1. Clinical Aspects of Treatment with Tipranavir Dr Kevin Curry Boehringer Ingelheim, Bracknell, UK

2. Profile and Pharmacokinetics

3. Tipranavir Profile The first in a new generation of PIs Non-peptidic structure: less Hydrogen bonds gives flexible binding Retains in vitro activity against >90% of HIV-1 strains resistant to first generation PIs Potent in vitro activity against wild-type HIV-1 and HIV-2 strains

4. Tipranavir Profile Wild Type EC 90 0.5-1.0  M Target C min for multiple PI resistant HIV-1 – 20 µM – 10x Protein adjusted EC 90 for multiple PI resistant HIV-1

5. Tipranavir Pharmacokinetics TPV exhibits linear pharmacokinetics TPV exposure is markedly enhanced by rtv TPV is a potent inducer of CYP3A – This is overwhelmed by rtv

6. ARV Naïve Patients Mean (+SD) Plasma Concentrations on Day 11 (SEDDS Formulation) Time (h) TPV Concentration (µM) 0 40 60 80 100 120 140 180 200 240 220 160 20 0123456 7 8 9101112 TPV 1,200 mg + rtv 200 mg bid TPV 300 mg + rtv 200 mg bid TPV 1,200 mg bid Target Cmin

7. Pharmacokinetics Conclusions All doses of TPV/rtv (except 250/200) had median C min >20 µM TPV induction of P450 3A4 was fully reversed by rtv co-administration rtv 200 provided more consistent P450 inhibition regardless of TPV dose

8. Studies in ARV Naïve Patients BI 1182.3

9. ARV Naïve Patients Study Design HIV-1 RNA  5,000 copies/mL CD4 count  50 cells/mm 3 Treatment arms: –TPV 1200mg (SEDDS) bid –TPV 300 mg (SEDDS) + rtv 200 mg bid –TPV 1200 mg (SEDDS) + rtv 200 mg bid

10. -2 -1.5 -0.5 0 3581115 TPV 1200 mg bid TPV 300 mg bid + rtv 200 mg bid TPV 1200 mg bid + rtv 200 mg bid Day on Therapy HIV-1 RNA (log 10 copies/mL) -1.44 log -1.63 log -0.77 log ARV Naïve Patients Mean Changes in Viral Load

11. Studies in Multiple PI Failure BI 1182.2

12. Multiple PI Failures Study Design Open-label, parallel groups HIV-1+, multi-PI–experienced, NNRTI-naive adults History of 2 or more PI-containing regimens – No wash-out period – No genotype or phenotype eligibility criteria Primary endpoint – Mean plasma HIV -1 RNA reduction at 48 weeks

13. Plasma HIV-1 RNA (log 10 copies/mL) CD4 + T cell count (cells/mm 3 ) 4.51 (3.87–5.21) 314 (38–1067) 4.46 (3.68–5.47) 290 (41–610) Low DoseHigh Dose Number of subjects 19 22 Multiple PI Failures Baseline Values

14. 32% 95% 53% 63% 55% 91% 68% 50% 44% 93% 61% 56% 0 20 40 60 80 100 IDVSQVNFVRTV Percent Prior Experience (N = 41) Low DoseHigh DoseTotal Multiple PI Failures Prior PI Experience

15. Low Dose High Dose TPV HFC 1200 mg bid + rtv 100 mg bid TPV HFC 2400 mg bid + rtv 200 mg bid TPV SEDDS 500 mg bid + rtv 100 mg bid + EFV 600 mg qd + 1 new NRTI TPV SEDDS 1000 mg bid + rtv 100 mg bid + EFV 600 mg qd + 1 new NRTI Most patients initially took TPV 300 mg (HFC), then switched to TPV 250 mg soft-gel capsules (SEDDS) when these became available. 7/41 received SEDDS alone. Multiple PI Failures Dosing

16. Low Dose, ITT-MCF High Dose, ITT-MCF Low Dose, AT-OC High Dose, AT-OC 0 20 40 60 80 100 48162448 Percent BLQ 93.8% 78.9% 78.6% 50.0% 0 Number of patients below detection 10141515 15 8121311 11 Weeks Multiple PI Failures Viral Load Reduction: BLQ<400

17. TPV 500/100 and 1000/100 effectively suppressed VL in multiple-PI–experienced patients at 48 weeks Patients taking 1000/100 had a higher incidence of adverse events, considered undesirable for chronic administration –The primary AEs seen for both doses were GI SEDDS formulation was better tolerated than the HFC formulation Multiple PI Failures Conclusions

18. Adverse Event and Laboratory Profiles

19. TPV 1200 mg N=10 TPV 300 mg +rtv 200 mg N=10 TPV 1200 mg +rtv 200 mg N=11 n (%) Fatigue 1 (10%)3 (30%)0 (0%) Diarrhea 6 (60%)3 (30%)7 (64%) Nausea 1 (10%)0 (0%)6 (54%) Vomiting 1 (10%) 2 (18%) ARV Naïve Patients (1182.3) Adverse Events

20. Gastrointestinal Diarrhea59% (15/24 Grade 1) Nausea31% Vomiting17% Non-gastrointestinal Headache39% Fatigue29% Dizziness27% Abnormal 27% dreams Insomnia24% NB. Not all these AEs were considered TPV-related Multiple PI Failure (1182.2) Most Common Adverse Events

21. Low DoseHigh Dose GGT, n (%)6 (31.6)4 (18.2) ALT2 (10.5)5 (22.7) AST03 (13.6) TG4 (21.1)4 (18.2) Cholesterol2 (10.5)2 (9.1) Multiple PI Failure (1182.2) Laboratory Abnormalities

22. Tipranavir Conclusions Co-administration with low dose rtv substantially enhances PK BID dosing with rtv 100/200 achieves target Cmin TPV induction on CYP450 is neutralized by rtv Promising efficacy in PI failure patients TPV/rtv is generally well tolerated - GI AEs are DAIDS Grade 1 to 2, self limited, or controllable with OTC medications