Tipranavir NDA 21-814: Efficacy Evaluation

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Tipranavir NDA 21-814Efficacy Evaluation

• Rafia Bhore, Ph.D.
• Statistician Reviewer
• Division of Antiviral Drug Products
• Food and Drug Administration

May 19, 2005 FDA Antiviral Drugs Advisory
Committee Meeting
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Outline of Efficacy Presentation

• Study Design of Phase 3 Trials
• Patient Disposition
• Demographics and Baseline Characteristics
• Evaluation of Open-Label Design
• Efficacy Evaluation
• Primary Efficacy (FDA Analysis)
• Subgroup Analyses by PI resistance, T-20 use
• Head-to-head comparison of TPV vs PIs
• Summary of Efficacy

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Study Design of RESIST Trials

• (Studies 1182.12 and 1182.48)
• Randomized Evaluation of Strategic Intervention
  in Multi-Drug ReSistant Patients with Tipranavir

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STUDIES 1182.12 (RESIST 1) and 1182.48 (RESIST
2) Open-label, Controlled, Highly ARV-experienced
patients
RESIST 1 USA, Canada, Australia RESIST 2
Europe, Latin America
SCREENING 3 ARV class and dual PI-experienced
Genotype Resistance Testing
At least 1 primary protease resistance
mutations at codons 30N, 46I/L, 48V, 50V, 82
A/F/L/T, 84V, or 90 M ?
Screening Failure
? 2 mutations at codons 33, 82, 84, or 90 ?
Enroll in Trial 1182.51
Enroll in RESIST Trial
Go to A
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Amendment 2 Allowed patients with highly PI
resistant virus to be treated with PI-based
regimen.
Open-label
Roll-over Trial 1182.17
NOTES PIProtease Inhibitor TPVtipranavir,
RTVritonavir APVamprenavir, SQVsaquinavir IDVi
ndinavir, LPVlopinavir
Patients in comparator PI/RTVgroup with lack of
initial virologic response or confirmed
virologic failure will roll-over to TPV/RTV
group in Roll-Over Trial 1182.17
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Patient Disposition
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Patient Disposition
Number of patients TPV/r OBR CPI/r OBR
Total randomized and treated with 16 week data 746 737
Randomized and treated with 24 week data (ITT) 582 (100) 577 (100)
Completed Study through 24 weeks 82 53
Prematurely discontinued before or at Week 24 17 47
Discontinuations due to Virologic Failure or no Virologic response 3 37
Adverse Events 8 4
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Demographics and Baseline Characteristics
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Demographics

• RESIST 1 (N620)
• USA (80), Canada (13), Australia (7)
• RESIST 2 (N539)
• Europe (85), Latin America (15)
• France 26, Germany 19, Italy 16, Spain 7,
  Greece 4, Belgium 3, UK 3, Denmark 3,
  Portugal 2, Netherlands 2, Switzerland 1,
  Sweden lt1, Austria lt1, Luxembourg lt1
• Argentina 14, Brazil 2, Mexico (not completed
  24 weeks treatment yet)

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Demographics (contd)

• Age Mean (range)
• RESIST 1 45 years (24 to 80 yrs)
• RESIST 2 43 years (17 to 76 yrs)
• Gender
• RESIST 1 91 male, 9 female
• RESIST 2 84 male, 16 female
• Race
• RESIST 1 77 Caucasian, 22 Black, 1 Asian
• RESIST 2 68 Caucasian, 5 Black, 1 Asian, 26
  Missing (France)

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Baseline Disease Characteristics
RESIST 1(1182.12) N620 RESIST 2(1182.48) N539
HIV RNA (log10 copies/mL) Mean (Range) Prop w/ HIV RNA copies/mL lt 10,000 gt10,000 to lt100,000 gt100,000 4.7 (2.0 to 6.3) 16 43 41 4.8 (2.9 to 6.8) 16 46 38
CD4 Cell Count (cells/mm3) Mean (Range) lt 200 cells/mm3 gt 200 cells/mm3 164 (0.5 to 1183.5) 67 33 224 (1.5 to 1893) 53 47
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Baseline Disease Characteristics
RESIST 1(1182.12) N620 RESIST 2(1182.48) N539
HIV infection stage Class A Class B Class C 24 19 57 17 27 56
Hepatitis B positive Hepatitis C positive Hepatitis B and C co-infected 5 7 0.5 5 14 0.9
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Protease Inhibitor Stratum
RESIST 1(1182.12) N620 RESIST 2(1182.48) N539
Genotypic resistance to Pre-selected PIs Not resistant Possibly resistant Resistant (TruGene Assay) 8 35 57 (Virtual Phenotype or TruGene Assay) 20 6 74
Protease Inhibitor Stratum LPV APV SQV IDV 61 14 21 4 38 40 20 3
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Evaluation of Potential Biases due toOpen-Label
Design
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Pre-determined T-20 Stratum versus Actual T-20 use

• Mismatches between Pre-determined vs Actual

Pre-selected T-20 (No) but Actual T-20 (Yes) Pre-selected T-20 (No) but Actual T-20 (Yes) Pre-selected T-20 (No) but Actual T-20 (Yes) Pre-selected T-20 (Yes) but Actual T-20 (No) Pre-selected T-20 (Yes) but Actual T-20 (No) Pre-selected T-20 (Yes) but Actual T-20 (No)
TPV/r N427 CPI/r N430 Total N857 TPV/r N155 CPI/r N147 Total N302
3 1 2 5 16 10
McNemars test p-value lt .001
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Pre-determined vs Actual Background Regimen

• Total of pre-determined regimen 155
• Total of actual regimen 161
• Mismatches between Pre-determined vs Actual

RESIST 1 RESIST 1 RESIST 1 RESIST 2 RESIST 2 RESIST 2
TPV/r N311 CPI/r N309 Total N620 TPV/r N271 CPI/r N268 Total N539
9 12 11 13 14 14
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Commonly Used Background Antiretroviral Regimen

• Balanced across TPV/r and CPI/r groups
• 3TC TDF (11),
• ddI TDF (8),
• 3TC ddI TDF (7),
• 3TC TDF ENF (4),
• 3TC ddI TDF ENF (3), 3TC ABC TDF
  (3), d4T TDF (3)

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Protocol Violations in RESIST 1 and RESIST 2
trials

• Unique patients with protocol violations
• 51 in TPV/r and 56 in CPI/r group
• Patients had 1 or more protocol violations of
  same or different type
• Types of protocol violations
• Screening (Entry Criteria) violations
• Treatment Regimen violations during study
• Other violations with use of concomitant drugs

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Screening Violations

• 29 TPV/r vs 32 CPI/r unique patients with
  screening violations
• E.g., no protease gene mutations at codons 30N,
  46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M
• Less than 2 PIs or less than 3 mos. of trt on
  historical therapy
• Screening viral load lt 1,000 copies/mL, etc.

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Treatment Regimen Violations

• 24 TPV/r vs 25 CPI/r unique patients with
  treatment regimen violations
• E.g., Dual-boosted PIs used
• Randomized to CPI/r group and pre-specified PI
  not taken or changed
• No new or recycled ARV in optimized background
  regimen, etc.

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Initial Lack of Virologic Response by Week 8

• Viral load has not dropped 0.5 log10 HIV RNA
  copies/mL after 8 weeks of treatment
• Failure to achieve a viral load lt100,000
  copies/mL after 8 weeks, despite a 0.5 log10 drop
  after 8 weeks of treatment
• Patients in CPI/r group may discontinue and
  roll-over to Study 1182.17 and receive
  tipranavir/ritonavir
• Escape clause may create bias in efficacy after
  Week 8

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Efficacy Evaluation
Primary Efficacy (FDA Analysis)
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Efficacy Endpoint at 24 Weeks

• Proportion of patients with confirmed 1 log
  reduction from baseline in HIV RNA without prior
  evidence of treatment failure, i.e.,
• Death
• Confirmed virologic failure
• Permanent discontinuation of study drug
• Introduction of a new ARV drug for reasons other
  than toxicity to background ARV

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Efficacy Outcomes at 24 Weeks(Intent-to-Treat
Analysis)
RESIST 1 (1182.12) RESIST 1 (1182.12) RESIST 2 (1182.48) RESIST 2 (1182.48)
TPV/r OBR N311 CPI/r OBR N309 TPV/r OBR N271 CPI/r OBR N268
Response (gt1 log reduction) 41 21 40 14
Virologic Failure 55 75 52 83
Initial Lack of Virologic Response at Week 8 35 53 35 66
Rebound Never suppressed through Week 24 13 7 13 9 10 7 10 8
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Efficacy Outcomes at 24 Weeks (contd.)
RESIST 1 (1182.12) RESIST 1 (1182.12) RESIST 2 (1182.48) RESIST 2 (1182.48)
TPV/r OBR N311 CPI/r OBR N309 TPV/r OBR N271 CPI/r OBR N268
Added ARV drug 2 2 6 1
Died 0 0 0 lt1
Discontinued due to adverse events 1 0 1 1
Discontinued due to other reasons 1 1 0 0
Discontinued while suppressed 0 1 1 0
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Sensitivity Analyses addressing Open-Label Biases

• Bias at Week 8 due to initial lack of virologic
  response
• incorporated into ITT analysis
• Probability of response (gt1 log reduction in HIV
  RNA) was 0.5 in TPV/r vs 1.5 in CPI/r if lack
  of virologic response (gt 0.5 log reduction) by
  Week 8
• Bias due to Wrong T-20 stratum
• Bias due to each type of protocol violation

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Sensitivity Analysis?Efficacy Results
Analysis type TPV/r OBR N582 CPI/r OBR N577 Difference (TPV/r-CPI/r) (95 CI)
ITT 234 (40) 103 (18) 22 (17, 27)
ITT adjusting wrong T-20 stratum 232 (40) 126 (22)
Per-Protocol (Exclude Treatment Regimen Violations) 215/507 (42) 98/480 (20)
Per-Protocol (Exclude Screening Violations) 191/465 (41) 82/457(18)
18(13, 23)
22(16, 27)
23(17, 29)
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Subgroup Analyses

• By T-20 stratum
• By Control Protease Inhibitors adjusting for
  Resistance and Experience

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Subgroup-Analysis by T-20 use stratum
Enfuvirtide (ENF, T-20) used? TPV/r CPI/r Difference in proportions (95 CI) P-value for treatment by subgroup interaction
Yes (25) 48 19 29 (19, 30) 0.02
No (75) 29 13 16 (10, 21) 0.02
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New Definition of Combined Resistance
Experience Patterns

• Susceptible Naïve
• Not resistant and prior duration of exposure to
  PI is lt1 month
• Susceptible Experienced
• Not resistant and prior duration of exposure to
  PI is 1-lt6 month or gt6 months
• Resistant
• Possibly resistant or Resistant according to
  TruGene or Virtual Phenotype assay regardless of
  prior duration of exposure to PI

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Baseline Resistance Patterns in PI Strata
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Confidence Intervals on Treatment Differences
(TPV/r CPI/r)
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Summary of Efficacy

• FDA analysis confirmed that tipranavir was
  statistically significantly better than the
  control with respect to the surrogate endpoint of
  percent with at least 1 log decrease in viral
  load at 24 weeks.
• Efficacy of tipranavir/ritonavir was shown when
  the best available comparator protease inhibitor
  was sub-optimal.
• Sensitivity analyses adjusting for open-label
  biases in RESIST trials
• Results were consistent with the efficacy shown
• Net treatment benefit will range from 13 to 29.

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Summary of Efficacy (contd.)

• Efficacy of tipranavir/ritonavir was demonstrated
  regardless of T-20 use, but the efficacy was
  significantly greater when combined with T-20
• Boosted tipranavir is not proven to be better
  than boosted lopinavir, or amprenavir, or
  saquinavir, if patients are naïve and not
  resistant to respective protease inhibitors.
• No data available on indinavir on susceptible
  naïve patients.

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Acknowledgment

• FDA colleagues
• Greg Soon, Ph.D., Statistics Team Leader
• Andrea James, M.D., Medical Reviewer
• Rosemary Johann-Liang, M.D., Medical Team Leader
• Tom Hammerstrom, Ph.D., Statistician Reviewer