Safety Presentation on NDA 21-814 Tipranavir

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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
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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

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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

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TPV/r Safety Summary
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Safety Summary RESIST trials
Treatment Emergent Events TPV/r (N 746) CPI/r (N 737)
AEs Grade 3/4 282 (38) 132 (18) 267 (36) 109 (15)
SAEs Grade 3/4 99 (13) 68 (9) 89 (12) 64 (9)
AEs leading to D/C 60 (8) 36 ( 5)
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Tipranavir Safety Concerns
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Hepatotoxicity

• ALT/AST DAIDS Toxicity Grading Scale
• Grade 1 1.25-2.5x ULN
• Grade 2 gt2.5-5.0x ULN
• Grade 3 gt5.0-10.0x ULN
• Grade 4 gt10.0x ULN
• ALT ULN ranged from 32 - 52 U/L
• AST ULN ranged from 34 - 59 U/L

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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)

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Study 1182.52 Dose Dependent Hepatotoxicity
N 71
N 72
N 73
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Study 1182.52 Exposures Across Doses RTV and TPV
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RESIST Trials Treatment Emergent Hepatotoxicity
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RESIST Trials ALT/AST Grades 3 and 4 Maximum
Values
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RESIST Trials Outcomes of Grade 3/4 ALT/AST
Elevations
TPV/r N 732 CPI/r N 723
Grade 3/4 ALT/AST Elevation 45 (6) 18 (2)
Discontinued 12 (27) 0
Resolved On tx Off tx 29 (64) 19 (42) 10 (22) 17 (94) 17 (94) 0
Unresolved On tx Off tx 16 (35) 14 (31) 2 (4) 1 (6) 1 (6) 0
Deaths 0 0
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RESIST Trials Hepatotoxicity Presentation

• Asymptomatic
• Median time to onset 56.5 days (8 176 days)

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RESIST Trials Potential Risk Factors for
Hepatotoxicity

• Baseline liver parameters
• ALT/AST
• Hepatitis status

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RESIST Trials Baseline ALT/AST

• Inclusion Criteria lt Gr 1 ALT/AST
• Subjects with ALT/AST Protocol Violations
• 3 TPV/r (N 746) gt Grade 1 at baseline
• 19 Grade 2 ALT/AST
• 2 Grade 3 ALT/AST
• 3 CPI/r (N 737) gt Grade 1 at baseline
• 22 Grade 2 ALT/AST
• 1 Grade 3 ALT/AST

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RESIST Trials Subjects With Baseline ALT/AST gt
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

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RESIST Trials Baseline Hepatitis as a Risk
Factor for TPV Induced Hepatotoxicity
of TPV/r CPI/r
Hepatotoxicity among subjects with baseline Hepatitis B or C 9/76 (12) 6/113 (5)
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RESIST Trials Baseline Hepatitis Status Not Sole
Predictor
of TPV/r CPI/r
Baseline Hepatitis B or C among subjects with Hepatotoxicity 9/45 (20) 6/18 (33)
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Hepatotoxicity Summary

• Transaminase elevations were common throughout
  the development program.
• ALT gt 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

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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

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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

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Rash

• TPV is a sulfonamide

TPV
Sulfamethoxazole
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Rash and Sulfa Allergy
1182.51 N315 RESIST N 746
Sulfa allergic with rash 17 11
No sulfa allergy with rash 7 11
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Rash

• Phase 1 trials
• 13 females (N265) versus 4 males (N345)
  developed rash
• Phase 2 trials
• 13 females (N108) versus 8 males (N733)
  developed rash.
• Study 1182.52 (N216)
• Suggests rash may be dose-related
• Overall 8.6 of subjects developed rash
• 10 (n7/73)TPV/r 500/100 mg
• 4 (n3/72) TPV/r 500/200 mg
• 15 (n11/71) TPV/r 750/200 mg

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RESIST trials Rash
N17/118
N80/746
N 72/737
N8/90
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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

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Hyperlipidemia
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Hypertriglyceridemia

• Triglyceride toxicity scale
• Grade 2 400-750 mg/dL
• Grade 3 751-1200 mg/dL
• Grade 4 gt1200 mg/dL

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of Treatment Emergent Hypertriglyceridemia
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Hypercholesterolemia

• Cholesterol toxicity grading scale
• Grade 2 gt300 400 mg/dL
• Grade 3 gt400 500 mg/dL
• Grade 4 gt 500 mg/dL

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of Treatment Emergent Hypercholesterolemia
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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

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Clinical Progression Events
TPV/r (N 746) CPI/r (N 737)
AIDS Defining Illnesses ? ?
Deaths 15 (2) 13 (2)
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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

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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

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Contributors

• Melisse Baylor, M.D.
• Neville Gibbs, M.D., MPH
• Rosemary Johann-Liang, M.D.
• Jenny J. Zheng, Ph.D.
• Susan Zhou, Ph.D.

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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

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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

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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

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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.

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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.

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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.

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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

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Response by Baseline Number of PI Mutations
Proportion of Responders (confirmed gt1 log
decrease at Week 24)
Baseline FDA PI Mutations TPV/r N531 TPV/r N531 TPV/r N531 CPI/r N502 CPI/r N502 CPI/r N502
All No T20 T20 All No T20 T20
Overall 47 (241/531) 40 (148/369) 65 (93/144) 22 (110/502) 20 (76/389) 30 (34/113)
1 - 2 70 (30/43) 69 (27/39) 75 (3/4) 44 (19/43) 41 (17/41) 100 (2/2)
3 - 4 50 (117/236) 44 (78/176) 65 (39/60) 27 (60/221) 23 (39/169) 40 (21/52)
5 41 (94/231) 28 (43/151) 64 (51/80) 13 (31/236) 11 (20/178) 19 (11/58)
Any change at positions 30, 32, 36, 46, 47, 48,
50, 53, 54, 82, 84, 88 and 90
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Response by Baseline PI Mutations Median Change
from Baseline - Overall
2
4
8
16
24
0
Week
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Question 7

• Please discuss and recommend future study designs
  /data acquisition for the heavily pretreated
  population.