tipranavir nda 21-814: efficacy evaluation rafia bhore, ph.d. statistician reviewer division of...

Tipranavir NDA 21-814:Efficacy 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

May 19, 2005 FDA Antiviral Drugs Advisory Committee Meeting 2

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


Study Design of RESIST* Trials

(Studies 1182.12 and 1182.48)*Randomized Evaluation of Strategic Intervention in

Multi-Drug ReSistant Patients with Tipranavir

STUDIES 1182.12 (RESIST 1) and 1182.48 (RESIST 2)

Open-label, Controlled, Highly ARV-experienced patients

At least 1primary protease

resistance mutations atcodons: 30N, 46I/L, 48V,

50V, 82 A/F/L/T, 84V,or 90 M

?

Yes

ScreeningFailure

2mutations at

codons 33, 82, 84,

or 90 ?

GenotypeResistance

Testing

SCREENING3 ARV class and

dual PI-experienced

No

Enroll in Trial 1182.51

No

Yes

Enroll in RESIST Trial

Go to A

RESIST 1: USA, Canada, Australia

RESIST 2: Europe, Latin America

4

either

or

TPV 500 mg bid + RTV 200 mg bid + OBR

PI + RTV + OBR

APV/RTVSQV/RTVIDV/RTVLPV /RTV

RANDOMIZEto

Pre-select PI(Protease Inhibitor)based on genotypic

resistance test

Select OBR(OPTIMIZED BACKGROUND REGIMEN)

based on screening genotype test and ARV medication history

A

Week 8 Week 24 Week 48 Week 96

Open-label

Roll-overTrial 1182.17

Patients in comparator PI/RTVgroup with lack of initial

virologic response or confirmed virologic failure will roll-over to

TPV/RTV groupin Roll-Over Trial 1182.17

Week 8 Week 24 Week 48 Week 96

NOTES:

PI=Protease Inhibitor

TPV=tipranavir, RTV=ritonavir

APV=amprenavir, SQV=saquinavir

IDV=indinavir, LPV=lopinavir 5

Amendment # 2Allowed patients with

highly PI resistant virus to be treated with PI-based regimen.


Patient Disposition


Patient DispositionNumber of patients TPV/r + OBR CPI/r + OBRTotal 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%


Demographics and Baseline Characteristics


Demographics

• RESIST 1 (N=620)– USA (80%), Canada (13%), Australia (7%)

• RESIST 2 (N=539)– 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 <1%, Austria <1%, Luxembourg <1%

• Argentina 14%, Brazil 2%, Mexico (not completed 24 weeks treatment yet)


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)


Baseline Disease CharacteristicsRESIST 1(1182.12)

N=620

RESIST 2(1182.48)

N=539

HIV RNA (log10 copies/mL)

Mean (Range)

Prop w/ HIV RNA copies/mL

< 10,000

>=10,000 to <100,000

>=100,000

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)

< 200 cells/mm3

>= 200 cells/mm3

164 (0.5 to 1183.5)

67%

33%

224 (1.5 to 1893)

53%

47%


Baseline Disease Characteristics

RESIST 1(1182.12)

N=620

RESIST 2(1182.48)

N=539

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%


Protease Inhibitor StratumRESIST 1(1182.12)

N=620

RESIST 2(1182.48)

N=539

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%


Evaluation of Potential Biases due to

Open-Label Design


Pre-determined T-20 Stratum versus Actual T-20 use

Pre-selected T-20 (No) but

Actual T-20 (Yes)

Pre-selected T-20 (Yes) but

Actual T-20 (No)TPV/rN=427

CPI/rN=430

TotalN=857

TPV/rN=155

CPI/rN=147

TotalN=302

3% 1%* 2% 5% 16%* 10%

* McNemar’s test p-value < .001

• Mismatches between Pre-determined vs Actual


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 2

TPV/rN=311

CPI/rN=309

TotalN=620

TPV/rN=271

CPI/rN=268

TotalN=539

9% 12% 11% 13% 14% 14%


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%)


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


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 < 1,000 copies/mL, etc.


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.


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 <100,000 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


Efficacy EvaluationPrimary Efficacy (FDA Analysis)


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


Efficacy Outcomes at 24 Weeks(Intent-to-Treat Analysis)

RESIST 1 (1182.12) RESIST 2 (1182.48)

TPV/r + OBR

N=311

CPI/r + OBR

N=309

TPV/r + OBR

N=271

CPI/r + OBR

N=268

Response (>=1 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%


Efficacy Outcomes at 24 Weeks (contd.)

RESIST 1 (1182.12) RESIST 2 (1182.48)

TPV/r + OBR

N=311

CPI/r + OBR

N=309

TPV/r + OBR

N=271

CPI/r + OBR

N=268

Added ARV drug 2% 2% 6% 1%

Died 0% 0% 0% <1%

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%


Sensitivity Analyses addressing Open-Label Biases

• Bias at Week 8 due to initial lack of virologic

response – incorporated into ITT analysis

– Probability of response (>=1 log reduction in HIV RNA) was

0.5% in TPV/r vs 1.5% in CPI/r if lack of virologic response

(>= 0.5 log reduction) by Week 8

• Bias due to Wrong T-20 stratum

• Bias due to each type of protocol violation


Sensitivity AnalysisEfficacy Results

Analysis type

TPV/r + OBR

N=582

CPI/r + OBR

N=577

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%)


Subgroup Analyses• By T-20 stratum

• By Control Protease Inhibitors adjusting for Resistance and Experience


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%)

0.02No (75%) 29% 13% 16%

(10%, 21%)


New Definition of Combined Resistance & Experience Patterns

• Susceptible Naïve – Not resistant and prior duration of exposure to PI

is <=1 month

• Susceptible Experienced– Not resistant and prior duration of exposure to PI

is 1-<6 month or >=6 months

• Resistant– Possibly resistant or Resistant according to

TruGene or Virtual Phenotype assay regardless of prior duration of exposure to PI


Baseline Resistance Patterns in PI Strata

38

192

245

526

2

17

14

23

1

33

25

41

0 100 200 300 400 500 600

IDV

SQV

APV

LPV

Prot

ease

Inhi

bito

r Stra

tum

Number of Patients in Each Stratum

SusceptibleNaïve

SusceptibleExperienced

Resistant


Confidence Intervals on Treatment Differences (TPV/r – CPI/r)

40%35%

71%

26%35%

41%

64%

-28% -26%

-8%

12% 14%18% 16%

-40%

-20%

0%

20%

40%

60%

80%

LPV/r APV/r SQV/r LPV/r APV/r SQV/r IDV/r

% o

f Res

po

nd

ers

95% UCL

Difference

95% LCL

Active PI(Susceptible Naïve)

Sub-Optimal PI(Experienced or Resistant)


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%.


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.


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

tipranavir nda 21-814: efficacy evaluation rafia bhore, ph.d. statistician reviewer division of...

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