1	Antiviral Drugs Advisory Committee APTIVUS^® (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 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	Tipranavir – Proposed Indication
6	Presentation Overview Tipranavir Development Douglas Mayers, MD Efficacy Scott McCallister, MD Drug-Drug Interactions Safety Christopher Corsico, MD Resistance Douglas Mayers, MD Clinical Utility Daniel Kuritzkes, MD Conclusions Burkhard Blank, MD
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
8	Tipranavir Development Douglas Mayers, MD International Head, Therapeutic Area Virology
9	"Novel nonpeptidic protease inhibitor developed..." 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	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	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	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
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	Tipranavir Phase II-III Study Program
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	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	RESIST Pivotal Trial Program Scott McCallister, MD Global Medical Team Leader, TPV
18	Tipranavir Phase II-III Study Program
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	RESIST Studies Key Inclusion/Exclusion Criteria Inclusion ³ 3 months’ therapy with NRTIs, NNRTIs, and PIs ³ 2 PI regimens for ³ 3 consecutive months One PI must be current regimen Viral load ³ 1000 copies/mL on therapy, any CD4+ cell count Baseline genotype ³ 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 Studies Screening and Randomization
22	RESIST Studies 24-Week Endpoints Primary endpoint: treatment response defined as: Confirmed ³ 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 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	RESIST Studies Baseline Demographics
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	RESIST Studies Baseline PI Phenotype
27	RESIST Studies Pre-Selected Comparator PIs
28	RESIST Studies Primary Efficacy Results
29	RESIST Studies Treatment Response
30	RESIST Studies Undetectable Viral Load (<400, <50 copies/mL)
31	RESIST Studies VL Reduction and CD4 Increase
32	RESIST Studies Efficacy Endpoints (Week 24)
33	RESIST Studies Treatment Response in Patients Using Enfuvirtide
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 (³1 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
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
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	Tipranavir Phase II-III Study Program
39	Dual Boosted Protease Inhibitors
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	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	Tipranavir Safety Christopher Corsico, MD, MPH Head, Drug Surveillance and Information
43	Tipranavir Safety Database Safety 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
44	RESIST Studies Patients Remaining on Study
45	RESIST Studies Adverse Events >5%
46	RESIST Studies Adverse Events >5% (continued)
47	RESIST Studies Gender and Rash
48	Risk of MST Rash Among TPV Recipients in RESIST: CD4 Baseline
49	RESIST Studies Female Patients on TPV/r Who Developed Rash by CD4
50	Grade 3 or 4 ALT, AST or Total Bilirubin Actions Taken and Outcomes
51	RESIST Studies Cox Regression Model for Risk of Grade 3 or 4 ALT/AST
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
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54	RESIST Studies Mortality – Kaplan Meier
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	Resistance Douglas Mayers, MD International Head, Therapeutic Area Virology
57	Tipranavir Phase II-III Study Program
58	BI 1182.51 Study Design
59	1182.51 HIV RNA Median Change from Baseline at 2 Weeks: Comparative TPV, LPV, SQV, APV
60	Treatment Response by Key Mutations
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	Treatment Response by TPV Score
63	RESIST Studies Treatment Response by Phenotypic Resistance
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	Predictors of TPV/r Antiviral Response Multiple Regression Model
66	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 WT Susceptible > 3 to 10-Fold Decreased Susceptibility > 10-Fold Resistance
67	Utility of TPV Drug Levels Douglas Mayers, MD International Head, Therapeutic Area Virology
68	RESIST Trials 2-Week Viral Load Reduction According to TPV Trough (µMol)
69	RESIST Trials Patients with Grade 3 or 4 ALT, AST or Bilirubin by TPV Trough
70	TPV Trough Comparison in Patients With vs Without Grade 3 or 4 ALT, AST or Bilirubin
71	RESIST Trials 24-Week VL Reductions vs TPV Trough
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
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74	Conclusions Burkhard Blank, MD Senior Vice President Medicine and Drug Regulatory Affairs
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	TPV Development Program Ongoing Studies RESIST-1, RESIST-2 Treatment-naïve adults Pediatrics Emergency use, expanded access
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	Tipranavir Proposed Indication
79	Antiviral Drugs Advisory Committee APTIVUS^® (tipranavir) Capsules May 19, 2005