Design of the RESIST Study Program

Dr Kevin Curry

Boehringer Ingelheim, Bracknell, UK

1182.52Phase IIB500/100500/200750/200

RESIST-1N=500, 24W

TPV/RTV vs. PI/RTV +OBRNA, AUS

RESIST-2N=800, 16W

TPV/RTV vs. PI/RTV +OBREU, SA

1182.513-PI, PK/Safety

RESIST-33-PI, Efficacy

Tipranavir Clinical Development Plan - Phase II-III Program

1182.17/.57 Rollover Studies

Analysis, choose optimal dose

Tipranavir Trough Concentrations

*Study day 11 (prior to coadministration of RTV)† BLQ = below the limit of quantitation

TPV morning Cmin (minmedianmax µM) after 21 days exposure to TPV/RTV

-----59BLQ 173

60BLQ 102

320.7 71

150.1 47

200 n= 11 to 12

38

BLQ 173

76

BLQ 143

25

BLQ 80

23

BLQ† 66

------100 n= 10 to 14

1.810.13 5.88

0.950.11 4.74

0.690.06 3.13

0.630.25 1.32

0.280.06 0.48

0* n=12 to 25

12501000750500250

TPV (mg BID)

RTV (mg BID)

TPV 300RTV 200

(1182.3)

TPV 500RTV 100

(1182.2)

TPV 500RTV 100

(1182.4)

TPV 1000RTV 100

(1182.2)

TPV 1200RTV 200

(1182.3)

TPV 1250RTV 100

(1182.4)

Duration 14 days 48 weeks 16 weeks 48 weeks 14 days 16 weeks

N 10 19 21 22 11 21

PatientPopulation

Naïve Multiple PIFailure

Single PIFailure

Multiple PIFailure

Naïve Single PIFailure

Diarrhea(any Grade)

30% 42% 33% 73% 64% 43%

Nausea 0 26% 19% 36% 55% 43%

Vomiting 10% 11% 0 23% 18% 33%

All AEs 80% 100% 71% 100% 81.8% 81%

Tipranavir Adverse Event DataTrials 1182.2, .3, and .4

Tipranavir Efficacy DataTrials 1182.2, .3, and .4

TPV 300RTV 200

(1182.3)

TPV 500RTV 100

(1182.4)

TPV 1200RTV 200

(1182.3)

Analysis AT/OC ITT AT/OC

Duration 14 days 16 weeks 14 days

N 10 20 11

PatientPopulation

Naïve Single PIFailure

Naïve

Mean VLReduction

1.43 log 1.30 log 1.64 log

% BLQ 400 0.0 38.9% 20.0

% BLQ 50 0.0 22.2% 0.0

CD4 CountChange

+41.5 +80 +83

TPV 500RTV 100

(1182.2)

TPV 1000RTV 100

(1182.2)

TPV 1250RTV 100

(1182.4)

FAS FAS ITT

48 weeks 48 weeks 16 weeks

19 22 21

Multiple PIFailure

Multiple PIFailure

Single PIFailure

2.34 log 1.71 log 1.40 log

78.9% 50.0% 55.0%

68.4% 40.9% 35.0%

+184 +149 -6

Phase IIB Trial--Dose OptimizationBI 1182.52

DESIGN

Objective: define “maximum tolerated dose”

Primary endpoints

Viral load reduction (efficacy) at 14 days

Incidence of GI adverse events (safety) at 28 days

Patient population

HIV+ adults with >2 PI regimen experience & 3-class experience

>1 major PI mutation & <1 of 82T, 84V, 90M

Duration: up to 32 weeks before rollover

DESIGN

Objective: define “maximum tolerated dose”

Primary endpoints

Viral load reduction (efficacy) at 14 days

Incidence of GI adverse events (safety) at 28 days

Patient population

HIV+ adults with >2 PI regimen experience & 3-class experience

>1 major PI mutation & <1 of 82T, 84V, 90M

Duration: up to 32 weeks before rollover

Phase IIB Trial--Dose OptimizationBI 1182.52

TREATMENT

All patients receive TPV/RTV + optimized background regimen (OBR)

3 doses of TPV/RTV:

750mg/200mg

500mg/200mg

500mg/100mg

OBR is individually determined for each patient from baseline genotyping and treatment history

TREATMENT

All patients receive TPV/RTV + optimized background regimen (OBR)

3 doses of TPV/RTV:

750mg/200mg

500mg/200mg

500mg/100mg

OBR is individually determined for each patient from baseline genotyping and treatment history

Phase IIB Trial--Dose OptimizationBI 1182.52

STATUS UPDATE

Trial initiated 29 April 2002 in 9 countries

406 patients screened; 206 enrolled and receiving treatment

Final patient will complete 4 weeks on 31 July

Rapid data collection and analysis to follow

Discussions with regulatory authorities planned for fall 2002

Phase III program to begin following regulatory approval

STATUS UPDATE

Trial initiated 29 April 2002 in 9 countries

406 patients screened; 206 enrolled and receiving treatment

Final patient will complete 4 weeks on 31 July

Rapid data collection and analysis to follow

Discussions with regulatory authorities planned for fall 2002

Phase III program to begin following regulatory approval

1182.52Phase IIB500/100500/200750/200

RESIST-1N=500, 24W

TPV/RTV vs. PI/RTV +OBRNA, AUS

RESIST-2N=800, 16W

TPV/RTV vs. PI/RTV +OBREU, SA

1182.513-PI, PK/Safety

RESIST-33-PI, Efficacy

Tipranavir Clinical Development Plan - Phase II-III Program

1182.17/.57 Rollover Studies

Analysis, choose optimal dose

Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12)

DESIGN

Objective

Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults

Primary endpoints

Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48.

An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in viral load at 24 weeks.

DESIGN

Objective

Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults

Primary endpoints

Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48.

An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in viral load at 24 weeks.

Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12)

DESIGN

Patient population

HIV+ adults with >2 PI regimen experience & 3-class experience

>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)

<1 of 82L, 82T, 84V, 90M

Duration

48 weeks

Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment

DESIGN

Patient population

HIV+ adults with >2 PI regimen experience & 3-class experience

>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)

<1 of 82L, 82T, 84V, 90M

Duration

48 weeks

Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment

Phase III Trial--Registrational StudyRESIST-1 (BI 1182.12)

TREATMENT

Investigators must pre-declare preferred comparator PI and OBR from baseline genotyping and treatment history

Once randomized, patients will receive

TPV/RTV + OBR, or

Comparator PI/RTV +OBR

N= 247 patients per arm

PARTICIPATING COUNTRIES

Canada, USA, Australia (~100 sites)

TREATMENT

Investigators must pre-declare preferred comparator PI and OBR from baseline genotyping and treatment history

Once randomized, patients will receive

TPV/RTV + OBR, or

Comparator PI/RTV +OBR

N= 247 patients per arm

PARTICIPATING COUNTRIES

Canada, USA, Australia (~100 sites)

1182.52Phase IIB500/100500/200750/200

RESIST-1N=500, 24W

TPV/RTV vs. PI/RTV +OBRNA, AUS

RESIST-2N=800, 16W

TPV/RTV vs. PI/RTV +OBREU, SA

1182.513-PI, PK/Safety

RESIST-33-PI, Efficacy

Tipranavir Clinical Development Plan - Phase II-III Program

1182.17/.57 Rollover Studies

Analysis, choose optimal dose

Phase III Trial--Registrational StudyRESIST-2 (BI 1182.48)

DESIGN

Objective

Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults

Primary endpoints

Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48.

An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in

viral load at 16 weeks.

DESIGN

Objective

Determine the safety and efficacy of TPV/RTV versus RTV-boosted comparator PI in highly treatment experienced HIV+ adults

Primary endpoints

Proportion of patients with a > 1 log10 reduction in viral load at 48 weeks and the time to treatment failure up to Week 48.

An interim analysis will be conducted to evaluate the proportion of patients with a > 1 log10 reduction in

viral load at 16 weeks.

Phase III Trial--Registrational StudyRESIST-2 (BI 1182.48)

DESIGN

N= 404 patients per arm

PARTICIPATING COUNTRIES

France, Germany, Spain, United Kingdom, Sweden, Italy, Portugal, Greece, Denmark, Belgium, Netherlands

Argentina, Mexico

DESIGN

N= 404 patients per arm

PARTICIPATING COUNTRIES

France, Germany, Spain, United Kingdom, Sweden, Italy, Portugal, Greece, Denmark, Belgium, Netherlands

Argentina, Mexico

1182.52Phase IIB500/100500/200750/200

RESIST-1N=500, 24W

TPV/RTV vs. PI/RTV +OBRNA, AUS

RESIST-2N=800, 16W

TPV/RTV vs. PI/RTV +OBREU, SA

1182.513-PI, PK/Safety

RESIST-33-PI, Efficacy

Tipranavir Clinical Development PlanPhase II-III Program

1182.17/.57 Rollover Studies

Analysis, choose optimal dose

Phase I-II Trial--1st Companion StudyBI 1182.51

DESIGN

Objective

PK drug interaction between TPV/RTV and APV, LPV, and SQV

Primary endpoints

APV, LPV, SQV Cmin ratio between week 8 and baseline

Safety

DESIGN

Objective

PK drug interaction between TPV/RTV and APV, LPV, and SQV

Primary endpoints

APV, LPV, SQV Cmin ratio between week 8 and baseline

Safety

Phase I-II Trial--1st Companion StudyBI 1182.51

DESIGN

Patient population

HIV+ adults with >2 PI regimen experience & 3-class experience

>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)

>2 of 82L, 82T, 84V, 90M

Duration

48 weeks

Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment

DESIGN

Patient population

HIV+ adults with >2 PI regimen experience & 3-class experience

>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)

>2 of 82L, 82T, 84V, 90M

Duration

48 weeks

Upon the last patient completing 48 weeks, all patients may participate in a rollover trial to receive continued treatment

Phase I-II Trial--1st Companion StudyBI 1182.51

TREATMENT

Patients will be randomized to one of four arms

TPV/RTV + OBR

TPV/RTV/APV +OBR

TPV/RTV/LPV +OBR

TPV/RTV/SQV + OBR

N= 50 patients per arm

PARTICIPATING COUNTRIES

ALL in either RESIST-1 and RESIST-2

TREATMENT

Patients will be randomized to one of four arms

TPV/RTV + OBR

TPV/RTV/APV +OBR

TPV/RTV/LPV +OBR

TPV/RTV/SQV + OBR

N= 50 patients per arm

PARTICIPATING COUNTRIES

ALL in either RESIST-1 and RESIST-2

1182.52Phase IIB500/100500/200750/200

RESIST-1N=500, 24W

TPV/RTV vs. PI/RTV +OBRNA, AUS

RESIST-2N=800, 16W

TPV/RTV vs. PI/RTV +OBREU, SA

1182.513-PI, PK/Safety

RESIST-33-PI, Efficacy

Tipranavir Clinical Development Plan - Phase II-III Program

1182.17/.57 Rollover Studies

Analysis, choose optimal dose

Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13)

DESIGN

Objective

Safety and efficacy of a 3-PI regimen in very highly treatment experienced HIV+ adults

Primary endpoints

Viral load reduction at 24/48 weeks

Timing

Will follow analysis of 8-week data from trial 1182.51

DESIGN

Objective

Safety and efficacy of a 3-PI regimen in very highly treatment experienced HIV+ adults

Primary endpoints

Viral load reduction at 24/48 weeks

Timing

Will follow analysis of 8-week data from trial 1182.51

Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13)

DESIGN

Patient population

HIV+ adults with >2 PI regimen experience & 3-class experience

>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)

>2 of 82L, 82T, 84V, 90M

Duration

48 weeks

DESIGN

Patient population

HIV+ adults with >2 PI regimen experience & 3-class experience

>1 major PI mutation (30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M)

>2 of 82L, 82T, 84V, 90M

Duration

48 weeks

Phase III Trial--2nd Companion StudyRESIST-3 (BI 1182.13)

TREATMENT

Patients will be randomized to one of four arms

TPV/RTV/APV +OBR

TPV/RTV/LPV +OBR

TPV/RTV/SQV + OBR

N= ~50 patients per arm

PARTICIPATING COUNTRIES

ALL in either RESIST-1 and RESIST-2

TREATMENT

Patients will be randomized to one of four arms

TPV/RTV/APV +OBR

TPV/RTV/LPV +OBR

TPV/RTV/SQV + OBR

N= ~50 patients per arm

PARTICIPATING COUNTRIES

ALL in either RESIST-1 and RESIST-2

1182.52Phase IIB

Phase III Program

Tipranavir Clinical Development PlanPhase III, Peds, Naïve, & EA Program

Dose Selection,

PK Analysis

Pediatric PK Trial.14

EXPANDEDACCESS

Naïve Trial.33

Tipranavir PK Development Program

Completed or ongoing studies

Grid study

Antivirals:

Multiple ARV regimens

NRTIs: ZDV, ddI

NTRTI: tenofovir

NNRTIs: EFV

Oral contraceptive, loperamide

Completed or ongoing studies

Grid study

Antivirals:

Multiple ARV regimens

NRTIs: ZDV, ddI

NTRTI: tenofovir

NNRTIs: EFV

Oral contraceptive, loperamide

Tipranavir PK Development Program

Planned studies

Other drugs: clarithromycin, fluconazole, rifampin, methadone, rifabutin, atorvastatin

PK/PD: ADME, bioequivalence, GI transit, high fat/antacid

Special populations: hepatic/renal insufficiency

Planned studies

Other drugs: clarithromycin, fluconazole, rifampin, methadone, rifabutin, atorvastatin

PK/PD: ADME, bioequivalence, GI transit, high fat/antacid

Special populations: hepatic/renal insufficiency

1182.52Phase IIB500/100500/200750/200

RESIST-1N=500, 24W

TPV/RTV vs. PI/RTV +OBRNA, AUS

RESIST-2N=800, 16W

TPV/RTV vs. PI/RTV +OBREU, SA

1182.513-PI, PK/Safety

RESIST-33-PI, Efficacy

Tipranavir Clinical Development Plan - Phase II-III Program

1182.17/.57 Rollover Studies

Analysis, choose optimal dose