1. Overview of Drug Interactions Between Brecanavir (BCV) and Other HIV Protease Inhibitors (PIs) M Shelton, S Ford, M Anderson, S Murray, J Ng-Cashin XVI International AIDS Conference, Toronto, Canada, 13-18 August 2006, Abstract TUAB0105

2. 640385 (Brecanavir*, BCV) Potent new protease inhibitor Median IC 50 in PBMCs = 0.03 nM Range (0.02-0.10 nM) Substrate for CYP450 3A4 and p-gp Bioavailability significantly increased with RTV 100mg and meals No significant pharmacokinetic interaction with TFV, ZDV or 3TC Generally well tolerated Currently in Phase II development *USAN Approved Only

3. BCV Clinical Development Strategy (I) Resistance profile suggests BCV could be highly effective for treatment-experienced HIV patients For this population, dual RTV boosted PIs have been evaluated, but robust clinical data is sparse Negative interactions observed for dual RTV boosted PI regimens Tipranavir (TPV): lowered exposure other PI APV/Kaletra: lowered exposure to both PIs

4. BCV Clinical Development Strategy (II) PI interaction studies in healthy subjects First drug interactions with CYP substrates 3 separate studies were planned: 1 st Lopinavir/ritonavir (LPV/r) – HPR10004* 2 nd Atazanavir (ATV) – HPR10009* 3 rd Tipranavir (TPV) – HPR103377 * Ford S, et al. 7th International Workshop on Clinical Pharmacology of HIV Therapy, Lisbon, Portugal, 20 – 22 April, 2006 (posters 51 and 76)

5. BCV PI Drug Interaction Studies Different strategies: LPV/r and ATV – hypothesis testing evaluate combination relative to boosted PI TPV – estimation approach confirm anticipated TPV effects on BCV PK evaluate higher RTV dose (200mg) Different BCV doses (during dose ranging): LPV/r and ATV - BCV 300mg /RTV 100mg BID TPV - BCV 600mg /RTV 100mg BID

6. Study Design for LPV/r & ATV Studies ArmSample Size Period 1 Days 1-14 Washout 21-28 Days Period 2 Days 1-14 A12PIBCV/r + PI B12BCV/r + PIPI C12BCV/rBCV/r + PI D12BCV/r + PIBCV/r Study Design for TPV Study ArmSample Size Period 1 Days 1-10 Period 2 Days 1-10 A12BCV/rBCV/r + PI B12BCV/rBCV + RTV 200mg BCV 300mg BCV 600mg

7. Protease Inhibitor PK Comparisons Drugn GLS Mean Ratio (90% CI) AUC (ng  h/mL) Cmax (ng/mL) C  (ng/mL) LPV/r23 1.02 (0.94, 1.11) 1.01 (0.94, 1.08) 1.08 (0.94, 1.24) ATV16 1.44 (1.32, 1.58) 1.21 (1.12, 1.30) 2.11 (1.81, 2.45) TPV PK was not evaluated due to premature discontinuation prior to attainment of steady-state conditions for TPV

8. ATV/r = 300mg/100mg q24h BCV/r + ATV = 300mg/100mg q12h + 300mg q24h ATV Increased by Addition of BCV to ATV/r

9. BCV PK Comparisons Drugn GLS Mean Ratio (90% CI) AUC(0-  ) (ng  h/mL) Cmax (ng/mL) C  (ng/mL) LPV/r21 0.84 (0.75, 0.93) 0.88 (0.80, 0.98) 0.86 (0.73, 1.02) ATV/r18 1.38 (1.25, 1.53) 1.48 (1.29, 1.71) 1.44 (1.25, 1.65) Extra RTV (200mg total) 11 1.15 (0.99, 1.35) 1.10 (0.92, 1.32) 1.06 (0.93, 1.20) TPV Day 5 C  ratio 0.53 (non-steady state)

10. BCV Increased by Addition of ATV to BCV/r BCV/r = 300mg/100mg q12h BCV/r + ATV = 300mg/100mg q12h + 300mg q24h

11. Minor Reduction in BCV Combined with LPV/r BCV/r = 300mg/100mg q12h LPV/r + BCV = 400mg/100mg q12h + 300mg q12h Time (h) 024681012 Plasma BCV (ng/mL) 50 100 150 200 250 300 BCV/r (C+D) LPV/r + BCV (C+D)

12. Hepatic Transaminases in TPV Study BCV 600mg + RTV 200mg + TPV 500mg q12h 7/12 subjects had increased ALT Maximum DAIDS Toxicity Criteria Grade 1 (N=3), Grade 2 (N=2), Grade 3 (N=2) Regimen terminated prematurely low risk tolerance, high probability of interaction Elevations returned to baseline following d/c BCV 600mg + RTV 200mg q12h 1/12 subjects with Grade 1 increase in ALT Regimen completed as planned

13. Study Safety Summary LPV/r study (HPR10004): Combination generally well-tolerated (expected AEs) ATV study (HPR10009): No SAEs, clinically significant trends in vitals/ECGs Total AEs and ocular icterus more common with ATV Increased bilirubin common with ATV, none with BCV/r Treatment discontinuations and Grade 4 elevations in total bilirubin more common for combination TPV study (HPR103377): BCV with TPV 500mg + RTV 200mg regimen was discontinued prematurely due to hepatic transaminase elevations BCV with RTV 200mg regimen generally well tolerated – no treatment-related discontinuations

14. Phase I Summary of Drug Related AEs (  5%)* Adverse Event BCV 300mg/r N=72 BCV 600mg/r N=32 Any Event31 (43%)9 (38%) Gastrointestinal16 (22%)7 (22%) Diarrhea6 (8%)3 (9%) Nausea3 (4%)3 (9%) Flatulence4 (6%)0 Nervous System9 (13%)6 (19%) Headache6 (8%)2 (6%) Dizziness2 (3%)3 (9%) Skin/Subcutaneous7 (10%)0 Pruritis5 (7%)0 Rash5 (7%)0 * Phase I studies conducted in healthy subjects

15. Conclusions BCV may be co-administered with LPV/r without dose adjustment For BCV/r + ATV, plasma exposure to both BCV and ATV increased. Clinical significance unknown, but ATV dose reduction may be considered. BCV should not be co-administered with TPV/r due to reduced plasma BCV trough concentrations Potential for increased hepatic transaminases in patients RTV 200mg does not significantly increase steady- state plasma BCV exposure Dual boosted PI options for BCV include LPV/r and ATV