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, August 2006, Abstract TUAB0105

(Brecanavir*, BCV) Potent new protease inhibitor Median IC 50 in PBMCs = 0.03 nM Range ( 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

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

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) – HPR * Ford S, et al. 7th International Workshop on Clinical Pharmacology of HIV Therapy, Lisbon, Portugal, 20 – 22 April, 2006 (posters 51 and 76)

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

Study Design for LPV/r & ATV Studies ArmSample Size Period 1 Days 1-14 Washout 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

Protease Inhibitor PK Comparisons Drugn GLS Mean Ratio (90% CI) AUC (ng  h/mL) Cmax (ng/mL) C  (ng/mL) LPV/r (0.94, 1.11) 1.01 (0.94, 1.08) 1.08 (0.94, 1.24) ATV (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

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

BCV PK Comparisons Drugn GLS Mean Ratio (90% CI) AUC(0-  ) (ng  h/mL) Cmax (ng/mL) C  (ng/mL) LPV/r (0.75, 0.93) 0.88 (0.80, 0.98) 0.86 (0.73, 1.02) ATV/r (1.25, 1.53) 1.48 (1.29, 1.71) 1.44 (1.25, 1.65) Extra RTV (200mg total) (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)

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

Minor Reduction in BCV Combined with LPV/r BCV/r = 300mg/100mg q12h LPV/r + BCV = 400mg/100mg q12h + 300mg q12h Time (h) Plasma BCV (ng/mL) BCV/r (C+D) LPV/r + BCV (C+D)

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

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

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

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