1 may 19, 2005 antiviral drugs advisory committee aptivus ® (tipranavir) capsules

1

May 19, 2005

Antiviral Drugs Advisory CommitteeAPTIVUS® (tipranavir) Capsules

2

Introduction

Burkhard Blank, MDSenior Vice PresidentMedicine and Drug Regulatory Affairs

3

Clinical Need Growing population of treatment-experienced HIV+ patients

with limited treatment options

3% to 5% of newly HIV-infected patients have multidrug resistant HIV-1

Multidrug resistant HIV-1 is associated with increased AIDS progression and death

4

Tipranavir Shows significant antiviral activity against the majority

of multidrug resistant HIV-1

Challenging clinical development program in PI treatment- experienced HIV+ patients

Offers a significant new treatment option for PI treatment-experienced patients

5

Tipranavir – Proposed Indication

“Tipranavir, co-administered with low-dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients who are protease inhibitor treatment‑experienced.”

6

Presentation Overview

Tipranavir Development Douglas Mayers, MD

Efficacy Scott McCallister, MD

Drug-Drug Interactions

Safety Christopher Corsico, MD

Resistance Douglas Mayers, MD

Clinical Utility Daniel Kuritzkes, MD

Conclusions Burkhard Blank, MD

7

Consultants Available to the Committee

Angela D.M. Kashuba, PharmD University of North Carolina- Chapel Hill

Daniel R. Kuritzkes, MDHarvard Medical School

Jens D. Lundgren, MDUniversity of CopenhagenDenmark

Joel Morganroth, MDUniversity of Pennsylvania

Jonathan M. Schapiro, MDStanford University Schoolof Medicine

Mark Sulkowski, MDJohns Hopkins University School of Medicine

8

Tipranavir Development

Douglas Mayers, MDInternational Head, Therapeutic Area Virology

9

Novel nonpeptidic protease inhibitor developed to provide a new treatment option for PI-experienced patients

Potent in vitro activity against both WT HIV-1 and HIV-2, and the majority of multiple PI-resistant HIV-1

Requires co-administration with ritonavir

Available as a soft-gel capsule (250 mg)

CH3OH

NH

O O

SO2

NF3C

H3C

TipranavirOverview

10

TipranavirDevelopment Initial development by P & U; BI acquired in 2000

End of Phase II Meeting with FDA 17 December 2002 Concurrence with TPV/r dose selection of 500mg/200mg BID Agreement on original clinical trial protocol design for pivotal

Phase III trials

Tipranavir NDA for accelerated approval submitted toFDA 22 December 2004 Based on 24-week efficacy/safety data

11

TipranavirClinical Development Program 39 clinical trials

25 trials by BI 11 in HIV+ patients 14 in HIV- subjects

Two nearly identical Phase III studies (RESIST) began in early 2003: 1485 patients, more than 270 sites, 21 countries

1411 patients treated with the TPV/r 500/200 dose,1206 patients treated for at least 24 weeks

Pediatric and treatment-naïve adult studies ongoing

12

TipranavirCo-Administration with Ritonavir

TPV exposure markedly enhanced with RTV co-administration

Cytochrome P450 3A is the major metabolic pathway

TPV induces CYP 3A

TPV and RTV co-administration results in net inhibition of CYP 3A

Mea

n Pl

asm

aTi

pran

avir

Con

cent

ratio

n (

M)

125

100

75

50

25

0Target

0 2 4 6 8 10 12

4x Cmaxss

9x greater exposure at steady-state

Time (h)

48x Cminss

TPV/r 500/200mgTPV 500mg alone

13

TipranavirCombined with Ritonavir ADMEIn Vitro Using human microsomes, the inhibition potential for TPV had a rank order of:

CYP 2C9 > CYP 3A4 > CYP 2C19 > CYP 2D6 > CYP 1A2

Absorption Formulated in a “self-emulsifying drug delivery system” (SEDDS) for solubility Food improves emulsification TPV/r induces the P-gp efflux transporter system

Distribution Protein binding >99.9%

Metabolism Substrate for and inducer of the cytochrome P450 3A system Must be taken with RTV to inhibit first pass effect Predominantly unchanged drug measured in plasma, urine, and feces

Excretion Half-life of 6 hours (TPV/r 500/200) in HIV+ patients Majority excreted in feces Less than 5% excreted in urine

14

Dose FindingBI 1182.52NA, EU, AUS

N=216

RESIST-1 BI 1182.12

North AmericaAustralia

RESIST-2BI 1182.48Europe

Latin America

Companion StudyBI 1182.51

All RESIST Countries

Pediatrics, Naïve AdultsEmergency Use Expanded Access

TipranavirPhase II-III Study Program

Rollover Study, BI 1182.17, All RESIST Countries

Optimal DoseTPV/r 500/200

15

TipranavirDose Finding Study Conclusions 3 TPV/r doses (500/100, 500/200, 750/200) BID studied in

216 patients with 3-class and 2 PI-regimen experience

500/200 dose selected for the Phase III trial program 500/100 dose eliminated due to inferior efficacy in patients with

drug resistant viruses and more variable PK results 500/200 and 750/200 doses had similar efficacy and PK profiles 750/200 dose eliminated due to a higher rate of Grade 3 / 4

ALT/AST elevations and treatment discontinuations

16

TipranavirKey Mutations Mutations at codons 33, 82, 84 and 90 of HIV-1 protease

Were either selected in early in vitro or in vivo studies or seen in HIV-1 isolates with decreased susceptibility to tipranavir

In the Phase II program multiple mutations at these sites: Associated with decreased TPV/r responses Associated with broad, high level resistance to other PIs

(SQV, IDV, LPV, APV)

Used to select patients unlikely to get a durable response to any single PI-based regimen who were offered dual-boosted PI regimens containing TPV

17

RESIST Pivotal Trial Program

Scott McCallister, MDGlobal Medical Team Leader, TPV

18


RESIST-1 BI 1182.12


N=620, SafetyN=620, Efficacy


Latin AmericaN=865, Safety

N=539, Efficacy







19

RESIST StudiesKey Design IssuesChallenging heterogeneous study population with limitedtreatment options

Open label studies Four treatment options for comparator arm PI Efforts made to reduce potential for bias

Week 8 escape: patients in comparator arms could leaveand receive TPV in rollover study Must have confirmed virologic failure Could not roll over due to AEs only

Optimized background regimen (OBR) Any available approved NRTIs or NNRTIs ENF could be used All drugs must be pre-declared prior to randomization

20

RESIST StudiesKey Inclusion/Exclusion Criteria

Inclusion 3 months’ therapy with NRTIs, NNRTIs, and PIs

2 PI regimens for 3 consecutive months One PI must be current regimen

Viral load 1000 copies/mL on therapy, any CD4+ cell count

Baseline genotype 1 primary PI mutation at codons:30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M

Exclusion > 2 mutations at codons 33, 82, 84, or 90

DAIDS Grade > 1 safety labs (except lipids)

Expected survival less than 12 months

21

RESIST StudiesScreening and Randomization

Pre-Selection of CPI/r and

OBR

Resistance Expert

Consultation

Stratified Randomization

(by CPI/r and ENF)

Screening Genotype

(Virtual Phenotype™ or TruGene®)

LPV/rIDV/rSQV/rAPV/r

TPV/r

Best PI choice

PlusOBR

1:1

22

RESIST Studies24-Week EndpointsPrimary endpoint: treatment response defined as:

Confirmed 1 log10 reduction in viral load from baseline

at 24 weeks without Viral rebound

ARV treatment change

Study discontinuation

Death

Secondary efficacy endpoints Change in viral load from baseline

Proportion of patients with VL < 50 and < 400 copies/mL

Change from baseline in CD4 cell count

AIDS progression events

23

RESIST StudiesEarly Protocol Modification Amendment #2 implemented prior to any patient randomizations Allowed PIs that the genotype report interpreted as pan-resistant

Rationale Interpretation guidelines changed just prior to study initiations

Resistance interpretation on genotype reports not based on RTV-boosting

Investigators had genotype results and expert consultation available to select optimal treatment regimen using any currently available ARVs Each patient therefore received the best treatment available

at the time of trial initiation

Study would have enrolled extremely slowly

24

RESIST StudiesBaseline Demographics

TPV/r CPI/r

Total Screened 3309

Total Treated (N) 582 577

Median Age (years) 43.0 43.0

Male Gender (%) 86.4 89.4

Race (%)

White 73.9 71.8

Black 14.3 13.9

Asian 0.7 1.4

Median Baseline VL (log) 4.83 4.82

Median Baseline CD4 Count 155 158

Hepatitis B and/or C + (%) 10.2 15.3

25

RESIST StudiesBaseline History

Advanced HIV disease status 88% prior AIDS diagnosis

Prior antiviral use Median ARV use: 6 NRTIs, 1 NNRTI, 4 PIs

45% ≥ 5 PIs

11.9% prior ENF

Limited options for background ARV selection 44% had a GSS 1

26

RESIST StudiesBaseline PI Phenotype

1.7

87.4

41.0

20.112.2

40.755.3

194.7

0

2040

6080

100

120140

160180

200

TPV LPV IDV SQV APV NFV RTV ATZ(454) (452) (423) (450) (445)N=

Med

ian

Fold

Cha

nge

in IC

50

(452) (449) (456)

Analysis of randomly selected samples

27

RESIST StudiesPre-Selected Comparator PIs

TPV/rN (%)

CPI/rN (%)

Total Treated 582 (100.0) 577 (100.0)

Pre-Selected PI

LPV 293 (50.3) 290 (50.3)

APV 151 (25.9) 149 (25.8)

SQV 117 (20.1) 118 (20.5)

IDV 21 (3.6) 20 (3.5)

28

RESIST StudiesPrimary Efficacy Results

Week 24

RESIST 1 RESIST 2

TPV/r CPI/r TPV/r CPI/r

Number of Patients 311 309 271 268

Primary Endpoint

% of Patients With 1 log Drop

(FAS NCF)

41.5 22.3 41.0 14.9

P value P < 0.0001 P < 0.0001

29

RESIST StudiesTreatment Response

0

10

20

30

40

50

60

0 8 16 24

Trea

tmen

t Res

pond

ers

(%)

CPI/r (n=577)TPV/r (n=582)

Week 24: P <0.0001

Weeks

(41.2)

(18.9)

RESIST Studies Combined

1 log10 Viral Load Reduction, Confirmed, ITT: NCF

30

RESIST StudiesUndetectable Viral Load (<400, <50 copies/mL)

CPI/r (n=577)TPV/r (n=582)

ITT: NCF

05

10152025303540

0 8 16 24

Viro

logi

c R

espo

nse

VL <

400

Cop

ies/

mL

(%)

Week 24: P <0.0001

(34.2%)

(14.9%)

Weeks of Treatment

Viro

logi

c R

espo

nse

VL <

50 C

opie

s/m

L (%

)

05

10152025303540

0 8 16 24

Week 24: P <0.0001

(23.9%)

(9.4%)

31

RESIST StudiesVL Reduction and CD4 Increase

Weeks of Treatment

0 (0.25 log10 copies/mL)

-1.8-1.6-1.4-1.2

-1-0.8-0.6-0.4-0.2

0 8 16 24

Med

ian

VL lo

g 10 C

hang

e Fr

om B

asel

ine

Week 24: P <0.0001

(0.80 log10 copies/mL)

ITT: LOCF

(+34 cells, range 3-87)

(+4 cells, range 0-61)

Week 24 difference: P <0.0001

Med

ian

Cha

nge

From

Bas

elin

e in

CD

4+ C

ell C

ount

05

10152025303540

0 8 16 24

CPI/r (n=577)TPV/r (n=582)

32

RESIST StudiesEfficacy Endpoints (Week 24)

All Patients in 24-Week Analysis Set

TPV/rN=582

CPI/rN=577 P Value

≥ 1 log10 VL Reduction (%) 240 (41.2%) 109 (18.9%) <0.0001

Total VL Reduction (log10) -0.80 -0.25 <0.0001

VL <400 Copies/mL 199 (34.2%) 86 (14.9%) <0.0001

VL <50 Copies/mL 139 (23.9%) 54 (9.4%) <0.0001

Median CD4+ Cell Change + 34 + 4 <0.0001

AIDS Progression Events 25 (3.4%) 34 (4.6%) NS

33

RESIST StudiesTreatment Response in Patients Using Enfuvirtide

69.6

28.7 27.9

17.6

0

10

20

30

40

50

60

70

80

TPV/r + naïve ENF

CPI/r + naïve ENF

TPV/r + prior ENF

CPI/r + prior ENF

% T

reat

men

t Res

pons

e

N=115 N=43N=94 N=34

Median

Baseline

TPV/r + ENF

(N=158)

CPI/r + ENF

(N=128)

CD4+ 72 77

HIV RNA 5.07 5.10

Prior ARVs 13 14

34

TipranavirEfficacy Conclusions

TPV/r was superior at 24 weeks to comparator PIs in two well-controlled studies with PI treatment-experienced patients

Treatment response (1 log10 VL reduction)

Absolute VL reduction from baseline

Proportion of patients with undetectable VL (<400, <50 copies/mL)

CD4+ cell count increase

35

Drug-Drug Interactions

Scott McCallister, MDGlobal Medical Team Leader, TPV

36

Drug Interaction Program

Antiretroviral drugs Seven common 3-drug ARV combinations (HIV+)

Dual-boosted PI regimens with LPV, SQV, and APV (HIV+)

ZDV, ddI, TDF, EFV (HIV-)

Drugs commonly used by HIV+ patients Ethinyl estradiol and norethindrone

Loperamide

Atorvastatin

Other studies Antacid interaction

ADME

Clarithromycin

Fluconazole

Rifabutin

37

Notable Drug Interactions – RT Inhibitors

No relevant changes in drug levels 3TC, D4T, TDF, NVP, EFV

ZDV ZDV AUC reduced 3343% with TPV/r

TPV Cmin and AUC unchanged with either dose

ABC ABC AUC reduced 3546% with TPV/r

ddI ddI AUC reduced 10% with TPV/r 500/100

TPV Cmin reduced 34% and AUC unchanged

38

Dose Finding

BI 1182.52NA, EU, AUS

RESIST-1 BI 1182.12



Latin America


All RESIST CountriesN=315





39

Dual Boosted Protease Inhibitors

Drug PK Test After Addition of TPV/r

LopinavirAUC

Cmax

Cmin

55%

47%

70%

SaquinavirAUC

Cmax

Cmin

76%

70%

82%

AmprenavirAUC

Cmax

Cmin

44%

39%

55%

All patients received single boosted PI Weeks 02 TPV/r 500/100 was added to each single boosted PI at Week 2 Week 2 plasma sampling was compared to Week 4

40

TPV/r Drug InteractionConclusionsNo relevant changes in drug levels 3TC, d4T, TDF, NVP, EFV Loperamide

Drug level reductions of uncertain relevance –A dose adjustment cannot be recommended ZDV, ABC, ddI

Significant drug level reductions – Not recommended LPV/r, SQV/r, APV/r

Clinical monitoring advised, if an alternative agent is not available Atorvastatin

Clarithromycin, fluconazole

Ethinyl estradiol (hormone replacement)

Change in dosing advised Rifabutin

41

Potential Drug Interactions with TPV/rPotential drug level increases

– monitoring recommended Itraconazole, ketoconazole,

voriconazole Sildenafil, tadalafil, vardenafil Desipramine

Potential drug level decreases

– monitoring recommended Methadone, buprenorphine Meperidine

Currently unpredictable interactions

– monitoring recommended Warfarin Theophylline Serotonin re-uptake inhibitors Calcium channel blockers Immunosuppressants Anti-psychotics Oral hypoglycemics

Potential disulfiram reaction Disulfiram Metronidazole

42

Tipranavir Safety

Christopher Corsico, MD, MPHHead, Drug Surveillance and Information

43

Total HIV + patients treated

with TPV/r N = 3367

RESIST TPV/rN = 748

Phase I, II and 1182.51N = 894

EUP/EAPN = 879Rollover to TPV/r

N = 298

RESIST CPI/r N = 737

PediatricN = 74

Long Term Follow Up

N = 474

1411 HIV+ patients treated with the TPV/r 500/200 mg BID dose 1276 patient-years of exposure 86% HIV+ patients have been treated for >24 weeks

Maximum exposure to TPV/r in the long-term follow-up trial is 5 years

Tipranavir Safety DatabaseSafety Update – September 30, 2004

44

0

100

200

300

400

500

600

700

800

0 8 16 24 32Weeks

Patie

nts

TPV/rCPI/r

N=576N=703

N=715

N=285

Reason for Discontinuation

TPV/r

N=748

CPI/r

N=737

Adverse Event 10% 5%

Lack of Efficacy 9% 43%

Patient-Years of Exposure

TPV/r 615 years

CPI/r 406 years

RESIST StudiesPatients Remaining on Study

45

RESIST StudiesAdverse Events >5%

Body System Event TPV/r (N=748) CPI/r (N=737)

Gastrointestinal Diarrhea 27.9% 21.8% Nausea 19.3% 15.1%

Vomiting 10.8% 9.0%

Abdominal pain 8.2% 6.0%Infections Nasopharyngitis 7.9% 5.0%

Oral Candidiasis 5.6% 4.5% Influenza 5.2% 3.3% Herpes simplex 5.1% 3.3% Bronchitis 6.0% 3.7% Sinusitis 6.3% 4.5% URTI 6.6% 4.6%

General Fatigue 11.6% 10.2% Pyrexia 11.9% 8.7%

46

RESIST StudiesAdverse Events >5% (continued)

Body System Event TPV/r (N=748) CPI/r (N=737)

Nervous System Headache 13.0% 8.4%

Dizziness 5.6% 4.1%

Skin Rash 6.8% 5.7%

Psychiatric Depression 5.5% 5.0%

Investigations Weight decrease 5.1% 3.5%

Musculoskeletal Arthralgia 6.0% 5.0%

Back pain 6.6% 3.8%

Respiratory Cough 8.8% 5.4%

47

RESIST StudiesGender and Rash

Female PatientsMale Patients

System Organ Class/Preferred Term

10 (8.5)25 (4.0)Pruritus

10 (8.5)41 (6.5)Rash

33 (28.2)163 (25.8)Skin and SubcutaneousTissue Disorders

48

Risk of MST Rash Among TPV Recipients in RESIST:CD4 Baseline

Factor ComparatorOddsRatio 95% C.I. P Value

Age NA 0.998 0.969, 1.027 0.8825

Gender Females 0.673 0.352, 1.286 0.2306

Baseline CD4+ (cells/μL)

>200 >200 1 NA NA

50 – 200 1.203 0.704, 2.057 0.5

<50 2.060 1.119, 3.793 0.02

TPV trough (μMol) NA 1.003 0.993, 1.012 0.5961

RTV trough (mcg/mL) NA 2.034 0.728, 5.682 0.1755

Race Non-white 1.973 0.911, 4.273 0.0846

Hepatitis coinfection No 0.657 0.282, 1.527 0.3289

Weight (Kg) NA 1.005 0.986, 1.024 0.6040

Fixed logistic regression model among TPV/r recipients in RESIST.

Variables shown are all variables tested in the model.

49

RESIST StudiesFemale Patients on TPV/r Who Developed Rash by CD4

0

5

10

15

20

25

<50 50 - 200 >200 - 350 >350

CD4 Strata

Perc

enta

ge

Rash 2 9 9 2

No Rash 16 30 32 17

50

Grade 3 or 4 ALT, AST or Total Bilirubin Actions Taken and Outcomes

Action TakenTPV/rN=748

CPI/rN=737

Total Number of Grade 3 or 4 Abnormalities 74 (9.9) 26 (3.5)

Continuation or Temporary Interruptionof Study Medication

57 (7.6) 26 (3.5)

SAE with hepatic term 4 (0.5) 0 (0.0)

Discontinuation of Study Medication 17 (2.3) 0 (0.0)

LFTS returned to baseline or normaland no SAE with hepatic term

12 (1.6)

SAE with hepatic terms 5 (0.7)

Resolved 4 (0.5)

RESIST StudiesCox Regression Model for Risk of Grade 3 or 4 ALT/AST

Baseline risk factors for Grade 34 ALT/AST are similar in TPV/r and CPI/r

Independent variables: age, gender, race, ΔCD4, baseline triglycerides, NRTI, NNRTI, viral load, CDC HIV stage, duration of HIV infection

Factor/Comparison Risk Ratio 95% CI

Treatment Group:TPV/r vs CPI/r 2.4 1.5 – 3.8

Baseline ALT,AST Total Bilirubin:(Grade > 1 vs Grade < 1) 2.5 1.3 – 4.8

CD4+ Cell Count at Baseline: >200 vs ≤200 cells/mm3 2.0 1.3 – 2.5

HBV or HCV Co-infection:Co-infected vs not co-infected 2.3 1.4 – 3.7

51

52

Hepatic Monitoring and Management Recommendations Routine clinical and laboratory monitoring to detect liver

abnormalities is recommended

Patients with chronic hepatitis B or C, or elevated LFTsat initiation of TPV/r therapy, require more frequent clinical and laboratory monitoring

Patients who are symptomatic in the setting of elevated LFTs should have their TPV/r discontinued

53

3 (0.4)91 (12.3)

CPI/rN=737

2 (0.3)

2 (0.3)

3 (0.4)

29 (3.9) 176 (23.5)

TPV/rN=748

1 (0.1)3 (0.4)

4 (0.5)

Grade 3 / 4 CholesterolGrade 3 / 4 Triglycerides

Category

Ischemic Heart DiseaseAngina

Myocardial ischemia

Pancreatic DisordersPancreatitis

RESIST StudiesLipid Abnormalities

54

RESIST StudiesMortality – Kaplan Meier

Weeks

Prob

abili

ty (%

)

CPI

TPV

0

2

4

6

8

10

0 12 24 36 48 60 72 84

P = 0.64

CPITPV

737748

465735

131319

55

Tipranavir SafetyConclusions 1206 patients treated with the to be marketed dose of

TPV/r 500mg/200mg BID for at least 24 weeks

Treatment-experienced, ARV-resistant patients Infections and AIDS progression events

Adverse event profile for TPV/r is similar to CPI/rexcept for: Elevated LFTs, clinical hepatic events Elevated triglycerides and cholesterol

56

Resistance


57


RESIST-1 BI 1182.12



Latin America







58

BI 1182.51Study Design

* OBR=optimized background regimen

Open-label, parallel-group, multicenter studyN=315 randomized

N=284 included in resistance analysis

LPV/r + OBR*(400 mg/100 mg)

(n=78)

SQV/r + OBR(1000 mg/100 mg)

(n=71)

APV/r + OBR(600 mg/100 mg)

(n=71)

TPV/r + OBR(500 mg/200 mg)

(n=64)

TPV/r 500 mg/100 mg added at 2 weeksFinal RTV dose 200 mg twice daily in all arms

All twice daily

1182.51HIV RNA Median Change from Baseline at 2 Weeks:Comparative TPV, LPV, SQV, APV

0

-1.15

0

-0.21

0

-0.29

0

-0.38

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0 2Weeks of Treatment

HIV

RN

A (l

og10

cop

ies)

TPV (n=64) APV (n=71) SQV (n=71) LPV (n=78)

2 Weeks Single Boosted PI

59

60

Treatment Response by Key Mutations

Number of Mutations at Positions 33, 82, 84, 90

BaselineTPV Susceptibility

(N) Q25,Q75

Change in VL* at 2 Weeks(N) Q25,Q75

Change in VL*at 24 Weeks(N) Q25,Q75

0 0.7 (82) 0.4, 1.0 -1.49 (26) -0.99, -1.82-1.35

(22) -0.35, -2.18

1 1.1 (232) 0.7, 2.1 -1.27 (229) -0.73, -1.87 -1.27 (183) -0.24, -2.62

2 1.7 (371) 0.9, 3.7 -1.39 (473) -0.67, -1.83 -0.78 (402) -0.14, -2.42

3 3.4 (112) 1.9, 8.4 -1.25 (68) -0.26, -1.68 -0.24 (71) 0.13, -1.87

4 12.0 (13) 2.5,16.6 -1.08 (10) -0.33, -1.54 -0.33 (10) -0.14, -0.66

*Change in viral load was the change in HIV RNA from baseline through week 2 (OT) or week 24 (LOCF) in log10 copies/mL.

61

TPV Mutation Score Development Uni- and multivariate regression analyses used to correlate

291 Phase II baseline genotypes to TPV phenotype, and Week 2 or 24 VL reduction

Uni- and multivariate regression analyses then applied to569 Phase III baseline genotypes (RESIST) with phenotype and genotype to validate mutations selected by Phase II datasets Reduced TPV susceptibility or reduced response associated

with 21 mutations at 16 positions: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E,

69K, 74P, 82L/T, 83D, and 84V

62

Treatment Response by TPV Score

Number of TPV Score Mutations

BaselineTPV Susceptibility

(N) Q25,Q75



0 to 1 0.8 (186) 0.5, 1.1 -1.25 (135) -0.91, -1.78 -2.10 (114) -0.82, -2.77

2 to 3 1.2 (276) 0.7, 2.2 -1.37 (289)-0.79, -1.83 -0.89(242)-0.21, -2.35

4 to 5 2.4 (267) 1.2, 5.0 -1.40(302)-0.57, -1.87

-0.45(260) -0.03, -2.15

6 to 7 3.6 (74) 2.1, 12.0 -1.27 (76) -0.23, -1.81 -0.49 (68) -0.03, -1.60

8+ 16.3 (7) 4.9, 50.3 -0.33 (4) +0.11, -0.83 -0.08 (4) +0.01, -0.18

* Change in viral load was the change in HIV RNA from baseline through week 2 (OT)or week 24 (LOCF) in log10 copies/mL.

63

RESIST StudiesTreatment Response by Phenotypic Resistance

Enfuvirtide Use

Fold-Changeat Baseline inTipranavir IC50

Treatment Response at 24 Weeksin TPV/r Arm

No 0 to 3 75/193 (38.9%)

>3 to 10 10/53 (18.9%)

>10 0/12 (0.0%)

Yes 0 to 3 45/61 (73.8%)

>3 to 10 12/32 (37.5%)

>10 5/10 (50.0%)

64

TPV/r Emergent Mutations

Patients with paired baseline and on-treatment genotypesfor assessment of emergence: Phase II = 217

Phase III = 59

Total 276

Predominant emerging mutations with tipranavir are: L33F/I/V, V82T/L and I84V

V82WT V82L V82A V82T

65

Predictors of TPV/r Antiviral Response Multiple Regression Model

P ValueEstimate

<0.010.17TPV Score

(per mutation)

<0.01-0.24Per Available Drugin OBR

<0.01-0.91Enfuvirtide Use

<0.01-1.25Tipranavir/r

24 Weeks

Parameter

66

For TPV Genotypic Resistance

Predominant emerging mutations with tipranavir are: L33F/I/V, V82T/L and I84V

Tipranavir Resistance Conclusions TPV has a high genetic barrier to resistance

TPV mutation score represents a unique group of protease gene mutations,and is most specific marker of TPV resistance

For TPV susceptibility: 3-Fold WT Susceptible > 3 to 10-Fold Decreased Susceptibility > 10-Fold Resistance

Fold-Change at Baseline in Tipranavir IC50

Key Mutation Score(33, 82, 84, 90)

Tipranavir Score

0 to 3 0 to 2 0 to 4

> 3 to 10 3 5 to 7

> 10 4 8+

67

Utility of TPV Drug Levels


68

RESIST Trials2-Week Viral Load Reduction According to TPV Trough (µMol)

-2

-1

0

6.5

6.5 to

<13

13 to

<19.5

19.5

to <26

26 to

<32.5

32.5

to <39

39 to

<45.5

45.5

to <52 52

Log1

0 C

hang

e H

IV R

NA

N=23 30 52 53 42 52 43 42 110

RESIST TrialsPatients with Grade 3 or 4 ALT, AST or Bilirubinby TPV Trough

0

10

20

30

40

50

<20 20 - <40 40 - <80 80 - <120 120

TPV Concentration (µMol)

Perc

enta

ge

Gr 3-4 12 26 20 6 4At Risk 148 234 205 42 9 69

TPV Trough Comparison in PatientsWith vs Without Grade 3 or 4 ALT, AST or Bilirubin

Normal Grade 3/4 LFT

0

20

40

60

80

100

120

140

160

180

200

Pla

sma

Tipr

anav

ir C

p (

M)

Normal AST ALT Bilirubin

0

20

40

60

80

100

120

140

160

180

200

Pla

sma

Tipr

anav

ir C

p (

M)

70

71

RESIST Trials24-Week VL Reductions vs TPV Trough

Geom. Mean TPV Trough Levels (M)

VL C

hang

e Fr

om B

asel

ine

(log

copi

es/m

L)

72

TPV Drug Level Conclusions TPV trough levels > 6.5 uM associated with > 1 log VL

response at 2 weeks

TPV trough levels > 120 uM associated with increased hepatic events

93% of patients have TPV trough levels between 6.5120 uM

Weak trends associating TPV trough levels with hepatic events and treatment responses

Large inter-patient variability will limit the utility of these measurements in clinical practice

Potential Utility of Tipranavirin Current Clinical Practice

Daniel R. Kuritzkes, MDDirector of AIDS Research

Brigham and Woman’s HospitalDivision of AIDS

Associate Professor of MedicineHarvard Medical School

Boston, MA

73

74

Conclusions

Burkhard Blank, MDSenior Vice PresidentMedicine and Drug Regulatory Affairs

75

TipranavirConclusions24-week RESIST data supports accelerated approval for TPV/r

Greater reductions in viral load and increases in CD4 cells thanthe best alternative protease inhibitors in this patient population

Adverse events similar to other CPI/r with mainly GI side effects

Increased adverse event rates for LFT and lipid elevations Routine clinical and laboratory monitoring for most patients.

Patients with elevated LFTs or HBV/HCV co-infection shouldhave increased monitoring.

Overall, TPV/r offers a significant new treatment optionfor PI treatment-experienced patients

76

TPV Development ProgramOngoing Studies

RESIST-1, RESIST-2

Treatment-naïve adults

Pediatrics

Emergency use, expanded access

77

TPV Development ProgramPlanned Studies

Special populations Cohorts of patients with cirrhosis or HBV/HCV co-infection

Additional studies in women

Additional drug interaction trials dNTP study with zidovudine and abacavir

Atazanavir, TMC-114, TMC-125, novel CCR5 antagonists

CYP/P-gp study to determine effect of TPV/r on individual CYPs

Methadone, buprenorphine

Tadalafil, carbamazepine, omeprazole

78

TipranavirProposed Indication

“Tipranavir, co-administered with low-dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients who are protease inhibitor treatment‑experienced.”

79

May 19, 2005

Antiviral Drugs Advisory CommitteeAPTIVUS® (tipranavir) Capsules

1 may 19, 2005 antiviral drugs advisory committee aptivus ® (tipranavir) capsules

Documents