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Tenofovir Disoproxil Fumarate

Tenofovir Disoproxil Fumarate. NDA 21-356 October 3, 2001 Gilead Sciences, Inc. Foster City, CA. Gilead Consultants. Harry K. Genant, M.D. Professor of Radiology, Orthopedic Surgery and Medicine University of California, San Francisco Robert T. Schooley, M.D.

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Tenofovir Disoproxil Fumarate

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  1. Tenofovir Disoproxil Fumarate NDA 21-356 October 3, 2001 Gilead Sciences, Inc. Foster City, CA

  2. Gilead Consultants Harry K. Genant, M.D. Professor of Radiology, Orthopedic Surgery and Medicine University of California, San Francisco Robert T. Schooley, M.D. Chair, Adult AIDS Clinical Trials Group (AACTG) Executive Committee Head, Division of Infectious Diseases, and Tim Gill Professor of Medicine University of Colorado Health Sciences Center Steven L. Teitelbaum, M.D. Wilma and Roswell Messing Professor of Pathology and Immunology Washington University, St. Louis

  3. Tenofovir Disoproxil Fumarate (TDF) Overview of Development Program Norbert Bischofberger, Ph.D. Clinical Trial Results Jay Toole, M.D., Ph.D. Concluding Remarks Norbert Bischofberger, Ph.D.

  4. NH 2 N O N O N N O O O P O O O O O Tenofovir Disoproxil Fumarate (TDF) • Orally bioavailable prodrug of tenofovir (PMPA) • Nucleotide RTI • One tablet, once daily • Durable activity against nucleoside resistant HIV

  5. In Vitro Virology • Active in vitro against recombinant HIV with • ZDV resistance (D67N, K70R or T215Y) • ddl resistance (L74V) • ddC resistance (T69D) • multinucleoside drug resistance (Q151M complex) • Increased activity against HIV with 3TC resistance (M184V) • Can select in vitro for the K65R mutation in RT • 3- to 4-fold reduced in vitro susceptibility to tenofovir

  6. Susceptibility of Nucleoside-ResistantHIV-1 Clinical Isolates (Virco) Normal Range (< 3-fold) 100 Intermediate Susceptibility (3-10-fold) Resistant (> 10-fold) 11.7 10.0 3.1 2.5 3.0 Fold Change from Wild-Type 1.7 1.0 0.7 0.7 0.6 0.1 M184V(n=10) L74V(n=5) L74V + Y115F + M184V(n=5) Q151MComplex(n=10) K65R(n=8) T215Y +other TAMs(n=20) T69 Insertions(n=15)

  7. Pharmacology • Once-daily dosing • Long intracellular half-life (10-50 hours) • Terminal serum t½ ~17 hours • Not a substrate, inhibitor or inducer of CYP450 • No clinically significant drug interactions with EFV, IDV, LPV/RTV (Study 909) • Renally cleared • Clearance not affected with co-administration of 3TC or ddI (Study 909) • Oral Bioavailability: 25% (fasted); 39% (fed)

  8. Preclinical Toxicology • No effect on mitochondrial DNA or lactate production in vitro • In vivo studies designed to identify potential target organs in humans: • GI • Kidney • Proximal tubular changes • Bone • Osteomalacia associated with nephrotoxicity in juvenile monkeys at 12x human AUC • Reversible • No radiographic evidence of bone changes in monkeys dosed at 4x human AUC for 3 years

  9. NDA Safety Database Patients receiving 300 mga Total 48 weeks NDA Submission 978 154 (May 1, 2001) NDA Safety Update 978 642 (August 15, 2001) a Includes placebo-controlled studies and compassionate access (Study 908)

  10. Tenofovir Disoproxil Fumarate (TDF) Overview of Development Program Norbert Bischofberger, Ph.D. Clinical Trial Results Jay Toole, M.D., Ph.D. Concluding Remarks Norbert Bischofberger, Ph.D.

  11. Overview • Placebo-controlled Studies Design Dose (qd) Study 901 Monotherapy (n=49) 75,150, 300 & 600 mg Study 902 Intensification (n=186) 75,150 & 300 mg Study 907 Intensification (n=550) 300 mg • Renal and Bone Parameters • Clinical Virology

  12. Study 901Design • Randomized, double-blind, placebo-controlled, dose-escalation study of TDF monotherapy • 4 dose levels (75 mg, 150 mg, 300 mg, 600 mg/day) • HIV RNA 10,000 copies/mL; CD4 200 cells/mm3 • 10 patients per dose level (8 TDF, 2 placebo) • Single dose (day 1) followed by one week washout, then once-daily dosing (days 8 to 35) • Treatment-naïve and experienced patients were enrolled

  13. Study 901Baseline HIV Characteristics Placebo TDF (n=11) (n=38) Mean CD4 (cells/mm3) 346 391 Mean HIV RNA (copies/mL) 115,593 85,351 Prior ART use36% 68%

  14. Study 901HIV RNA Mean Change from Baseline to Day 35 (log10 c/mL) As Treated Placebo 75 mg 150 mg 300 mg 600 mg (n=9) (n=10) (n=8) (n=6) (n=8) 0.03 -0.33* -0.51* -1.20* -0.84* *p<0.003

  15. Daily Dosing Off Treatment Single Dose 0.5 Placebo TDF 75 mg 0.0 TDF 150 mg TDF 300 mg TDF 600 mg Mean log10 copies/mL -0.5 -1.0 -1.5 BL 4 8 14 21 28 35 42 63 Days Placebo 11 9 8 9 8 9 9 8 TDF 75 mg 12 12 12 12 11 10 10 11 TDF 150 mg 8 7 8 8 8 8 8 8 TDF 300 mg 8 8 8 8 7 8 7 7 TDF 600 mg 10 9 8 9 8 8 7 4 Study 901Mean Change from Baseline in HIV-1 RNA Intent to Treat

  16. Study 902Design • Randomized, double-blind placebo-controlled study of TDF added to existing antiretroviral regimens • Entry criteria: • Stable ART 8 weeks prior to entry consisting of 4 concomitant antiretroviral agents • HIV RNA 400 - 100,000 copies/mL • Primary Efficacy Endpoint • Time-weighted average change from baseline in HIV RNA (log10 copies/mL) at week 24 (DAVG24)

  17. Study 902Design Open Label Double-blind 24 wks 48 wks 300 mg 300 mg 300 mg 150 mg 150 mg 300 mg Stable ART 8 weeks randomized 2:2:2:1 75 mg 75 mg 300 mg Placebo 300 mg 300 mg n=186

  18. Study 902Baseline HIV Characteristics (n=186) Mean CD4 (cells/mm3) 374 Median HIV RNA (copies/mL) 5010 Mean prior ART (years) 4.6 Baseline resistance NNRTI 32% PI 57% NRTI 94%

  19. Study 902Patient Disposition (0-24 weeks) TDF Placebo 75 mg 150 mg 300 mg Patients who received drug 28 53 51 54 Patients discontinued (%) 7 (25%) 5 (9%) 8 (16%) 6 (11%) Adverse events 1 (4%) 2 (4%) 5 (10%) 2 (4%) Lost to follow up 2 (7%) 1 (2%) 2 (4%) 1 (2%) Lack of virologic response 2 (7%) 0 0 0 Death 0 1 (2%) 0 0 Other 2 (7%) 1 (2%) 1 (2%) 3 (6%)

  20. Study 902Patient Disposition (0-48 weeks) TDF 75 mg 150 mg 300 mg Patients who received drug 53 51 54 Patients discontinued (%) 14 (26%) 12 (24%) 13 (24%) Adverse events 6 (11%) 5 (10%) 5 (9%) Lost to follow up 3 (6%) 5 (10%) 3 (6%) Lack of virologic response 2 (4%) 0 0 Death 1 (2%) 0 0 Other 2 (4%) 2 (4%) 5 (9%)

  21. Study 902Primary Efficacy Endpoint Mean DAVG24 (log10 copies/mL) TDF Placebo 75 mg 150 mg 300 mg Intent to Treat +0.02 -0.26 -0.34 -0.58* As Treated +0.16 -0.16 -0.32* -0.52* *p<0.001

  22. 0.8 0.6 0.4 0.2 0.0 Mean log10 copies/mL -0.2 Placebo 75 mg -0.4 150 mg -0.6 300 mg -0.8 -1.0 -1.2 BL 1 1 1 1 2 2 2 2 4 4 4 4 8 8 8 8 12 12 12 12 16 16 16 16 20 20 20 20 24 24 24 24 32 32 32 32 40 40 40 40 48 48 48 48 Weeks Placebo 28 27 27 26 26 22 23 0 0 0 75 mg 53 49 53 49 48 49 48 49 46 42 150 mg 51 48 49 49 46 44 45 42 39 35 300 mg 54 51 52 52 50 49 48 49 43 43 Study 902Mean Change from Baseline in HIV-1 RNA Intent to Treat

  23. Study 902CD4 Count Mean Change From Baseline (cells/mm3) Intent to Treat TDF Placebo 75 mg 150 mg 300 mg (n=28) (n=53) (n=51) (n=54) Week 24 20 18 0 -14 Week 48 N/A 10 20 11

  24. Study 902Grade 3/4 Adverse Eventsa (0-24 weeks) TDF Placebo 75 mg 150 mg 300 mg (n=28) (n=53) (n=51) (n=54) Patients (%) with Events 4 (14%) 10 (19%) 9 (18%) 9 (17%) Depression 0 2 (4%) 0 3 (6%) Asthenia 1 (4%) 0 2 (4%) 0 Hepatitis 1 (4%) 1 (2%) 0 0 Fever 1 (4%) 1 (2%) 0 0 Headache 1 (4%) 0 1 (2%) 0 Pancreatitis 1 (4%) 0 0 1 (2%) Allergic reaction 0 0 0 2 (4%) Pain 0 1 (2%) 1 (2%) 0 a1% in either group

  25. Study 902Grade 3/4 Laboratory Abnormalitiesa (0 - 24 weeks) TDF Placebo 75 mg 150 mg 300 mg (n=28) (n=53) (n=51) (n=54) Patients (%) with Abnormality9 (32%) 18 (34%) 16 (31%) 16 (30%) Triglyceride elevation4 (14%) 9 (17%) 4 (8%) 5 (9%) Creatine kinase elevation 4 (14%) 5 (9%) 4 (8%) 6 (11%) AST elevation 1 (4%) 3 (6%) 3 (6%) 4 (7%) Neutropenia 1 (4%) 3 (6%) 1 (2%) 3 (6%) ALT elevation 1 (4%) 2 (4%) 2 (4%) 1 (2%) Lipase elevation 1 (4%) 1 (2%) 2 (4%) 1 (2%) Amylase elevation 1 (4%) 2 (4%) 2 (4%) 0 Hyperglycemia 0 3 (6%) 2 (4%) 0 Glucosuria 0 2 (4%) 1 (2%) 0 Bilirubin elevation 0 1 (2%) 1 (2%) 1 (2%) Thrombocytopenia 0 0 2 (4%) 0 a 1% in any group

  26. Study 907Design • Randomized, double-blind, placebo-controlled study of TDF added to existing antiretroviral regimens • Entry criteria: • Stable ART 8 weeks prior to entry consisting of 4 concomitant antiretroviral agents • HIV RNA 400 - 10,000 copies/mL • Primary efficacy endpoint • Time-weighted average change from baseline in HIV-1 RNA (log10 copies/mL) at week 24 (DAVG24)

  27. Study 907 Design Double- Blind Open Label 24 wks 48 wks Tenofovir DF 300 mg Stable ART 8 weeks randomized 2:1 24 wks 48 wks Placebo Tenofovir DF 300 mg n=550

  28. Study 907Baseline Characteristics Placebo TDF (n=182) (n=368) Mean age (years) 41 42 Male88% 84% Ethnicity Caucasian 65% 71% African-American 19% 16% Other 16% 13% Antiretroviral Regimen Protease-containing 58% 53% NNRTI-containing 36% 43%

  29. Study 907Baseline HIV Characteristics Placebo TDF Median HIV RNA (copies/mL) 2340 2340 Mean CD4 count (cells/mm3) 447 417 Mean ART use (years) 5.3 5.5

  30. Study 907Virology Substudy Baseline Genotyping (n=253) Primary Resistance Mutations Placebo TDF NNRTI 52% 46% PI 62% 57% NRTI 94% 94%

  31. Study 907Patient Disposition (0-24 weeks) PlaceboTDF Patients who received drug 182 368 Patients discontinued (%) 11 (6%) 23 (6%) Adverse event 5 (3%) 11 (3%) Lack of virologic response 1 (<1%) 0 Pregnancy 1 (<1%) 1 (<1%) Lost to follow up 2 (1%) 6 (2%) Other 2 (1%) 5 (1%)

  32. Study 907Primary Efficacy Endpoint Intent to Treat Mean DAVG24 (log10 copies/mL) Placebo TDF (n=182) (n=368) p-value -0.03 -0.61 <0.0001

  33. 0.2 0.0 Placebo -0.2 HIV-1 RNA log10 c/mL (95% CI) -0.4 -0.6 TDF 300 mg -0.8 0 2 4 8 12 16 20 24 Weeks Placebo 182 170 179 175 175 173 173 172 TDF 300 mg 368 335 358 353 354 353 346 346 Study 907Mean Change from Baseline in HIV-1 RNA Intent to Treat

  34. Study 907Subgroup Analyses Mean DAVG24 Placebo TDF p-value HIV RNA <5,000 0.03 -0.59 <0.0001 5,000 -0.22 -0.67 <0.0001 CD4 <200 0.05 -0.39 <0.0001 200 -0.04 -0.64 <0.0001 Male -0.02 -0.61 <0.0001 Female -0.08 -0.66 <0.0001 Caucasian -0.02 -0.60 <0.0001 Non-caucasian -0.05 -0.65 <0.0001

  35. Study 907Secondary Efficacy Endpoints Intent to Treat Placebo TDF p-value HIV RNA 400 copies/mL 13% 45% <0.0001 HIV RNA 50 copies/mL 1% 22% <0.0001 DAVG24 CD4 (cells/mm3) -11 +13 0.0008

  36. Study 907Grade 3/4 Adverse Eventsa (0-24 weeks) Placebo TDF (n=182) (n=368) Patients (%) with events 24 (13%) 51 (14%) Diarrhea 3 (2%) 3 (<1%) Pain 2 (1%) 3 (<1%) Hyperlipidemia 2 (1%) 2 (<1%) Nausea 2 (1%) 2 (<1%) Depression 2 (1%) 1 (<1%) Peripheral neuritis 2 (1%) 1 (<1%) Sinusitis 2 (1%) 1 (<1%) Gastrointestinal disorder 2 (1%) 0 a 1% in either group

  37. Study 907Grade 3/4 Laboratory Abnormalitiesa (0-24 weeks) Placebo TDF (n=182) (n=368) Patients (%) with abnormality 68 (37%) 89 (25%) Triglyceride elevation 24 (13%) 30 (8%) Creatine kinase elevation 26 (15%) 24 (7%) Amylase elevation 13 (7%) 21 (6%) Glucosuria 6 (3%) 11 (3%) AST elevation 5 (3%) 10 (3%) Hyperglycemia 8 (4%) 7 (2%) ALT elevation 3 (2%) 8 (2%) a 1% in either group

  38. Renal and Bone Parameters

  39. Studies 902 and 907Integrated Safety Analysis • Includes all patients who received 300 mg (n=687) • As randomized (n=422) • Following cross-over from placebo (n=191) • Following 48 weeks of either 75 or 150 mg (n=74)

  40. Studies 902 and 907Integrated Safety Analysis • Number of patients 687 • n 48 weeks exposure 480 • n 72 weeks exposure 156 • Mean (weeks) 58 • Maximum (weeks) 143

  41. Study 907Serum Creatinine Maximum Toxicity Grade(0-24 weeks) Grade (mg/dL) Placebo TDF (n=182) (n=368) 1 (0.5 from baseline) 2 (1%) 6 (2%) 2 (2.1-3.0) 0 0 3 (3.1-6.0) 0 0 4 (>6.0) 0 0

  42. Studies 902 & 907Serum Creatinine Maximum Toxicity Grade(0-143 weeks) Grade (mg/dL) TDF (n=687) 1 (0.5 from baseline) 32 (5%) 2 (2.1-3.0) 0 3 (3.1-6.0) 0 4 (>6.0) 0

  43. Studies 902 & 907Consecutive Visits with Grade 1 Creatinine 35 32 30 25 20 Number of patients 15 10 6 5 1 1 0  1  2  3 4 Visits

  44. Study 907Serum Phosphorus Maximum Toxicity Grade(0-24 weeks) Placebo TDF Grade (mg/dL)(n=182) (n=368) 1 (2.0-2.2) 10 (5%) 21 (6%) 2 (1.5-1.9) 4 (2%) 23 (6%) 3 (1.0-1.4) 1 (<1%) 0 4 (<1.0) 0 1 (<1%)

  45. Studies 902 & 907Serum Phosphorus Maximum Toxicity Grade(0-143 weeks) TDF Grade (mg/dL) (n=687) 1 (2.0-2.2) 51 (7%) 2 (1.5-1.9) 58 (8%) 3 (1.0-1.4) 3 (<1%) 4 (<1.0) 1 (<1%)

  46. Studies 902 & 907 Consecutive Visits Serum Phosphate <2.0 mg/dL 70 62 60 50 40 Number of patients 30 20 11 10 1 0  1  2 3 Visits

  47. Studies 902 & 907Bone Fracture Rate Total Exposure No. Fracture n (patient-yrs) Fractures Ratea Placebo (0-24 wks) 210 99 3 3.0 TDF (0-143 wks) 687 778 13 1.7 a Per 100 patient-years

  48. Studies 902 and 907Bone Fracture Summary • External review of radiographs (H. Genant, M.D., UCSF) • Fractures result of high-impact trauma • Normal healing observed while TDF continued • No vertebral compression fractures • TDF fracture rate is similar to placebo • Rate has not increased with longer exposure

  49. Safety Summary • The safety of TDF 300 mg is similar to placebo through 24 weeks • The safety profile of TDF shows no significant change with extended dosing

  50. Efficacy Summary • TDF 300 mg monotherapy for 28 days resulted in -1.2 log10 copies/mL change from baseline • Active in highly treatment-experienced patients • Increases the percentage of patients with HIV RNA  400 and  50 copies/mL • Consistent across subgroups • Durable through 48 weeks

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