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DEVELOPMENT PROGRAM & STUDY RESULTS

DEVELOPMENT PROGRAM & STUDY RESULTS. Slide # 31. IV GANCICLOVIR. IV GCV is a first-line treatment for CMVR Approved in US in 1989 Current Indications treatment of CMVR in immunocompromised patients prevention of CMV disease in transplant patients at risk

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DEVELOPMENT PROGRAM & STUDY RESULTS

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  1. DEVELOPMENT PROGRAM & STUDY RESULTS Slide # 31

  2. IV GANCICLOVIR • IV GCV is a first-line treatment for CMVR • Approved in US in 1989 • Current Indications • treatment of CMVR in immunocompromised patients • prevention of CMV disease in transplant patients at risk • Well-described efficacy and safety profile Slide # 32

  3. ORAL GANCICLOVIR • Oral GCV approved in US in 1994 • Current Indications: • maintenance treatment of CMVR in immunocompromised patients • prevention of CMV disease in SOT patients & in HIV patients at risk • Limited by bioavailability (6%) and t.i.d. dosing regimen Slide # 33

  4. Viral Protein Kinase (UL97) Cellular Enzymes GCV GCV-DP GCV-TP GCV-MP Inhibits Viral DNA Polymerase (UL54) Intracellular Extracellular MECHANISM OF ACTION Slide # 34

  5. O N HN N H2N N O OH HO PRO-DRUG OF GANCICLOVIR O HCl N HN N H2N N O H2N O HO O valganciclovir HCl ganciclovir Slide # 35

  6. VALGANCICLOVIR KEY CHARACTERISTICS • GCV exposure (AUC) following 900 mg Val-GCV similar to IV GCV (5 mg/kg) • Bioavailability approx. 60% (10X higher than oral GCV) • < 2% of absorbed dose appears as valganciclovir in plasma (t1/2 1 hour) • 450 mg film-coated tablet Slide # 36

  7. COMPARATIVE GANCICLOVIR PK PROFILES GANS2230 Slide # 37

  8. COMPARATIVE GANCICLOVIR PK PROFILES GANS2230 Slide # 38

  9. COMPARATIVE GANCICLOVIR PK PROFILES GANS2230 (IV & Oral GCV) WP15509 (GCV from Val-GCV) Slide # 39

  10. COMPARATIVE PK: MEAN (%CV) * Concentrations at 24h after single dose Slide # 40

  11. COMPARATIVE PK: MEAN (%CV) * Concentrations at 24h after single dose Slide # 41

  12. PK/PD SUPPORTS GCV AUC AS CORRELATE OF EFFICACY • PK/PD explored in GANS2226- dose-ranging maintenance study- included IV and three oral GCV doses • Population PK approach (NONMEM) • AUC0-24 significantly correlated with efficacy (time to progression) Slide # 42

  13. BASIS OF DOSE SELECTION 900 mg Val-GCV achieves target AUC ( 26 g•h/mL) induction maintenance Slide # 43

  14. METABOLISM AND ELIMINATION • Rapid hydrolysis to GCV • Intestinal and hepatic esterases represent a high-capacity system • No other metabolites detected • GCV drug interactions applicable to Val-GCV • Renal impairment requires dose adjustment Slide # 44

  15. DEVELOPMENT RATIONALE The PK profile of GCV from Val-GCV provided the potential for: • Therapeutic alternative to IV GCV treatment of CMVR (induction and maintenance) • Avoidance of risks associated with IV access required for IV GCV therapy • Simple oral regimen that could improve patient adherence during maintenance treatment Slide # 45

  16. EARLY CHALLENGE • Pilot Study: potential efficacy in induction treatment • Enrollment initiated Jan,1997 • Impact of HAART • 11/70 patients enrolled in 4 months (17 sites) Slide # 46

  17. IMPACT OF HAART r Slide # 47 From Kovacs JA and Masur H. N Engl J Med. 2000 342: 1415-1429

  18. DEVELOPMENT PROGRAM Overall N = 491 Therapeutic Studies in AIDS Patients N=372 Clinical Pharmacology Studies N=119 MultipleDose Study WP15347 N=39 Controlled Study WV15376 N=160 Single-Dose and Special Population Studies GANS2661, WP15509 WP15511 N= 80 Uncontrolled Study WV15705 N=212 Transplant: PV16000 (n=121 as of Aug 31, 2000); WP15711 (n=28) Slide # 48

  19. United Kingdom Canada United States Germany Spain Mexico France Italy Brazil Australia PARTICIPATING COUNTRIES 372 patients in 26 months (50 sites) Slide # 49

  20. DEVELOPMENT PROGRAM • Built on the proven efficacy of GCV • Primary interest: Comparison of Val-GCV and IV GCV efficacy & safety • Induction setting - highest efficacy hurdle for CMVR treatment Slide # 50

  21. EFFICACY Slide # 51

  22. WV15376 STUDY DESIGN IV Ganciclovir 5 mg/kg bid 3 weeks 5 mg/kg qd 1 week Valganciclovir Randomize 900 mg qd N = 160 Valganciclovir 900 mg bid 3 weeks 900 mg qd 1 week Week 4 Baseline RANDOMIZED PHASE EXTENSION Slide # 52

  23. WV15376 PRIMARY ENDPOINT Proportion of Patients Demonstrating Progression of CMV Retinitis by Week 4 • Progression defined as movement  750 m (along a  750 m front ) or new retinitis lesion  750 m diameter • Assessed by retinal photography Slide # 53

  24. PHOTO ASSESSMENT METHODS • Full-field, bilateral photographs • Central retinal photograph reading center (independent) • Scored by experienced grader (masked) • Scored: progression, distance of border movement, border activity Slide # 54

  25. WV15376: ANALYSIS CONSIDERATIONS Is efficacy of Val-GCV similar to(no worse than) IV GCV for induction therapy? • Non-inferiority is a standard statistical approach to address this • Non-inferiority test utilizes only the lower bound of confidence interval • Non-inferiority limit (d = -0.25) chosen to represent the limit of a clinically acceptable treatment group difference Slide # 55

  26. ASSESSING NON-INFERIORITY d Treatment difference (Pg-Pv) - 0.25 0 Val-GCV No Worse than IV GCV Slide # 56

  27. ASSESSING NON-INFERIORITY (cont’d) (Hypothetical) d Treatment difference (Pg-Pv) - 0.25 0 Slide # 57

  28. ASSESSING NON-INFERIORITY (cont’d) (Hypothetical) d Treatment difference (Pg-Pv) - 0.25 0 Val-GCV No Worse than IV GCV Slide # 58

  29. ASSESSING NON-INFERIORITY (cont’d) (Hypothetical) d (WV15376 Results) Treatment difference (Pg-Pv) - 0.25 0 Val-GCV No Worse than IV GCV Slide # 59

  30. BASELINE STATUS [1] IV GCV n=80 Val-GCV n=80 Gender (M/F) 73 / 7 72 / 8 Age Median (yr) 37 39 Ethnicity Caucasian Hispanic Black Asian Other 42 (53%) 25 (30%) 9 (11%) 1 ( 1%) 3 ( 4%) 43 (54%) 25 (30%) 9 (11%) 1 ( 1%) 2 ( 3%) Slide # 60

  31. CD4 median (cells/L) (range) 26 (2-365) 20 (2-390) 4.9 (1.7-5.9) 4.8 (1.7-5.9) HIV Load, median (log) (range) CMV-Positive Plasma PCR 51% (n =39/76) 40% (n = 31/77) CMV-Positive Culture 65% (n = 46/71) 46% (n = 33/71) BASELINE STATUS [2] IV GCV n=80 Val-GCV n=80 3.4(2.5-5.5) 3.6 (2.6-4.8) CMV Load, median (log) (range) Slide # 61

  32. BASELINE - HIV THERAPY IV GCV n=80 Val-GCV n=80 Protease Inhibitors (PI) at entry 47 (59%) 53 (66%) PI Use - ongoing/prior 64 (80%) 64 (80%) PI-Naïve 16 (20%) 16 (20%) No Anti-Retrovirals at entry 18 (23%) 17 (21%) Anti-Retroviral-Naïve 7 ( 9%) 5 ( 6%) Slide # 62

  33. BASELINE RETINITIS IV GCV n=80 Val-GCV n=80 Zone 1 19 (24%) 19 (24%) Zone 2/3 55 (69%) 53 (66%) Bilateral 20 (25%) 20 (25%) Unilateral 54 (68%) 52 (65%) Active Lesion Border 71 (89%) 68 (85%) Slide # 63

  34. STUDY POPULATIONS IV GCV Val-GCV ITT - All Randomized 80 (100%) 80 (100%) EFFICACY (STD) Population 73 ( 91%) 73 ( 91%) - Subjects excluded 7 ( 9%) 7 ( 9%) Slide # 64

  35. PRIMARY ENDPOINT(COMPARABLE EFFICACY AT WEEK 4) IV GCV n=73 Val-GCV n=73 7 Photo Progression 7 63 No Photo Progression 64 3 Unevaluable 2 Proportion progressed 0.100 (10%) 0.099 (9.9%) Difference 0.001 (0.1%) 95% Confidence Interval (-0.097, 0.100) Slide # 65

  36. PROGRESSION AT WEEK 4 BY CMVR ZONE AT BASELINE (PHOTO) IV-GCV Val-GCV Prog n=7 Non-Prog n=63 Prog n=7 Non-Prog n=64 Zone 1 Zone 2/3 Uneval. 2 (13%) 5 ( 9%) 0 14 (88%) 48 (91%) 1 2 (11%) 5 (10%) 0 16 (89%) 45 (90%) 3 Slide # 66

  37. VISUAL ACUITY & FUNCTIONAL VISION (To Clinical Cut-Off) IV GCV Val-GCV Decreased Acuity By 1 Category 10/77 (13%) 12/77 (16%) Decreased Acuity By 2 Categories 11/77 (14%) 13/77 (17%) Decreased Functional Vision By 1 Category 24/77 (31%) 25/79 (32%) Slide # 67

  38. Median Time To Progression IV GCV/Val-GCV 125 days Val-GCV/Val-GCV 160 days * IV GCV/Val-GCV Pts still at risk K-M: TIME TO PROGRESSION (PHOTOGRAPHY) 72/7465/62 39/4933/3425/3221/2618/2217/1815/16 14/14 * Slide # 68

  39. CMV CULTURES % of patients with IV GCV Val-GCV CMV-positive culture 65% (46/71) 46% (33/71) Baseline Week 4 6% ( 4/64) 7% ( 4/58) Slide # 69

  40. CMV PCR % of patients with CMV viremia (plasma) IV GCV Val-GCV 51% (39/76) 40% (31/77) Baseline 4% ( 3/71) 3% ( 2/70) Week 4 Slide # 70

  41. 80/8077/74 74/6568/6164/5858/5153/4646/3939/35 36/33 * * IV GCV/Val-GCV Pts still at risk K-M : TIME TO WITHDRAWAL Median Time To Withdrawal IV GCV/Val-GCV 419 days Val-GCV/Val-GCV 376 days Slide # 71

  42. WITHDRAWALS BETWEEN WEEKS 4 & 12 IV GCV Val-GCV Death Adverse Event Refused Treatment Failed to Return Insufficient Response Total 2 1 1 0 0 4 1 5 2 2 4 14 • Adverse Events: • IV GCV - Pneumocystis carinii pneumonia • Val-GCV - hypoaesthesia & pain in limb; neutropenia; lymphoma; dehydration; pancytopenia Slide # 72

  43. Median Time To Progression or Withdrawal IV GCV/Val-GCV 102 days Val-GCV/Val-GCV 112 days 77/8067/66 43/5235/3627/3322/2819/2317/1915/16 14/14 * * IV GCV/Val-GCV Pts still at risk K-M: TIME TO PROGRESSION OR WITHDRAWAL Slide # 73

  44. WV15376 MEAN STEADY-STATE CONC. OF GCV AFTER IV GCV & VAL-GCV Week 1 Slide # 74

  45. WV15376 MEAN STEADY-STATE CONC. OF GCV AFTER IV GCV & VAL-GCV Week 4 Slide # 75

  46. WV15376 MEAN STEADY-STATE CONC. OF GCV & VAL-GCV AFTER IV GCV & VAL-GCV Weeks 1 & 4 Slide # 76

  47. WV15376 MEAN GCV PK PARAMETERS WEEK 4 WEEK 1 IV GCV n=18 Val-GCV n=25 IV GCV n=18 Val-GCV n=20 Dose 5 mg/kg b.i.d. 900 mg b.i.d. 5 mg/kg q.d. 900 mg q.d. Slide # 77

  48. WV15376 MEAN GCV PK PARAMETERS WEEK 4 WEEK 1 IV GCV n=18 Val-GCV n=25 IV GCV n=18 Val-GCV n=20 Dose 5 mg/kg b.i.d. 900 mg b.i.d. 5 mg/kg q.d. 900 mg q.d. 28.6 (31.6) 32.8 (30.7) 30.7 (25) 34.9 (38.1) 12 hr AUC (CV%) 24 hr AUC AUC: µg•h/mL Slide # 78

  49. WV15376 MEAN GCV PK PARAMETERS WEEK 4 WEEK 1 IV GCV n=18 Val-GCV n=25 IV GCV n=18 Val-GCV n=20 Dose 5 mg/kg b.i.d. 900 mg b.i.d. 5 mg/kg q.d. 900 mg q.d. 28.6 (31.6) 32.8 (30.7) 30.7 (25) 34.9 (38.1) 12 hr AUC (CV%) 24 hr AUC 10.4 6.71 9.86 5.87 (n=21) Cmax AUC: µg•h/mL; Cmax: µg/mL Slide # 79

  50. SAFETY Slide # 80

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