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Introduction

Introduction. Geraldine Reilly Gilead Science. Objectives. To review TDF interaction data To review triple nucleoside data To discuss the relevance of these data to clinical practice To present the EMTRIVA dataset

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Introduction

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  1. Introduction Geraldine Reilly Gilead Science

  2. Objectives • To review TDF interaction data • To review triple nucleoside data • To discuss the relevance of these data to clinical practice • To present the EMTRIVA dataset • To discuss questions regarding Emtriva and requirements for additional data or information • To review TDF safety data

  3. EMTRIVA™(emtricitabine) • Nucleoside (cytosine) analogue • One capsule, once daily, without food restrictions • Long intracellular half-life • Significant HIV RNA reductions • Favorable safety profile • Durable efficacy and safety in treatment-naïve and treatment-experienced patients

  4. Mean Steady-State Plasma Emtricitabine Concentration Following 200 mg QD Dose 10 1 Plasma half-life ~ 10 hours Plasma Emtricitabine Conc (µg/mL) 0.1 Mean In Vitro IC90 0.01 Mean In Vitro IC50 0.001 0 24 48 72 96 120 Time (hrs post dose) Wang L, et al. XIV International AIDS Conference, Barcelona 2002, Poster #4546

  5. Intracellular FTC-TP Concentration Following 200 mg QD Dose¹ 10 FTC-TP mean half-life ~ 39 hours 1 FTC-5'-TP Conc in PBMC (pmole/106cells 0.1 3TC-TP mean half-life ~ 16 hours² 0.01 0 24 48 72 96 120 Time (hrs post dose) 1Wang L, et al. XIV International AIDS Conference, Barcelona 2002, Poster #4546 2Moore K., et al, AIDS 1999;13:2239-50

  6. ** * ** Pharmacokinetic Considerations for Approved and Investigational Once-daily NRTIs Investigational Approved Approved Approved Approved QD as QD or BID as QD or BID as QD as QD 50 45 40 35 30 Hours 25 24 hours 20 15 12 hours 10 5 0 ZDV d4T ABC 3TC ddI FTC TDF Indicates range where available Serum half-life Intracellular half-life * Piliero, et al. 43rd ICAAC, Chicago, 2003. ** Anderson, et al. AIDS 2003; 17(15):2159-2168. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002;51(RR-7):1-64

  7. BID QD short half-life QD long half-life Forgiveness and Once-dailyAntiretroviral Therapy (ART) Missed Dose Day 1 Day 2 Hypothetical and notrepresentative of specificARV agents Drug concentration IC90 Zone of potential replication IC50 12 0 24 36 48 Time (hours)

  8. Emtricitabine Pharmacology • Once-daily dosing • Serum t1/210 hours • Long intracellular half-life (FTC-TP); t1/2 39 hours • Can be taken without regard to food • 93% in fed or fasted state • Renally cleared • 83% cleared through the kidneys • Dosage reduction required in renally impaired patients • Few drug interactions • Not a substrate or inhibitor of human CYP450 enzymes • No known clinically significant drug interactions • Pregnancy Category B

  9. EmtricitabineMonotherapy Studies Design Patient Population Study 101 Monotherapy 14-day dosing (n=41) 3TC and ABC naive Study 102 Monotherapy 10-day dosing vs 3TC (n=81) 3TC and ABC naive

  10. Study 101Emtricitabine Antiviral Activity During Short Term (14 days) Monotherapy 0.5 25 mg bid (n = 9) 100 mg qd (n = 8) 0.0 100 mg bid (n = 8) 200 mg qd (n = 8) Mean Changein HIV-1 RNA (log10) –0.5 200 mg bid (n = 8) –1.0 –1.5 -1.92 log –2.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Study Day F. Rousseau, et al. JAC(2001) 48, 507-513

  11. Study 102Emtricitabine Antiviral Activity Compared to Lamivudine150 mg BID in Short Term (10 Days) Monotherapy 0 3TC 150 mg bid (n=20) FTC 25 mg qd (n=21) –0.5 FTC 100 mg qd (n=19) FTC 200 mg qd (n=21) Mean Change in HIV-1 RNA (Log10) –1.0 p<0.05* -1.5 log –1.5 -1.7 log –2.0 1 2 3 4 5 6 7 8 9 10 11 12 Study Day *p<0.05 for FTC 200 mg QD compared to each of the other treatment arms Delehanty J. et al, 6th CROI. Chicago 1999. Abstract #16

  12. Study 102Emtricitabine Antiviral Activity Compared to Lamivudine150 mg BID in Short Term (10 Days) Monotherapy 0 3TC 150 mg bid (n=20) –0.5 FTC 200 mg qd (n=21) Mean Change in HIV-1 RNA (Log10) –1.0 p<0.05* -1.5 log –1.5 -1.7 log –2.0 1 2 3 4 5 6 7 8 9 10 11 12 Study Day *p<0.05 for FTC 200 mg QD compared to each of the other treatment arms Delehanty J. et al, 6th CROI. Chicago 1999. Abstract #16

  13. Summary: Preclinical and PK • In vitro preclinical findings • 10-fold greater relative substrate specificity for HIV-1 RT than 3TC • 24-fold less relative substrate specificity for mtDNA gamma polymerase • Pharmacokinetics clearly support QD dosing • Plasma half life of 10 hours with linear kinetics and plasma values > IC90 ~ 84 hrs • Triphosphate intra-cellular half life ~ 39 hrs • Potent antiviral activity • 1.92 log10 reduction in plasma HIV-1 RNA after 14 days of monotherapy (FTC-101) • Statistically greater reduction in plasma HIV-1 RNA after 10 days of monotherapy compared to 3TC (FTC-102)

  14. ANRS 091(MONTANA) FTC/ddI/EFV - Open Label (n=40) HIV RNA >5000 copies/ml CD4 >100 cells/mm³ Study 301 FTC vs d4T [+ddI/EFV] (n=571) HIV RNA >5000 copies/ml CD4: no restriction Clinical Program Overview:Efficacy and Safety Studies Design Patient Population Treatment-Naïve Studies Switch Studies ANRS 099(Alize) PI switch to FTC/ddI/EFV (n=355) HIV RNA <400 copies/ml CD4: no restriction Study 303 3TC switch to FTC in 3TC-stable patients(n=440) HIV RNA <400 copies/ml CD4: no restriction

  15. Study 301

  16. Study 301 Study Design Week 48 ART-naive patients (N = 571) randomized 1:1, double-blind Week 48 Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.

  17. Study 301Baseline Characteristics FTC+ddI+EFV (n=286) d4T+ddI+EFV (n=285) Mean age (y) 36 36 Male 84% 86% Caucasian 48% 56% Mean HIV-1 RNA (log10) 4.8 4.8 Mean CD4 count (cells/mm3) 312 324 HIV-1 RNA >100,000 (%) 41 40 Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.

  18. Study 301Patient Disposition at Week 48 *p<0.05 Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.

  19. Intent to Treat (Missing = Failure) 100 74% 58% 80 60 % Patients with HIV-1 RNA < 50 copies/mL FTC+ddI+EFV d4T+ddI+EFV 40 p = 0.0001 20 0 BL 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Study 301 % Patients < 50 copies/mL Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.

  20. As Treated (Missing = Excluded) 100 91% 84% 80 FTC+ddI+EFV 60 d4T+ddI+EFV % Patients with HIV-1 RNA < 50 copies/mL 40 20 0 BL 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Study 301 % Patients < 50 copies/mL p<0.05 Data on file. Gilead Sciences, Inc. June 2003.

  21. Intent to Treat (Missing = Failure) 200 168 134 160 120 Mean Change From Baseline - Absolute CD4+ Cell Count FTC+ddI+EFV d4T+ddI+EFV 80 p = <0.05 40 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Study 301Mean Change From Baseline in Absolute CD4+ Data on file. Gilead Sciences, Inc. June 2003.

  22. Adverse Events FTC + ddI + EFV (n=286) D4T+ddI+EFV (n=285) Abdominal Pain Headache Asthenia 14% 22% 12% 17% 25% 17% Diarrhea** Nausea** Dyspepsia Vomiting 23% 13% 8% 9% 32% 23% 12% 12% Dizziness Insomnia Abnormal dreams** Neuropathy/Peripheral neuritis** Paresthesia** Depressive disorders 25% 16% 11% 4% 6% 9% 26% 21% 19% 13% 12% 13% Study 301Selected* Treatment-Emergent Adverse EventsThrough 48 Weeks (All Grades, Regardless of Causality) p<0.05* * * Reported in > 3% of FTC-treated patients in Study 301 or 303 Only events that occurred in > 10% in either arm were analyzed for statistical significance.

  23. Adverse Events FTC + ddI + EFV (n=286) D4T+ddI+EFV (n=285) Rash event 30% 33% Rhinitis Increased cough** 12% 14% 10% 8% Myalgia Arthralgia 6% 5% 3% 6% Study 301Selected* Treatment-Emergent Adverse EventsThrough 48 Weeks (All Grades, Regardless of Causality) p<0.05* * * Reported in > 3% of FTC-treated patients in Study 301 or 303 Only events that occurred in > 10% in either arm were analyzed for statistical significance.

  24. Number of Patients Treated FTC + ddI + EFV (n=286) D4T+ddI+EFV (n=285) Percentage with Grade 3 or Grade 4 laboratory abnormality 34% 38% Creatinine Kinase (>4.0 x ULN) 12% 11% AST (>5.0 x ULN) 6% 9% ALT (>5.0 x ULN) 5% 6% Bilirubin (>2.5 x ULN) <1% <1% Study 301Treatment-Emergent Grade 3/4 Laboratory Abnormalities* Through 48 Weeks * Reported in > 1% of FTC-treated patients in Study 301 or 303 ** Only events that occurred in > 10% in either arm were analyzed for statistical significance.

  25. Number of Patients Treated FTC + ddI + EFV (n=286) D4T+ddI+EFV (n=285) Serum lipase (>2.0 x ULN) 1% 2% Serum amylase (>2.0 x ULN)** 5% 10% Pancreatic amylase (>2.0 x ULN) <1% 1% Serum Glucose (<40 or >250 mg/dL) 2% 3% Triglycerides (>750 mg/dL) 9% 6% Neutrophils (<750 mm3) 5% 7% Study 301Treatment-Emergent Grade 3/4 Laboratory Abnormalities* Through 48 Weeks, Cont p<0.05* * * Reported in > 1% of FTC-treated patients in Study 301 or 303 Only events that occurred in > 10% in either arm were analyzed for statistical significance.

  26. Study 301Virology • FTC-resistant isolates have been selected in vitro • Genotypic analyses demonstrated M184V or M184I mutation • 37.5 % (6/16) of isolates from FTC-treated patients with virologic failure in study 301 showed reduced susceptibility to FTC associated with the development of the M184V/I mutation

  27. Study 301DSMB Interim Analysis Review • Interim Analysis: • After last enrolled patient completed 24-weeks of treatment • Median duration of follow-up was 42-weeks • Efficacy and safety data • Results presented at the 42nd ICAAC, September 2002 • DSMB Recommendation: • Termination of the double-blind comparative phase of study • d4T-treatment group discontinued and all patients offered open-label access to the FTC-treatment group • Study Completion: • After last enrolled patient completed 48-weeks of treatment • Median duration of follow-up was 60-weeks • Update of efficacy and results

  28. FTC in Treatment-naïve Patients: Conclusions • FTC+ddI+EFV is a convenient, potent and well- tolerated once-daily regimen in ARV-naïve patients • Durable efficacy reported to 3 years (MONTANA) • Once-daily FTC demonstrated superior efficacy and safety as compared to twice-daily d4T (FTC 301)

  29. Dose and Dose Interval Adjustments of NRTIs for Patients with Renal Impairment Drug Renal Impairment CBV Not recommended TZV Not recommended AZT Dose adjust per guidelines 3TC Dose adjust per guidelines FTC Dose interval adjust per guidelines TDF Dose interval adjust per guidelines d4T Dose adjust per guidelines ddI EC Dose adjust per guidelines ABC Unknown

  30. Emtricitabine: Dose Interval Adjustment in Renal Impairment

  31. ARV Pregnancy Categorization • Category B:TDF, FTC, ddI • - NFV, RTV, SQV, T-20 • Category C: CBV, TRZ, 3TC, AZT, d4T, ABC, ddC • - DLV, NVP, EFV, APV, IDV, IDV/r, fos-APV/r • Category D: Hydroxyurea

  32. FDA Pregnancy Categories – Definitions* • A: Controlled studies in women in first trimester show no risk • B: Animal studies do not indicate risk OR human studies show no risk to fetus (although animal studies may show adverse effect) • C: Animal studies show adverse effects (teratogenic or embryocidal); no controlled studies in pregnant women; weigh benefits versus risks • D: Positive evidence of human risk; benefits may outweigh risks for serious diseases where alternatives not available • X: Risk shown; risk outweighs benefit *FDA Federal Register

  33. Hyperpigmentation • Hyperpigmentation was rare and generally mild and non-progressive • 3% (29/814) of patients in studies 301,302,303 • 28/29 Grade 1; 1/29 Grade 2 • Only 2 progressed from Grade 1 to 2 • Observed primarily on the palms/soles after 3 months • Median time to onset 88 days • Occurred at a higher rate in black patients (8%) • Never required FTC discontinuation • Resolved in some patients (5/29) while on treatment Emtricitabine NDA filing June 2003

  34. Hyperpigmentation of the Palms

  35. Nail Discoloration Observed with AZT • Observed primarily on fingernails and toenails1-3 • Color ranges from dark brown to purple1-3 • Onset: 4 months to 1 year after starting AZT1-4 • Incidence: • In a study of Combivir (AZT/3TC) + ABC, the incidence of nail discoloration was 5.7%4 • In two retrospective studies, the incidence was 42% and 39%, respectively2,3 • Of those who developed it, 67-82% were African American2,3 1 Rahav et l. Scan J Infect Dis 1992; 24:557-61 2 Groark et al. J Am Acad Dermatol 1989; 21:1032-3 3 Don et al. Ann Intern Med 1990; 112-145-6 4 GlaxoWellcome Medical Information

  36. Emtricitabine Virology

  37. Triple NRTI ComparisonsIncidence of the M184V/I Mutation in Patients who Experienced Virological Failure 100% Historical Studies of ABC/3TC/ZDV 90% 78% 80% 74% 73% 70% 67% 67% 60% 52% 50% 40% 30% 20% p < 0 .02 10% 0% FTC + All 3TC + CNAAB3005 CNAA3003 EPV40001 QD EPV40001 BID d4T+ABC AZT+ABC • Incidence of M184V/I mutation was significantly lower for FTC regimen compared to 3TC+ AZT+ABC regimens (-21% treatment difference with a 95% CI [-37%, -5%]; p < 0.02) Sanne I, et al. 43rd ICAAC, Chicago, 2003, #H-868.

  38. Future StudiesDiscussion

  39. The Future: TDF/FTC Fixed Dose Combination Tablet Tenofovir and Emtricitabine fixed dose combination Study 934 in progress TDF/FTC/EFV vs COM/EFV Bioequivalence and stability studies in progress

  40. Other Studies • TDF + FTC backbone -- • What other studies should be performed to better characterize the clinical role of this NRTI backbone? • Specific regimens or third agents? • Different patient populations? • Other?

  41. Other Studies • EMTRIVA -- • What other studies should be performed to better characterize Emtriva and its place in clinical care? • Comparative trials? • Different patient populations? • Other?

  42. Emtriva & VireadSummary of Similar Characteristics • Durable efficacy in clinical trials • Both Emtriva and Viread have shown efficacy in both treatment-naïve and treatment-experienced patients • Tolerability and safety • Convenience • Both one tablet dosed once-daily • Pharmacokinetics • Both have long intracellular half-lives, true once-daily dosing • Both can be taken without regard to food • Co-infection • Though not indicated for hepatitis B, both have demonstrated potency against hepatitis B in co-infected patients

  43. Thank you!

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