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Antiviral Drugs Advisory Committee APTIVUS ® ( tipranavir) Capsules

Antiviral Drugs Advisory Committee APTIVUS ® ( tipranavir) Capsules. May 19, 2005. Introduction. Burkhard Blank, MD Senior Vice President Medicine and Drug Regulatory Affairs. Clinical Need. Growing population of treatment-experienced HIV+ patients with limited treatment options

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Antiviral Drugs Advisory Committee APTIVUS ® ( tipranavir) Capsules

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

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

  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. Tipranavir • Shows significant antiviral activity against the majorityof 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. 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. Tipranavir DevelopmentDouglas Mayers, MD EfficacyScott McCallister, MDDrug-Drug Interactions SafetyChristopher Corsico, MD ResistanceDouglas Mayers, MD Clinical UtilityDaniel Kuritzkes, MD ConclusionsBurkhard Blank, MD Presentation Overview

  7. Angela D.M. Kashuba, PharmD University of North Carolina- Chapel Hill Daniel R. Kuritzkes, MDHarvard Medical School Jens D. Lundgren, MDUniversity of CopenhagenDenmark Consultants Available to the Committee Joel Morganroth, MDUniversity of Pennsylvania Jonathan M. Schapiro, MDStanford University Schoolof Medicine Mark Sulkowski, MDJohns Hopkins University School of Medicine

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

  9. CH3 OH H3C O O NH SO2 N F3C TipranavirOverview • 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)

  10. TipranavirDevelopment • 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 toFDA 22 December 2004 • Based on 24-week efficacy/safety data

  11. TipranavirClinical 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. 125 100 4x Cmaxss 75 Mean PlasmaTipranavir Concentration (M) 50 9x greater exposure at steady-state 25 48x Cminss Target 0 0 2 4 6 8 10 12 Time (h) TPV/r 500/200mg TPV 500mg alone TipranavirCo-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

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

  15. TipranavirDose 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. TipranavirKey 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. RESIST Pivotal Trial Program Scott McCallister, MD Global Medical Team Leader, TPV

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

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

  22. RESIST Studies24-Week Endpoints Primary endpoint: treatment response defined as: Confirmed  1 log10 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. RESIST StudiesEarly 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 availableat the time of trial initiation • Study would have enrolled extremely slowly

  24. RESIST StudiesBaseline Demographics

  25. RESIST StudiesBaseline 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. RESIST StudiesBaseline PI Phenotype Analysis of randomly selected samples Median Fold Change in IC50 N= (454) (452) (423) (450) (445) (452) (449) (456)

  27. RESIST StudiesPre-Selected Comparator PIs

  28. RESIST StudiesPrimary Efficacy Results

  29. 60 50 40 Treatment Responders (%) 30 20 10 0 0 8 16 24 CPI/r (n=577) TPV/r (n=582) RESIST StudiesTreatment Response RESIST Studies Combined (41.2) Week 24: P <0.0001 (18.9) 1 log10 Viral Load Reduction, Confirmed, ITT: NCF Weeks

  30. ITT: NCF 40 (34.2%) 35 30 Week 24: P <0.0001 25 Virologic ResponseVL <400 Copies/mL (%) 20 15 (14.9%) 10 5 0 0 8 16 24 40 35 30 (23.9%) 25 Virologic ResponseVL <50 Copies/mL (%) 20 Week 24: P <0.0001 15 10 (9.4%) 5 0 0 8 16 24 CPI/r (n=577) TPV/r (n=582) RESIST StudiesUndetectable Viral Load (<400, <50 copies/mL) Weeks of Treatment

  31. ITT: LOCF (0.25 log10 copies/mL) 0 -0.2 -0.4 Week 24: P <0.0001 -0.6 -0.8 Median VL log10 Change From Baseline -1 (0.80 log10 copies/mL) -1.2 -1.4 -1.6 -1.8 0 8 16 24 40 (+34 cells, range 3-87) 35 30 25 Median Change From Baseline in CD4+ Cell Count Week 24 difference: P <0.0001 20 15 (+4 cells, range 0-61) 10 5 0 0 8 16 24 TPV/r (n=582) CPI/r (n=577) RESIST StudiesVL Reduction and CD4 Increase Weeks of Treatment

  32. RESIST StudiesEfficacy Endpoints (Week 24)

  33. RESIST StudiesTreatment Response in Patients Using Enfuvirtide N=34 N=43 N=115 N=94

  34. TipranavirEfficacy Conclusions TPV/r was superior at 24 weeks to comparator PIs in two well-controlled studies with PI treatment-experienced patients • Treatment response (1 log10 VL reduction) • Absolute VL reduction from baseline • Proportion of patients with undetectable VL (<400, <50 copies/mL) • CD4+ cell count increase

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

  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. 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 Cmin 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 Cmin reduced 34% and AUC unchanged

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

  39. Dual Boosted Protease Inhibitors • 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. TPV/r Drug InteractionConclusions 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. 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 Potential Drug Interactions with TPV/r

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

  43. Tipranavir Safety DatabaseSafety Update – September 30, 2004 • 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 Phase I, II and 1182.51N = 894 RESIST TPV/rN = 748 Total HIV + patients treated with TPV/r N = 3367 Long Term Follow Up N = 474 RESIST CPI/r N = 737 EUP/EAPN = 879 Rollover to TPV/rN = 298 PediatricN = 74

  44. RESIST StudiesPatients Remaining on Study N=715 N=576 N=703 N=285

  45. RESIST StudiesAdverse Events >5%

  46. RESIST StudiesAdverse Events >5% (continued)

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

  48. Risk of MST Rash Among TPV Recipients in RESIST:CD4 Baseline Fixed logistic regression model among TPV/r recipients in RESIST. Variables shown are all variables tested in the model.

  49. Rash 2 9 9 2 No Rash 16 30 32 17 RESIST StudiesFemale Patients on TPV/r Who Developed Rash by CD4

  50. Grade 3 or 4 ALT, AST or Total Bilirubin Actions Taken and Outcomes

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