 15 Tipranavir Dose Finding Study Conclusions  3 TPV/r doses (500/100, 500/200, 750/200) BID studied in 216 patients with 3-class and 2 PI-regimen experience  500/200 dose selected for the Phase III trial program  500/100 dose eliminated due to inferior efficacy in patients with drug resistant viruses and more variable PK results  500/200 and 750/200 doses had similar efficacy and PK profiles  750/200 dose eliminated due to a higher rate of Grade 3 / 4 ALT/AST elevations and treatment discontinuations

16. 16 Tipranavir Key Mutations  Mutations at codons 33, 82, 84 and 90 of HIV-1 protease  Were either selected in early in vitro or in vivo studies or seen in HIV-1 isolates with decreased susceptibility to tipranavir  In the Phase II program multiple mutations at these sites:  Associated with decreased TPV/r responses  Associated with broad, high level resistance to other PIs (SQV, IDV, LPV, APV)  Used to select patients unlikely to get a durable response to any single PI-based regimen who were offered dual-boosted PI regimens containing TPV

17. 17 RESIST Pivotal Trial Program Scott McCallister, MD Global Medical Team Leader, TPV

18. 18 Dose Finding BI 1182.52 NA, EU, AUS RESIST-1 BI 1182.12 North America Australia N=620, Safety N=620, Efficacy RESIST-2 BI 1182.48 Europe Latin America N=865, Safety N=539, Efficacy Companion Study BI 1182.51 All RESIST Countries Rollover Study, BI 1182.17, All RESIST Countries Pediatrics, Naïve Adults Emergency Use Expanded Access Tipranavir Phase II-III Study Program Optimal Dose TPV/r 500/200

19. 19 RESIST Studies Key Design Issues Challenging heterogeneous study population with limited treatment options Open label studies  Four treatment options for comparator arm PI  Efforts made to reduce potential for bias Week 8 escape: patients in comparator arms could leave and receive TPV in rollover study  Must have confirmed virologic failure  Could not roll over due to AEs only Optimized background regimen (OBR)  Any available approved NRTIs or NNRTIs  ENF could be used  All drugs must be pre-declared prior to randomization

20. 20 RESIST Studies Key Inclusion/Exclusion Criteria Inclusion   3 months’ therapy with NRTIs, NNRTIs, and PIs   2 PI regimens for  3 consecutive months  One PI must be current regimen  Viral load  1000 copies/mL on therapy, any CD4+ cell count  Baseline genotype  1 primary PI mutation at codons: 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M Exclusion  > 2 mutations at codons 33, 82, 84, or 90  DAIDS Grade > 1 safety labs (except lipids)  Expected survival less than 12 months

21. 21 RESIST Studies Screening and Randomization Pre-Selection of CPI/r and OBR Resistance Expert Consultation Stratified Randomization (by CPI/r and ENF) Screening Genotype (Virtual Phenotype™ or TruGene ® ) LPV/r IDV/r SQV/r APV/r TPV/r Best PI choice Plus OBR 1:1

22. 22 RESIST Studies 24-Week Endpoints Primary endpoint: treatment response defined as: Confirmed  1 log 10 reduction in viral load from baseline at 24 weeks without  Viral rebound  ARV treatment change  Study discontinuation  Death Secondary efficacy endpoints  Change in viral load from baseline  Proportion of patients with VL < 50 and < 400 copies/mL  Change from baseline in CD4 cell count  AIDS progression events

23. 23 RESIST Studies Early Protocol Modification  Amendment #2 implemented prior to any patient randomizations  Allowed PIs that the genotype report interpreted as pan-resistant Rationale  Interpretation guidelines changed just prior to study initiations  Resistance interpretation on genotype reports not based on RTV- boosting  Investigators had genotype results and expert consultation available to select optimal treatment regimen using any currently available ARVs  Each patient therefore received the best treatment available at the time of trial initiation  Study would have enrolled extremely slowly

24. 24 RESIST Studies Baseline Demographics TPV/rCPI/r Total Screened3309 Total Treated (N)582577 Median Age (years)43.0 Male Gender (%)86.489.4 Race (%) White73.971.8 Black14.313.9 Asian0.71.4 Median Baseline VL (log)4.834.82 Median Baseline CD4 Count155158 Hepatitis B and/or C + (%)10.215.3

25. 25 RESIST Studies Baseline History Advanced HIV disease status  88% prior AIDS diagnosis Prior antiviral use  Median ARV use: 6 NRTIs, 1 NNRTI, 4 PIs  45% ≥ 5 PIs  11.9% prior ENF Limited options for background ARV selection  44% had a GSS  1

26. 26 RESIST Studies Baseline PI Phenotype (454)(452)(423)(450)(445)N= Median Fold Change in IC 50 (452)(449)(456) Analysis of randomly selected samples

27. 27 RESIST Studies Pre-Selected Comparator PIs TPV/r N (%) CPI/r N (%) Total Treated582 (100.0)577 (100.0) Pre-Selected PI LPV293 (50.3)290 (50.3) APV151 (25.9)149 (25.8) SQV117 (20.1)118 (20.5) IDV21 (3.6)20 (3.5)

28. 28 RESIST Studies Primary Efficacy Results Week 24 RESIST 1RESIST 2 TPV/rCPI/rTPV/rCPI/r Number of Patients311309271268 Primary Endpoint % of Patients With 1 log Drop (FAS NCF) 41.522.341.014.9 P valueP < 0.0001

29. 29 RESIST Studies Treatment Response 0 10 20 30 40 50 60 081624 Treatment Responders (%) CPI/r (n=577)TPV/r (n=582) Week 24: P <0.0001 Weeks (41.2) (18.9) RESIST Studies Combined  1 log 10 Viral Load Reduction, Confirmed, ITT: NCF

30. 30 RESIST Studies Undetectable Viral Load (<400, <50 copies/mL) CPI/r (n=577)TPV/r (n=582) ITT: NCF 0 5 10 15 20 25 30 35 40 081624 Virologic Response VL <400 Copies/mL (%) Week 24: P <0.0001 (34.2%) (14.9%) Weeks of Treatment Virologic Response VL <50 Copies/mL (%) 0 5 10 15 20 25 30 35 40 081624 Week 24: P <0.0001 (23.9%) (9.4%)

31. 31 RESIST Studies VL Reduction and CD4 Increase Weeks of Treatment 0 (0.25 log 10 copies/mL) -1.8 -1.6 -1.4 -1.2 -0.8 -0.6 -0.4 -0.2 081624 Median VL log 10 Change From Baseline Week 24: P <0.0001 (0.80 log 10 copies/mL) ITT: LOCF (+34 cells, range 3-87) (+4 cells, range 0-61) Week 24 difference: P <0.0001 Median Change From Baseline in CD4+ Cell Count 0 5 10 15 20 25 30 35 40 081624 CPI/r (n=577)TPV/r (n=582)

32. 32 RESIST Studies Efficacy Endpoints (Week 24) All Patients in 24-Week Analysis Set TPV/r N=582 CPI/r N=577P Value ≥ 1 log 10 VL Reduction (%)240 (41.2%)109 (18.9%)<0.0001 Total VL Reduction (log 10 )-0.80 -0.25<0.0001 VL <400 Copies/mL199 (34.2%)86 (14.9%)<0.0001 VL <50 Copies/mL139 (23.9%)54 (9.4%)<0.0001 Median CD4+ Cell Change+ 34+ 4<0.0001 AIDS Progression Events25 (3.4%)34 (4.6%) NS

33. 33 RESIST Studies Treatment Response in Patients Using Enfuvirtide N=115 N=43 N=94 N=34 Median Baseline TPV/r + ENF (N=158) CPI/r + ENF (N=128) CD4+7277 HIV RNA5.075.10 Prior ARVs1314

34. 34 Tipranavir Efficacy Conclusions TPV/r was superior at 24 weeks to comparator PIs in two well-controlled studies with PI treatment-experienced patients  Treatment response (  1 log 10 VL reduction)  Absolute VL reduction from baseline  Proportion of patients with undetectable VL (<400, <50 copies/mL)  CD4+ cell count increase

35. 35 Drug-Drug Interactions Scott McCallister, MD Global Medical Team Leader, TPV

36. 36 Drug Interaction Program Antiretroviral drugs  Seven common 3-drug ARV combinations (HIV+)  Dual-boosted PI regimens with LPV, SQV, and APV (HIV+)  ZDV, ddI, TDF, EFV (HIV-) Drugs commonly used by HIV+ patients  Ethinyl estradiol and norethindrone  Loperamide  Atorvastatin Other studies  Antacid interaction  ADME  Clarithromycin  Fluconazole  Rifabutin

37. 37 Notable Drug Interactions – RT Inhibitors No relevant changes in drug levels  3TC, D4T, TDF, NVP, EFV ZDV  ZDV AUC reduced 33  43% with TPV/r  TPV C min and AUC unchanged with either dose ABC  ABC AUC reduced 35  46% with TPV/r ddI  ddI AUC reduced 10% with TPV/r 500/100  TPV C min reduced 34% and AUC unchanged

38. 38 Dose Finding BI 1182.52 NA, EU, AUS RESIST-1 BI 1182.12 North America Australia RESIST-2 BI 1182.48 Europe Latin America Companion Study BI 1182.51 All RESIST Countries N=315 Rollover Study, BI 1182.17, All RESIST Countries Pediatrics, Naïve Adults Emergency Use Expanded Access Tipranavir Phase II-III Study Program Optimal Dose TPV/r 500/200

39. 39 Dual Boosted Protease Inhibitors DrugPK TestAfter Addition of TPV/r Lopinavir AUC C max C min  55%  47%  70% Saquinavir AUC C max C min  76%  70%  82% Amprenavir AUC C max C min  44%  39%  55%  All patients received single boosted PI Weeks 0  2  TPV/r 500/100 was added to each single boosted PI at Week 2  Week 2 plasma sampling was compared to Week 4

40. 40 TPV/r Drug Interaction Conclusions No relevant changes in drug levels  3TC, d4T, TDF, NVP, EFV  Loperamide Drug level reductions of uncertain relevance – A dose adjustment cannot be recommended  ZDV, ABC, ddI Significant drug level reductions – Not recommended  LPV/r, SQV/r, APV/r Clinical monitoring advised, if an alternative agent is not available  Atorvastatin  Clarithromycin, fluconazole  Ethinyl estradiol (hormone replacement) Change in dosing advised  Rifabutin

41. 41 Potential Drug Interactions with TPV/r Potential drug level increases – monitoring recommended  Itraconazole, ketoconazole, voriconazole  Sildenafil, tadalafil, vardenafil  Desipramine Potential drug level decreases – monitoring recommended  Methadone, buprenorphine  Meperidine Currently unpredictable interactions – monitoring recommended  Warfarin  Theophylline  Serotonin re-uptake inhibitors  Calcium channel blockers  Immunosuppressants  Anti-psychotics  Oral hypoglycemics Potential disulfiram reaction  Disulfiram  Metronidazole

42. 42 Tipranavir Safety Christopher Corsico, MD, MPH Head, Drug Surveillance and Information

43. 43 Total HIV + patients treated with TPV/r N = 3367 RESIST TPV/r N = 748 Phase I, II and 1182.51 N = 894 EUP/EAP N = 879 Rollover to TPV/r N = 298 RESIST CPI/r N = 737 Pediatric N = 74 Long Term Follow Up N = 474  1411 HIV+ patients treated with the TPV/r 500/200 mg BID dose  1276 patient-years of exposure  86% HIV+ patients have been treated for >24 weeks  Maximum exposure to TPV/r in the long-term follow-up trial is 5 years Tipranavir Safety Database Safety Update – September 30, 2004

44. 44 N=576 N=703 N=715 N=285 Reason for Discontinuation TPV/r N=748 CPI/r N=737 Adverse Event10%5% Lack of Efficacy9%43% Patient-Years of Exposure TPV/r615 years CPI/r406 years RESIST Studies Patients Remaining on Study

45. 45 RESIST Studies Adverse Events >5% Body System EventTPV/r (N=748)CPI/r (N=737) Gastrointestinal Diarrhea27.9%21.8% Nausea19.3%15.1% Vomiting10.8%9.0% Abdominal pain8.2%6.0% Infections Nasopharyngitis7.9%5.0% Oral Candidiasis5.6%4.5% Influenza5.2%3.3% Herpes simplex5.1%3.3% Bronchitis6.0%3.7% Sinusitis6.3%4.5% URTI6.6%4.6% General Fatigue11.6%10.2% Pyrexia11.9%8.7%

46. 46 RESIST Studies Adverse Events >5% (continued) Body System EventTPV/r (N=748)CPI/r (N=737) Nervous System Headache13.0%8.4% Dizziness5.6%4.1% Skin Rash6.8%5.7% Psychiatric Depression5.5%5.0% Investigations Weight decrease5.1%3.5% Musculoskeletal Arthralgia6.0%5.0% Back pain6.6%3.8% Respiratory Cough8.8%5.4%

47. 47 RESIST Studies Gender and Rash Female Patients Male Patients System Organ Class/ Preferred Term 10 (8.5)25 (4.0) Pruritus 10 (8.5)41 (6.5) Rash 33 (28.2)163 (25.8) Skin and Subcutaneous Tissue Disorders

48. 48 Risk of MST Rash Among TPV Recipients in RESIST: CD4 Baseline FactorComparator Odds Ratio95% C.I.P Value AgeNA0.9980.969, 1.0270.8825 GenderFemales0.6730.352, 1.2860.2306 Baseline CD4+ (cells/μL) >200 1NA 50 – 2001.2030.704, 2.0570.5 <502.0601.119, 3.7930.02 TPV trough (μMol)NA1.0030.993, 1.0120.5961 RTV trough (mcg/mL)NA2.0340.728, 5.6820.1755 RaceNon-white1.9730.911, 4.2730.0846 Hepatitis coinfectionNo0.6570.282, 1.5270.3289 Weight (Kg)NA1.0050.986, 1.0240.6040 Fixed logistic regression model among TPV/r recipients in RESIST. Variables shown are all variables tested in the model.

49. 49 RESIST Studies Female Patients on TPV/r Who Developed Rash by CD4 Rash 2 9 9 2 No Rash16303217

50. 50 Grade 3 or 4 ALT, AST or Total Bilirubin Actions Taken and Outcomes Action Taken TPV/r N=748 CPI/r N=737 Total Number of Grade 3 or 4 Abnormalities74 (9.9)26 (3.5) Continuation or Temporary Interruption of Study Medication 57 (7.6)26 (3.5) SAE with hepatic term 4 (0.5)0 (0.0) Discontinuation of Study Medication17 (2.3)0 (0.0) LFTS returned to baseline or normal and no SAE with hepatic term 12 (1.6) SAE with hepatic terms 5 (0.7) Resolved 4 (0.5)

51. RESIST Studies Cox Regression Model for Risk of Grade 3 or 4 ALT/AST Baseline risk factors for Grade 3  4 ALT/AST are similar in TPV/r and CPI/r Independent variables: age, gender, race, ΔCD4, baseline triglycerides, NRTI, NNRTI, viral load, CDC HIV stage, duration of HIV infection Factor/Comparison Risk Ratio 95% CI Treatment Group: TPV/r vs CPI/r2.41.5 – 3.8 Baseline ALT,AST Total Bilirubin: (Grade > 1 vs Grade < 1)2.51.3 – 4.8 CD4+ Cell Count at Baseline: >200 vs ≤200 cells/mm 3 2.01.3 – 2.5 HBV or HCV Co-infection: Co-infected vs not co-infected2.31.4 – 3.7 51

52. 52 Hepatic Monitoring and Management Recommendations  Routine clinical and laboratory monitoring to detect liver abnormalities is recommended  Patients with chronic hepatitis B or C, or elevated LFTs at initiation of TPV/r therapy, require more frequent clinical and laboratory monitoring  Patients who are symptomatic in the setting of elevated LFTs should have their TPV/r discontinued

53. 53 3 (0.4) 91 (12.3) CPI/r N=737 2 (0.3) 3 (0.4) 29 (3.9) 176 (23.5) TPV/r N=748 1 (0.1) 3 (0.4) 4 (0.5) Grade 3 / 4 Cholesterol Grade 3 / 4 Triglycerides Category Ischemic Heart Disease Angina Myocardial ischemia Pancreatic Disorders Pancreatitis RESIST Studies Lipid Abnormalities

54. 54 RESIST Studies Mortality – Kaplan Meier Weeks Probability (%) CPI TPV 0 2 4 6 8 10 012243648607284 P = 0.64 CPI TPV 737 748 465 735 131 319

55. 55 Tipranavir Safety Conclusions  1206 patients treated with the to be marketed dose of TPV/r 500mg/200mg BID for at least 24 weeks  Treatment-experienced, ARV-resistant patients  Infections and AIDS progression events  Adverse event profile for TPV/r is similar to CPI/r except for:  Elevated LFTs, clinical hepatic events  Elevated triglycerides and cholesterol

56. 56 Resistance Douglas Mayers, MD International Head, Therapeutic Area Virology

57. 57 Dose Finding BI 1182.52 NA, EU, AUS RESIST-1 BI 1182.12 North America Australia RESIST-2 BI 1182.48 Europe Latin America Companion Study BI 1182.51 All RESIST Countries Rollover Study, BI 1182.17, All RESIST Countries Pediatrics, Naïve Adults Emergency Use Expanded Access Tipranavir Phase II-III Study Program Optimal Dose TPV/r 500/200

58. 58 BI 1182.51 Study Design * OBR=optimized background regimen Open-label, parallel-group, multicenter study N=315 randomized N=284 included in resistance analysis LPV/r + OBR* (400 mg/100 mg) (n=78) SQV/r + OBR (1000 mg/100 mg) (n=71) APV/r + OBR (600 mg/100 mg) (n=71) TPV/r + OBR (500 mg/200 mg) (n=64) TPV/r 500 mg/100 mg added at 2 weeks Final RTV dose 200 mg twice daily in all arms All twice daily

59. 1182.51 HIV RNA Median Change from Baseline at 2 Weeks: Comparative TPV, LPV, SQV, APV 2 Weeks Single Boosted PI 59

60. 60 Treatment Response by Key Mutations Number of Mutations at Positions 33, 82, 84, 90 Baseline TPV Susceptibility (N) Q25,Q75 Change in VL* at 2 Weeks (N) Q25,Q75 Change in VL* at 24 Weeks (N) Q25,Q75 00.7(82) 0.4, 1.0 -1.49(26) -0.99, -1.82-1.35(22) -0.35, -2.18 11.1(232) 0.7, 2.1-1.27(229) -0.73, -1.87-1.27(183)-0.24, -2.62 21.7(371) 0.9, 3.7-1.39(473)-0.67, -1.83-0.78(402) -0.14, -2.42 33.4(112) 1.9, 8.4-1.25(68)-0.26, -1.68-0.24(71)0.13, -1.87 412.0(13) 2.5,16.6-1.08(10)-0.33, -1.54-0.33(10)-0.14, -0.66 *Change in viral load was the change in HIV RNA from baseline through week 2 (OT) or week 24 (LOCF) in log 10 copies/mL.

61. 61 TPV Mutation Score Development  Uni- and multivariate regression analyses used to correlate 291 Phase II baseline genotypes to TPV phenotype, and Week 2 or 24 VL reduction  Uni- and multivariate regression analyses then applied to 569 Phase III baseline genotypes (RESIST) with phenotype and genotype to validate mutations selected by Phase II datasets  Reduced TPV susceptibility or reduced response associated with 21 mutations at 16 positions:  10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V

62. 62 Treatment Response by TPV Score Number of TPV Score Mutations Baseline TPV Susceptibility (N) Q25,Q75 Change in VL* at 2 Weeks (N) Q25,Q75 Change in VL* at 24 Weeks (N) Q25,Q75 0 to 10.8(186) 0.5, 1.1-1.25(135) -0.91, -1.78-2.10(114) -0.82, -2.77 2 to 31.2(276) 0.7, 2.2-1.37(289)-0.79, -1.83-0.89(242)-0.21, -2.35 4 to 52.4(267) 1.2, 5.0-1.40(302)-0.57, -1.87-0.45(260) -0.03, -2.15 6 to 73.6(74) 2.1, 12.0-1.27 (76) -0.23, -1.81-0.49 (68) -0.03, -1.60 8+16.3(7) 4.9, 50.3-0.33 (4) +0.11, -0.83-0.08 (4) +0.01, -0.18 *Change in viral load was the change in HIV RNA from baseline through week 2 (OT) or week 24 (LOCF) in log 10 copies/mL.

63. 63 RESIST Studies Treatment Response by Phenotypic Resistance Enfuvirtide Use Fold-Change at Baseline in Tipranavir IC 50 Treatment Response at 24 Weeks in TPV/r Arm No0 to 375/193 (38.9%) >3 to 1010/53 (18.9%) >100/12 (0.0%) Yes0 to 345/61 (73.8%) >3 to 1012/32 (37.5%) >105/10 (50.0%)

64. 64 TPV/r Emergent Mutations Patients with paired baseline and on-treatment genotypes for assessment of emergence:  Phase II = 217  Phase III = 59  Total 276 Predominant emerging mutations with tipranavir are:  L33F/I/V, V82T/L and I84V  V82WT  V82L  V82A  V82T

65. 65 Predictors of TPV/r Antiviral Response Multiple Regression Model P ValueEstimate <0.010.17 TPV Score (per mutation) <0.01-0.24 Per Available Drug in OBR <0.01-0.91Enfuvirtide Use <0.01-1.25Tipranavir/r 24 Weeks Parameter

66. 66 For TPV Genotypic Resistance  Predominant emerging mutations with tipranavir are: L33F/I/V, V82T/L and I84V Tipranavir Resistance Conclusions  TPV has a high genetic barrier to resistance  TPV mutation score represents a unique group of protease gene mutations, and is most specific marker of TPV resistance  For TPV susceptibility:   3-Fold WTSusceptible  > 3 to 10-Fold Decreased Susceptibility  > 10-FoldResistance Fold-Change at Baseline in Tipranavir IC 50 Key Mutation Score (33, 82, 84, 90) Tipranavir Score 0 to 30 to 20 to 4 > 3 to 10 35 to 7 > 10 48+

67. 67 Utility of TPV Drug Levels Douglas Mayers, MD International Head, Therapeutic Area Virology

68. 68 RESIST Trials 2-Week Viral Load Reduction According to TPV Trough (µMol) N=23305253 42 52 43 42 110  

69. RESIST Trials Patients with Grade 3 or 4 ALT, AST or Bilirubin by TPV Trough 0 10 20 30 40 50 <2020 - <4040 - <8080 - <120  120 TPV Concentration (µMol) Percentage Gr 3-412262064 At Risk148234205429 69

70. TPV Trough Comparison in Patients With vs Without Grade 3 or 4 ALT, AST or Bilirubin 70

71. 71 RESIST Trials 24-Week VL Reductions vs TPV Trough Geom. Mean TPV Trough Levels (  M) VL Change From Baseline (log copies/mL)

72. 72 TPV Drug Level Conclusions  TPV trough levels > 6.5 uM associated with > 1 log VL response at 2 weeks  TPV trough levels > 120 uM associated with increased hepatic events  93% of patients have TPV trough levels between 6.5  120 uM  Weak trends associating TPV trough levels with hepatic events and treatment responses  Large inter-patient variability will limit the utility of these measurements in clinical practice

73. Potential Utility of Tipranavir in Current Clinical Practice Daniel R. Kuritzkes, MD Director of AIDS Research Brigham and Woman’s Hospital Division of AIDS Associate Professor of Medicine Harvard Medical School Boston, MA 73

74. 74 Conclusions Burkhard Blank, MD Senior Vice President Medicine and Drug Regulatory Affairs

75. 75 Tipranavir Conclusions 24-week RESIST data supports accelerated approval for TPV/r  Greater reductions in viral load and increases in CD4 cells than the best alternative protease inhibitors in this patient population  Adverse events similar to other CPI/r with mainly GI side effects  Increased adverse event rates for LFT and lipid elevations  Routine clinical and laboratory monitoring for most patients. Patients with elevated LFTs or HBV/HCV co-infection should have increased monitoring. Overall, TPV/r offers a significant new treatment option for PI treatment-experienced patients

76. 76 TPV Development Program Ongoing Studies  RESIST-1, RESIST-2  Treatment-naïve adults  Pediatrics  Emergency use, expanded access

77. 77 TPV Development Program Planned Studies Special populations  Cohorts of patients with cirrhosis or HBV/HCV co-infection  Additional studies in women Additional drug interaction trials  dNTP study with zidovudine and abacavir  Atazanavir, TMC-114, TMC-125, novel CCR5 antagonists  CYP/P-gp study to determine effect of TPV/r on individual CYPs  Methadone, buprenorphine  Tadalafil, carbamazepine, omeprazole

78. 78 Tipranavir Proposed Indication “Tipranavir, co-administered with low-dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients who are protease inhibitor treatment ‑ experienced.”

79. 79 May 19, 2005 Antiviral Drugs Advisory Committee APTIVUS ® (tipranavir) Capsules