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Safety Presentation on NDA 21-814 Tipranavir

Safety Presentation on NDA 21-814 Tipranavir. Andrea N. James, M.D. Primary Medical Reviewer Division of Antiviral Drug Products Food and Drug Administration. May 19, 2005 FDA Antiviral Drugs Advisory Committee Meeting. Presentation Outline. Safety Summary Data reviewed

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Safety Presentation on NDA 21-814 Tipranavir

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  1. Safety Presentation on NDA 21-814Tipranavir Andrea N. James, M.D. Primary Medical Reviewer Division of Antiviral Drug Products Food and Drug Administration May 19, 2005 FDA Antiviral Drugs Advisory Committee Meeting

  2. Presentation Outline • Safety Summary • Data reviewed • Summary of AEs, SAEs, AEs leading to discontinuation • Safety Concerns • Hepatotoxicity • Rash • Hyperlipidemia • Clinical Progression • AIDS Defining Illnesses, Death • Summary of the Risk/Benefit Analysis of TPV/r • Questions to the Committee FDA Antiviral Drugs Advisory Committee Meeting

  3. Data Reviewed • Review of data submitted with original NDA • Submitted December 22, 2004 • Covers TPV/r development program through June 11, 2004 • NDA Safety Update • Submitted February 22, 2005 • Covers TPV/r development program through September 30, 2004 • NDA Safety Update confirms conclusions drawn from the original NDA submission FDA Antiviral Drugs Advisory Committee Meeting

  4. TPV/r Safety Summary FDA Antiviral Drugs Advisory Committee Meeting

  5. Safety Summary: RESIST trials FDA Antiviral Drugs Advisory Committee Meeting

  6. Tipranavir Safety Concerns FDA Antiviral Drugs Advisory Committee Meeting

  7. Hepatotoxicity • ALT/AST DAIDS Toxicity Grading Scale • Grade 1 1.25-2.5x ULN • Grade 2 >2.5-5.0x ULN • Grade 3 >5.0-10.0x ULN • Grade 4 >10.0x ULN • ALT ULN ranged from 32 - 52 U/L • AST ULN ranged from 34 - 59 U/L FDA Antiviral Drugs Advisory Committee Meeting

  8. Hepatotoxicity • 19% of healthy volunteers in 18 Phase 1 studies had drug induced ALT elevations (N = 631) • 13% had ALT elevations above the ULN • 4% Grade 3 ALT • 2% Grade 4 ALT • Median time to onset • 16 days (range: 6- 46 days) FDA Antiviral Drugs Advisory Committee Meeting

  9. Study 1182.52: Dose Dependent Hepatotoxicity N = 71 N = 72 N = 73 FDA Antiviral Drugs Advisory Committee Meeting

  10. Study 1182.52: Exposures Across Doses RTV and TPV FDA Antiviral Drugs Advisory Committee Meeting

  11. RESIST Trials: Treatment Emergent Hepatotoxicity FDA Antiviral Drugs Advisory Committee Meeting

  12. RESIST Trials: ALT/AST Grades 3 and 4 Maximum Values FDA Antiviral Drugs Advisory Committee Meeting

  13. RESIST Trials: Outcomes of Grade 3/4 ALT/AST Elevations FDA Antiviral Drugs Advisory Committee Meeting

  14. RESIST Trials: Hepatotoxicity Presentation • Asymptomatic • Median time to onset = 56.5 days (8 – 176 days) FDA Antiviral Drugs Advisory Committee Meeting

  15. RESIST Trials: Potential Risk Factors for Hepatotoxicity • Baseline liver parameters • ALT/AST • Hepatitis status FDA Antiviral Drugs Advisory Committee Meeting

  16. RESIST Trials: Baseline ALT/AST • Inclusion Criteria: < Gr 1 ALT/AST • Subjects with ALT/AST Protocol Violations • 3% TPV/r (N = 746) > Grade 1 at baseline • 19 Grade 2 ALT/AST • 2 Grade 3 ALT/AST • 3% CPI/r (N = 737) > Grade 1 at baseline • 22 Grade 2 ALT/AST • 1 Grade 3 ALT/AST FDA Antiviral Drugs Advisory Committee Meeting

  17. RESIST Trials: Subjects With Baseline ALT/AST > Grade 1 • TPV/r arm • 5.0% (n= 1/21) of subjects developed a Grade 3 or 4 ALT/AST • CPI/r arm • 20% (4/23) of subjects developed a Grade 3 or 4 ALT/AST FDA Antiviral Drugs Advisory Committee Meeting

  18. RESIST Trials: Baseline Hepatitis as a Risk Factor for TPV Induced Hepatotoxicity FDA Antiviral Drugs Advisory Committee Meeting

  19. RESIST Trials: Baseline Hepatitis Status Not Sole Predictor FDA Antiviral Drugs Advisory Committee Meeting

  20. Hepatotoxicity Summary • Transaminase elevations were common throughout the development program. • ALT > AST • Healthy volunteers, HIV+ subjects • Presentation • Asymptomatic and can occur at any time • Outcome • Majority resolve either on or off treatment • Treatment limiting • Risk factors • Viral hepatitis • ? ALT value at baseline • Monitoring/Management • Early • Often FDA Antiviral Drugs Advisory Committee Meeting

  21. Rash • Study 1182.22 • Drug interaction study of Ortho-Novum 1/35 and TPV/r • 52 predominately white healthy females enrolled (mean age = 35.2 years ) • Randomized to TPV/r 500/100 mg or TPV/r 750/200 mg twice daily on d 4 – 16 and Ortho-Novum 1/35 on d 1 and d 16 FDA Antiviral Drugs Advisory Committee Meeting

  22. Rash: Study 1182.22 • 33% (n = 17) of subjects developed rash • An additional 18% of subjects had musculoskeletal symptoms or symptoms consistent with hypersensitivity. • Study prematurely stopped • ? Serum sickness FDA Antiviral Drugs Advisory Committee Meeting

  23. FDA Antiviral Drugs Advisory Committee Meeting

  24. FDA Antiviral Drugs Advisory Committee Meeting

  25. Rash • TPV is a sulfonamide TPV Sulfamethoxazole FDA Antiviral Drugs Advisory Committee Meeting

  26. Rash and Sulfa Allergy FDA Antiviral Drugs Advisory Committee Meeting

  27. Rash • Phase 1 trials • 13% females (N=265) versus 4% males (N=345) developed rash • Phase 2 trials • 13% females (N=108) versus 8% males (N=733) developed rash. • Study 1182.52 (N=216) • Suggests rash may be dose-related • Overall 8.6% of subjects developed rash • 10% (n=7/73)TPV/r 500/100 mg • 4% (n=3/72) TPV/r 500/200 mg • 15% (n=11/71) TPV/r 750/200 mg FDA Antiviral Drugs Advisory Committee Meeting

  28. RESIST trials: Rash N=17/118 N=80/746 N= 72/737 N=8/90 FDA Antiviral Drugs Advisory Committee Meeting

  29. Rash Summary • TPV is a sulfonamide • Cannot rule out relationship to rash • Overall rash is not more common on the TPV/r arms • Female subjects on TPV/r have a higher frequency of rash than male counterparts • Rate is consistent throughout Phase 1-3 studies (13-14%) • Few females in these studies • ? Cause • Immune mediated reaction • Hormonally mediated FDA Antiviral Drugs Advisory Committee Meeting

  30. Hyperlipidemia FDA Antiviral Drugs Advisory Committee Meeting

  31. Hypertriglyceridemia • Triglyceride toxicity scale • Grade 2: 400-750 mg/dL • Grade 3: 751-1200 mg/dL • Grade 4: >1200 mg/dL FDA Antiviral Drugs Advisory Committee Meeting

  32. % of Treatment Emergent Hypertriglyceridemia FDA Antiviral Drugs Advisory Committee Meeting

  33. Hypercholesterolemia • Cholesterol toxicity grading scale • Grade 2 >300 – 400 mg/dL • Grade 3 >400 – 500 mg/dL • Grade 4 > 500 mg/dL FDA Antiviral Drugs Advisory Committee Meeting

  34. % of Treatment Emergent Hypercholesterolemia FDA Antiviral Drugs Advisory Committee Meeting

  35. Hyperlipidemia Summary • TPV/r group has a much higher rate of hyperlipidemia than the CPI/r group • 46% of TPV/r subjects had Grade 2-4 treatment emergent hypertryglyceridemia vs. 24% of CPI/r subjects • 15% of TPV/r subjects had Grade 2-4 treatment emergent hypercholesterolemia vs. 5% of CPI/r subjects FDA Antiviral Drugs Advisory Committee Meeting

  36. Clinical Progression Events FDA Antiviral Drugs Advisory Committee Meeting

  37. RESIST Trials: Deaths • Possible cause of similar mortality rate • Advanced population studied • Natural disease course • Many comorbid diseases • Many concomitant medications • Study design • Early loss of control subjects • Time point too early to see a difference FDA Antiviral Drugs Advisory Committee Meeting

  38. TPV/r Risk/Benefit Assessment • Efficacy • Superior activity over a suboptimal control in 3 class experienced, advanced HIV-1 infected subjects • Resistance profile • Impact of TPV score and baseline PI mutations on treatment response • PK profile • Multiple drug-drug interactions • High inter-patient variability in TPV exposure • Safety profile • Hepatotoxicity, rash and hyperlipidemia FDA Antiviral Drugs Advisory Committee Meeting

  39. Contributors • Melisse Baylor, M.D. • Neville Gibbs, M.D., MPH • Rosemary Johann-Liang, M.D. • Jenny J. Zheng, Ph.D. • Susan Zhou, Ph.D. FDA Antiviral Drugs Advisory Committee Meeting

  40. Question 1 Do the data demonstrate that tipranavir/ritonavir (TPV/r) is safe and effective for the multi-drug resistant HIV-1 infected population? • If no, what additional data are needed to provide evidence of safety and efficacy? • If yes, please address the appropriate population for TPV/r use considering the following: • limited inclusion criteria of the RESIST trials • drug-drug interactions • resistance information and patterns associated with optimal use • safety considerations FDA Antiviral Drugs Advisory Committee Meeting

  41. Question 2 Given the data on transaminase elevations, please provide your recommendations for: • TPV/r use in patients with underlying liver disease • Monitoring and management of hepatotoxicity during clinical use • Future studies FDA Antiviral Drugs Advisory Committee Meeting

  42. Question 3 • The limited amount of data in females with HIV infection in the TPV program shows an increased incidence of rash in females. Please provide your recommendations for: • Investigation of this safety signal in future studies with TPV FDA Antiviral Drugs Advisory Committee Meeting

  43. Question 4 • Current information indicates the net effect of TPV/r on substrates of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 is not known, and there are competing effects of TPV/r on CYP3A (inhibition) and P-glycoprotein (induction). Please comment on additional post-marketing drug interaction studies. FDA Antiviral Drugs Advisory Committee Meeting

  44. Question 5 • Given the high inter-patient variability in TPV exposures following fixed doses and exposure (blood levels)-virologic response relationships, could a biomarker such as Cmin/IC50 be used for the individualization of TPV/r therapy? Please discuss the studies that would supplement the data presented today. FDA Antiviral Drugs Advisory Committee Meeting

  45. Question 6 • Please provide your recommendations regarding the display of TPV/r resistance data/analyses in the TPV package insert that would be useful to clinicians. FDA Antiviral Drugs Advisory Committee Meeting

  46. Examples • Baseline Outcome Analyses • Baseline Number of PI Mutations • Type of PI Mutation • Baseline Phenotype • TPV score • Key mutations • Endpoints • Primary endpoint (proportion of responders) • Change from Baseline (e.g. median, average) • +/-T20 use FDA Antiviral Drugs Advisory Committee Meeting

  47. Response by Baseline Number of PI Mutations Proportion of Responders (confirmed >1 log decrease at Week 24) # Any change at positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90 FDA Antiviral Drugs Advisory Committee Meeting

  48. Response by Baseline PI MutationsMedian Change from Baseline - Overall 0 2 4 8 16 24 Week FDA Antiviral Drugs Advisory Committee Meeting

  49. Question 7 • Please discuss and recommend future study designs /data acquisition for the heavily pretreated population. FDA Antiviral Drugs Advisory Committee Meeting

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