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

Profile and Pharmacokinetics

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

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

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

ARV Naïve Patients Mean (+SD) Plasma Concentrations on Day 11 (SEDDS Formulation) Time (h) TPV Concentration (µM) TPV 1,200 mg + rtv 200 mg bid TPV 300 mg + rtv 200 mg bid TPV 1,200 mg bid Target Cmin

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

Studies in ARV Naïve Patients BI

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

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) log log log ARV Naïve Patients Mean Changes in Viral Load

Studies in Multiple PI Failure BI

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

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 Multiple PI Failures Baseline Values

32% 95% 53% 63% 55% 91% 68% 50% 44% 93% 61% 56% IDVSQVNFVRTV Percent Prior Experience (N = 41) Low DoseHigh DoseTotal Multiple PI Failures Prior PI Experience

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

Low Dose, ITT-MCF High Dose, ITT-MCF Low Dose, AT-OC High Dose, AT-OC Percent BLQ 93.8% 78.9% 78.6% 50.0% 0 Number of patients below detection Weeks Multiple PI Failures Viral Load Reduction: BLQ<400

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

Adverse Event and Laboratory Profiles

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

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

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

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