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Agenda

Agenda. Update on Darunavir: Perry Mohammed Update on Etravirine: Rekha Sinha Update on TMC278: Peter Williams Update on TMC207: Karel De Beule HCV pipeline: Daniel de Schryver Questions and hopefully answers…. Darunavir . Once daily dosing Monotherapy Co-infection Formulation changes.

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Agenda

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  1. Agenda • Update on Darunavir: Perry Mohammed • Update on Etravirine: Rekha Sinha • Update on TMC278: Peter Williams • Update on TMC207: Karel De Beule • HCV pipeline: Daniel de Schryver • Questions and hopefully answers….

  2. Darunavir • Once daily dosing • Monotherapy • Co-infection • Formulation changes

  3. Once daily dosing • DRV/r currently licensed in treatment experienced patients • 600mg/100mg po bid • Positive CHMP approval Q408 • New indication: HIV naïve adult population • 800mg/100mg po od • Paediatric indication: Q309 • 75mg and 150mg tablets

  4. Once daily: treatment experienced patients?

  5. Darunavir/r 800/100 mg q.d.: trough levels remain above target concentrations 8000 6000 Plasma concentration of darunavir/r (ng/mL) 4000 Target concentration for HIV with FC ≤ 40* 2000 Target concentration for HIV with FC ≤ 10** 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours) *resistant virus **wild-type virus Tibotec. Data on file.

  6. The ODIN study Worldwide Treatment phase (48 weeks) DRV/r QD+ OBR n = 306 Pre-treated patients on stable HAART; VL > 1,000 copies/mL no DRV RAMs N = 612 DRV/r BID + OBR n = 306 • Primary endpoint: • non inferiority DRV/r QD vs DRV/r BID • Results available: Q1 10 Available from www.clinicaltrials.gov accessed November 2008

  7. Monotherapy

  8. MONET study • European study (13 countries, 250 patients) • First results expected Q309 Treatment phase (96 weeks) Follow-up (4 weeks) Screening phase (4 weeks) DRV/r 800/100 mg q.d. Follow-up Pre-treated patients on stable HAART DRV/r 800/100 mg q.d. plus 2 NRTIs Follow-up Tibotec, data on file.

  9. HBV/HCV co-infection

  10. ARTEMIS: Liver-related laboratory abnormalities in treatment-naive patients • Laboratory abnormalities, n (%) • PREZISTA/r qd • (N=343) • LPV/r qd or bid • (N=346) • Alanine aminotransferase (ALT) • Grade 2–4 • Grade 3–4 • Aspartate aminotransferase (AST) • Grade 2–4 • Grade 3–4 • 29 (8) • 12 (4) • 2 (9) • 13 (4) • 35 (10) • 17 (5) • 31 (9) • 10 (3) De Jesus E, et al. Oral Presentation at 47th ICAAC 2007.

  11. Co-infection and treatment-emergent liver-related AEs in treatment-naïve patients in ARTEMIS 13% (n=91) of patients in ARTEMIS were co-infected with HBV and/or HCV at baseline* †Occurring with an incidence 1% in either treatment group, regardless of severity & causality; laboratory abnormalities reported as AEs are included in the overall incidence of liver-related AEs, but not shown in the table Ortiz R, et al. HEP DART 2007. Abstract 94

  12. New formulations

  13. DRV/r dosing regimen for treatment-experienced patients • For treatment-experienced patients: administer from 2 x 300mg DRV tablets bid to 1 x 600mg DRV tablet bid 100mg RTV 100mg RTV 300mg DRV 600mg DRV • 100mg RTV capsule • 300mg DRV tablet (on the market) • 100 mg RTV capsule • 600mg DRV tablet

  14. DRV/r dosing regimen for treatment-naïve patients under development 100mg RTV 400mg DRV 1. 100mg RTV capsule 2. 400mg DRV tablet

  15. QD PK Study Design • Phase IIa, open label, single arm study (23 subjects enrolled) • Key eligibility criteria • ARV-naïve adults with HIV-1 • No evidence of resistance to study drugsa • HBV/HCV co-infection not allowed Treatment A Treatment B Treatment C Optional Extension Phase ETR 400mg qd + TDF/FTC 300/200mg qd ETR 400mg qd + TDF/FTC 300/200mg qd + DRV/r 800/100mg qd DRV/r 800/100mg qd + TDF/FTC 300/200mg qd DRV/r 800/100mg qd + TDF/FTC 300/200mg qd 14 days 42 weeks 14 days 14 days 24-hour PK analysis of etravirine 24-hour PK analysis of darunavir, ritonavir Fasting lipid assessment aBased on screening or historical resistance assays; presence of <3 ETR resistance-associated mutations (list of 13 RAMs) defined susceptibility to ETR

  16. Treatment B: ETR 400mg qd + TDF/FTC 300/200mg qd + DRV/r 800/100mg qd (n=20) Plasma Concentration-time Profile of ETR 400 mg qd Treatment A: ETR 400mg qd + TDF/FTC 300/200mg qd (n=21) 1200 1000 800 Mean ±SD plasma ETR concentration (ng/mL) 600 400 Protein binding-adjusted EC50 for WT virus (4 ng/mL) 200 0 0 4 8 12 16 20 24 Time (hours)

  17. Changes in Metabolic Parameters from Baseline Treatment A: ETR + TDF/FTC (Day 14) Treatment B: ETR + DRV/r + TDF/FTC (Day 28) Treatment C: DRV/r + TDF/FTC (Day 42) Baseline, median (range) 3.75 (2.84-5.74) 0.79 (0.40-2.81) 2.38 (1.53-3.59) 1.06 (0.78-1.55) 2 2 2 1 1 1 1 0.5 0.28 0.27 0.04 0.37 0.03 -0.16 0.01 -0.08 0 -0.03 -0.05 Median (range [IQR]) concentration, change from baseline, mmol/L -0.21 0 0 0 0 -1 -1 -1 -0.5 -2 -2 -2 -1 Total cholesterol Direct LDL cholesterol HDL cholesterol Triglycerides

  18. Changes in Metabolic Parameters from Baseline Treatment A: ETR + TDF/FTC (Day 14) Treatment B: ETR + DRV/r + TDF/FTC (Day 28) Treatment C: DRV/r + TDF/FTC (Day 42) Baseline, median (range) 5.05 (4.16-5.94) 5.00 (1.9-23.0) 3 36 27 2 18 1 Median (range [IQR]) concentration, change from baseline, mmol/L Median (range [IQR]) concentration, change from baseline, μU/mL 9 -0.11 -0.11 -0.08 0 -0.8 0 0 0 -1 -9 -2 -18 Glucose Insulin

  19. ETR 400 mg q.d. + BR + placebo 12 weeks ETR 400 mg q.d. + BR 12 weeks EFV 600 mg q.d. + BR + placebo Improving safety and convenience:efavirenz to etravirine switch study • Four UK- based hospitals (40 patients) • First results available Q409 Patients on EFV HAART with CNS or neuropsychiatric toxicity

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