Correctional Health Advisory Board Meeting 2000

1
Design of the RESIST Study Program
Dr Kevin Curry Boehringer Ingelheim, Bracknell,
UK
2
Tipranavir Clinical Development Plan - Phase
II-III Program
RESIST-1N500, 24W TPV/RTV vs. PI/RTV OBR NA,
AUS
1182.52Phase IIB 500/100 500/200 750/200
Analysis, choose optimal dose
RESIST-2N800, 16W TPV/RTV vs. PI/RTV OBR EU, SA
1182.51 3-PI, PK/Safety
RESIST-33-PI, Efficacy
1182.17/.57 Rollover Studies
3
Tipranavir Trough Concentrations
TPV morning Cmin (minmedianmax µM) after 21 days
exposure to TPV/RTV
TPV (mg BID)
RTV (mg BID)
1250
1000
750
500
250
1.81 0.13 5.88
0.95 0.11 4.74
0.69 0.06 3.13
0.63 0.25 1.32
0.28 0.06 0.48
0 n12 to 25
38 BLQ 173
76 BLQ 143
25 BLQ 80
23 BLQ 66
------
100 n 10 to 14
-----
59 BLQ 173
60 BLQ 102
32 0.7 71
15 0.1 47
200 n 11 to 12
Study day 11 (prior to coadministration of
RTV) BLQ below the limit of quantitation
4
Tipranavir Adverse Event DataTrials 1182.2, .3,
and .4
TPV 300
TPV 500
TPV 500
TPV 1000
TPV 1200
TPV 1250
RTV 200
RTV 100
RTV 100
RTV 100
RTV 200
RTV 100
(1182.3)
(1182.2)
(1182.4)
(1182.2)
(1182.3)
(1182.4)
14 days
48 weeks
16 weeks
48 weeks
14 days
16 weeks
Duration
N
10
19
21
22
11
21
Patient
Naïve
Multiple PI
Single PI
Multiple PI
Naïve
Single PI
Failure
Failure
Failure
Failure
Population
Diarrhea
30
42
33
73
64
43
(any Grade)
Nausea
0
26
19
36
55
43
Vomiting
10
11
0
23
18
33
All AEs
80
100
71
100
81.8
81
5
Tipranavir Efficacy DataTrials 1182.2, .3, and .4
TPV 300
TPV 500
TPV 1200
TPV 500
TPV 1000
TPV 1250
RTV 200
RTV 100
RTV 200
RTV 100
RTV 100
RTV 100
(1182.3)
(1182.4)
(1182.3)
(1182.2)
(1182.2)
(1182.4)
Analysis
AT/OC
ITT
AT/OC
FAS
FAS
ITT
Duration
14 days
16 weeks
14 days
48 weeks
48 weeks
16 weeks
N
10
20
11
19
22
21
Patient
Naïve
Single PI
Naïve
Multiple PI
Multiple PI
Single PI
Population
Failure
Failure
Failure
Failure
1.40 log
Mean VL
1.43 log
1.30 log
1.64 log
2.34 log
1.71 log
Reduction
BLQ 400
0.0
38.9
20.0
78.9
50.0
55.0
BLQ 50
0.0
22.2
0.0
68.4
40.9
35.0
CD4 Count
41.5
80
83
184
149
-6
Change
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 gt2 PI regimen experience
  3-class experience
• gt1 major PI mutation lt1 of 82T, 84V, 90M
• Duration up to 32 weeks before rollover

7
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

8
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

9
Tipranavir Clinical Development Plan - Phase
II-III Program
RESIST-1N500, 24W TPV/RTV vs. PI/RTV OBR NA,
AUS
1182.52Phase IIB 500/100 500/200 750/200
Analysis, choose optimal dose
RESIST-2N800, 16W TPV/RTV vs. PI/RTV OBR EU, SA
1182.51 3-PI, PK/Safety
RESIST-33-PI, Efficacy
1182.17/.57 Rollover Studies
10
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 gt 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
  gt 1 log10 reduction in viral load at 24 weeks.

11
Phase III Trial--Registrational StudyRESIST-1
(BI 1182.12)

• DESIGN
• Patient population
• HIV adults with gt2 PI regimen experience
  3-class experience
• gt1 major PI mutation (30N, 46I, 46L, 48V, 50V,
  82A, 82F, 82L, 82T, 84V or 90M)
• lt1 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

12
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)

13
Tipranavir Clinical Development Plan - Phase
II-III Program
RESIST-1N500, 24W TPV/RTV vs. PI/RTV OBR NA,
AUS
1182.52Phase IIB 500/100 500/200 750/200
Analysis, choose optimal dose
RESIST-2N800, 16W TPV/RTV vs. PI/RTV OBR EU, SA
1182.51 3-PI, PK/Safety
RESIST-33-PI, Efficacy
1182.17/.57 Rollover Studies
14
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 gt 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
  gt 1 log10 reduction in viral load at 16 weeks.

15
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

16
Tipranavir Clinical Development PlanPhase II-III
Program
RESIST-1N500, 24W TPV/RTV vs. PI/RTV OBR NA,
AUS
1182.52Phase IIB 500/100 500/200 750/200
Analysis, choose optimal dose
RESIST-2N800, 16W TPV/RTV vs. PI/RTV OBR EU, SA
1182.51 3-PI, PK/Safety
RESIST-33-PI, Efficacy
1182.17/.57 Rollover Studies
17
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

18
Phase I-II Trial--1st Companion StudyBI 1182.51

• DESIGN
• Patient population
• HIV adults with gt2 PI regimen experience
  3-class experience
• gt1 major PI mutation (30N, 46I, 46L, 48V, 50V,
  82A, 82F, 82L, 82T, 84V or 90M)
• gt2 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

19
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

20
Tipranavir Clinical Development Plan - Phase
II-III Program
RESIST-1N500, 24W TPV/RTV vs. PI/RTV OBR NA,
AUS
1182.52Phase IIB 500/100 500/200 750/200
Analysis, choose optimal dose
RESIST-2N800, 16W TPV/RTV vs. PI/RTV OBR EU, SA
1182.51 3-PI, PK/Safety
RESIST-33-PI, Efficacy
1182.17/.57 Rollover Studies
21
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

22
Phase III Trial--2nd Companion StudyRESIST-3 (BI
1182.13)

• DESIGN
• Patient population
• HIV adults with gt2 PI regimen experience
  3-class experience
• gt1 major PI mutation (30N, 46I, 46L, 48V, 50V,
  82A, 82F, 82L, 82T, 84V or 90M)
• gt2 of 82L, 82T, 84V, 90M
• Duration
• 48 weeks

23
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

24
Tipranavir Clinical Development PlanPhase III,
Peds, Naïve, EA Program
Pediatric PK Trial .14
Phase III Program
1182.52Phase IIB
Dose Selection, PK Analysis
Naïve Trial .33
EXPANDED ACCESS
25
Tipranavir PK Development Program

• Completed or ongoing studies
• Grid study
• Antivirals
• Multiple ARV regimens
• NRTIs ZDV, ddI
• NTRTI tenofovir
• NNRTIs EFV
• Oral contraceptive, loperamide

26
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

27
Tipranavir Clinical Development Plan - Phase
II-III Program
RESIST-1N500, 24W TPV/RTV vs. PI/RTV OBR NA,
AUS
1182.52Phase IIB 500/100 500/200 750/200
Analysis, choose optimal dose
RESIST-2N800, 16W TPV/RTV vs. PI/RTV OBR EU, SA
1182.51 3-PI, PK/Safety
RESIST-33-PI, Efficacy
1182.17/.57 Rollover Studies