# Presentation: 744678

## May 19, 2005

**Antiviral Drugs Advisory Committee****APTIVUS****®**** (****tipranavir) Capsules**

## Introduction

- Burkhard Blank, MD
- Senior Vice President
- Medicine and Drug Regulatory Affairs

## 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

## Tipranavir

- Shows significant antiviral activity against the majorityof 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

## 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.”

## 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

## Consultants Available to the Committee

**Angela D.M. Kashuba, PharmD** University of North Carolina- Chapel Hill
**Daniel R. Kuritzkes, MD**Harvard Medical School
**Jens D. Lundgren, MD**University of CopenhagenDenmark

**Joel Morganroth, MD**University of Pennsylvania
**Jonathan M. Schapiro, MD**Stanford University Schoolof Medicine
**Mark Sulkowski, MD**Johns Hopkins University School of Medicine

## Tipranavir Development

- Douglas Mayers, MD
- International Head, Therapeutic Area Virology

## 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)

- 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)

**Tipranavir*****Overview***

## TipranavirDevelopment

- 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

## TipranavirClinical 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

## TipranavirCo-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

## TipranavirCombined with Ritonavir ADME

**In 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

## TipranavirPhase II-III Study Program

- BI 1182.52
- NA, EU, AUS
***N=216***

_**RESIST-1**_
-  BI 1182.12
- North America
- Australia

_**RESIST-2**_
- BI 1182.48
- Europe
- Latin America

_**Companion Study**_
- BI 1182.51
- All RESIST Countries

- Pediatrics,
- Naïve Adults
- Emergency Use
- Expanded Access

**Tipranavir*****Phase II-III Study Program***

_**Rollover Study**_, BI 1182.17, All RESIST Countries

***Optimal Dose***
***TPV/r 500/200***

## TipranavirDose 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

## TipranavirKey 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

## RESIST Pivotal Trial Program

- Scott McCallister, MD
- Global Medical Team Leader, TPV

## TipranavirPhase II-III Study Program

- BI 1182.52
- NA, EU, AUS

_**RESIST-1**_
-  BI 1182.12
- North America
- Australia
*N=620, Safety**N=620, Efficacy*

_**RESIST-2**_
- BI 1182.48
- Europe
- Latin America
*N=865, Safety**N=539, Efficacy*

_**Companion Study**_
- BI 1182.51
- All RESIST Countries

_**Rollover Study**_, BI 1182.17, All RESIST Countries

- Pediatrics,
- Naïve Adults
- Emergency Use
- Expanded Access

**Tipranavir*****Phase II-III Study Program***

***Optimal Dose***
***TPV/r 500/200***

## RESIST StudiesKey Design Issues

**Challenging heterogeneous study population with limited**
**treatment 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 leave**
**and 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

## RESIST StudiesKey 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

## RESIST StudiesScreening and Randomization

**Pre-Selection of CPI/r and OBR**

**Resistance Expert Consultation**

**Stratified Randomization**
***(by CPI/r and ENF)***

**Screening Genotype**
**(*****Virtual *****Phenotype****TM**** or TruGene****®****)**

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

**TPV/r**

**Best   PI choice**

***Plus***
***OBR***

**1:1**

## RESIST Studies24-Week Endpoints

**Primary endpoint: treatment response ****defined as:**
**Confirmed ******** 1 log****10**** 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

## RESIST StudiesEarly 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 availableat the time of trial initiation
- Study would have enrolled extremely slowly

## RESIST StudiesBaseline 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 |

## RESIST StudiesBaseline 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

## RESIST StudiesBaseline PI Phenotype

- (454)

- (452)

- (423)

- (450)

- (445)

- N=

- Median Fold Change in IC50

- (452)

- (449)

- (456)

**Analysis of randomly selected samples**

## RESIST StudiesPre-Selected Comparator PIs

|  | TPV/rN (%) | CPI/rN (%) |
| --- | --- | --- |
| 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) |

## RESIST StudiesPrimary 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 |  |
|  |  |  |  |  |

## RESIST StudiesTreatment Response

- Week 24: *P *<0.0001

**Weeks**

- (41.2)

- (18.9)

**RESIST Studies**** Combined**

******1 log****10**** Viral Load Reduction, Confirmed, ITT: NCF**

## RESIST StudiesUndetectable Viral Load (<400, <50 copies/mL)

**Weeks of Treatment**

## RESIST StudiesVL Reduction and CD4 Increase

**Weeks of Treatment**

## RESIST StudiesEfficacy Endpoints (Week 24) 

| All Patients in 24-Week Analysis Set | TPV/rN=582 | CPI/rN=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 |

## RESIST StudiesTreatment Response in Patients Using Enfuvirtide

**N=115**

**N=43**

**N=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 |

## TipranavirEfficacy 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

## Drug-Drug Interactions

- Scott McCallister, MD
- Global Medical Team Leader, TPV

## 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

## Notable Drug Interactions – RT Inhibitors

**No relevant changes in drug levels**
- 3TC, D4T, TDF, NVP, EFV
**ZDV**
- ZDV AUC reduced 3343% with TPV/r
- TPV Cmin and AUC unchanged with either dose
**ABC**
- ABC AUC reduced 3546% with TPV/r
**ddI**
- ddI AUC reduced 10% with TPV/r 500/100
- TPV Cmin reduced 34% and AUC unchanged

## TipranavirPhase II-III Study Program

- BI 1182.52
- NA, EU, AUS

_**RESIST-1**_
-  BI 1182.12
- North America
- Australia

_**RESIST-2**_
- BI 1182.48
- Europe
- Latin America

_**Companion Study**_
- BI 1182.51
- All RESIST Countries***N=315***

_**Rollover Study**_, BI 1182.17, All RESIST Countries

- Pediatrics,
- Naïve Adults
- Emergency Use
- Expanded Access

**Tipranavir*****Phase II-III Study Program***

***Optimal Dose***
***TPV/r 500/200***

## Dual Boosted Protease Inhibitors

| Drug | PK Test | After Addition of TPV/r  |
| --- | --- | --- |
| 
Lopinavir | AUC
Cmax 
Cmin  | 55%
47%
70%  |
| 
Saquinavir | AUC
Cmax
Cmin  | 76%
70%
82%  |
| 
Amprenavir | AUC
Cmax
Cmin  | 44%
39%
55%  |

- All patients received single boosted PI Weeks 02
- TPV/r 500/100 was added to each single boosted PI at Week 2
- Week 2 plasma sampling was compared to Week 4

## TPV/r Drug InteractionConclusions

**No 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

## Potential Drug Interactions with TPV/r

**Potential 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

## Tipranavir Safety

- Christopher Corsico, MD, MPH
- Head, Drug Surveillance and Information

## 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

** **

**Total HIV + patients treated with TPV/r **
**N = 3367**
** **

**RESIST TPV/r****N = 748**

**Phase I, II and 1182.51****N = 894**

**EUP/EAP****N = 879**

**Rollover to TPV/r****N = 298**

**RESIST CPI/r ****N = 737**

**Pediatric****N = 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 Database*****Safety Update – September 30, 2004***

## RESIST StudiesPatients Remaining on Study

- N=576

- N=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 Studies*****Patients Remaining on Study***

## RESIST StudiesAdverse 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% |

## RESIST StudiesAdverse 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% |

## RESIST StudiesGender and Rash

**Female Patients**

**Male 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 Subcutaneous****Tissue Disorders**

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

| 
Factor | 
Comparator | Odds
Ratio | 
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.

## RESIST StudiesFemale Patients on TPV/r Who Developed Rash by CD4

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

| 
Action Taken | TPV/r
N=748 | CPI/r
N=737 |
| --- | --- | --- |
| Total Number of Grade 3 or 4  Abnormalities | 74 (9.9) | 26 (3.5) |
| Continuation or Temporary Interruptionof 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 normal
and no SAE with hepatic term | 12 (1.6) |  |
| SAE with hepatic terms | 5 (0.7) |  |
|     Resolved | 4 (0.5) |  |

## RESIST StudiesCox Regression Model for Risk of Grade 3 or 4 ALT/AST

- Baseline risk factors for Grade 34 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 |

## 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

## RESIST StudiesLipid Abnormalities

- 91 (12.3)

**CPI/r**
**N=737**

- 2 (0.3)

- 2 (0.3)

- 3 (0.4)

**29 (3.9)**

-  **176 (23.5)**

** **

**TPV/r**
**N=748**

** **

**1 (0.1)**

**3 (0.4)**

**4 (0.5)**

- Grade 3 / 4 Cholesterol

- Grade 3 / 4 Triglycerides

**Category**

- Ischemic Heart Disease

- Angina

- Myocardial ischemia

- Pancreatic Disorders

- Pancreatitis

**RESIST Studies*****Lipid Abnormalities***

## RESIST StudiesMortality – Kaplan Meier

**Weeks**

**Probability (%)**

**CPI**

**TPV**

- 0

- 12

- 24

- 36

- 48

- 60

- 72

- 84

***P***** = 0.64**

**CPI**

**TPV**

- 737

- 748

- 465

- 735

- 131

- 319

## Tipranavir SafetyConclusions

- 1206 patients treated with the to be marketed dose ofTPV/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

## Resistance

- Douglas Mayers, MD
- International Head, Therapeutic Area Virology

## TipranavirPhase II-III Study Program

- BI 1182.52
- NA, EU, AUS

_**RESIST-1**_
-  BI 1182.12
- North America
- Australia

_**RESIST-2**_
- BI 1182.48
- Europe
- Latin America

_**Companion Study**_
- BI 1182.51
**All RESIST Countries**

_**Rollover Study**_, BI 1182.17, All RESIST Countries

- Pediatrics,
- Naïve Adults
- Emergency Use
- Expanded Access

**Tipranavir*****Phase II-III Study Program***

***Optimal Dose***
***TPV/r 500/200***

## BI 1182.51Study Design

- * OBR=optimized background regimen

- Open-label, parallel-group, multicenter study
- N=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 weeks
- Final RTV dose 200 mg twice daily in all arms

- All twice daily

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

**2 Weeks Single Boosted PI**

## Treatment Response by Key Mutations

| Number of Mutations at Positions 33, 82, 84, 90 | BaselineTPV 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.

## 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 associatedwith 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

## Treatment Response by TPV Score

| Number of TPV Score Mutations | BaselineTPV Susceptibility(N) Q25,Q75 |  | Change in VL*at 2 Weeks(N) Q25,Q75 |  | Change in VL*at 24 Weeks(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.

## RESIST StudiesTreatment Response by Phenotypic Resistance

| 

Enfuvirtide Use | Fold-Changeat Baseline inTipranavir IC50 | Treatment Response at 24 Weeksin 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%) |

## TPV/r Emergent Mutations

**Patients with paired baseline and on-treatment genotypes**
**for 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

## Predictors of TPV/r Antiviral Response Multiple Regression Model

***P***** Value**

**Estimate**

- <0.01

**0.17**

**TPV Score **
**(per mutation)**

- <0.01

**-0.24**

**Per Available Drug****in OBR**

- <0.01

**-0.91**

**Enfuvirtide Use**

- <0.01

**-1.25**

**Tipranavir/r**

**24 Weeks**

**Parameter**

## Tipranavir Resistance Conclusions

- 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+ |

## Utility of TPV Drug Levels

- Douglas Mayers, MD
- International Head, Therapeutic Area Virology

## RESIST Trials2-Week Viral Load Reduction According to TPV Trough (μMol)

**N=23****	****30****	****52****	****53           42               52              43             42            110**

**  ******

**  ******

## RESIST TrialsPatients with Grade 3 or 4 ALT, AST or Bilirubinby TPV Trough

- 0

- 10

- 20

- 30

- 40

- 50

- <20

- 20 - <40

- 40 - <80

- 80 - <120

- 120

**TPV Concentration (****μ****Mol)**

**Percentage**

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

## TPV Trough Comparison in PatientsWith vs Without Grade 3 or 4 ALT, AST or Bilirubin

## RESIST Trials24-Week VL Reductions vs TPV Trough

**Geom. Mean TPV Trough Levels (********M)**

**VL Change From Baseline (log copies/mL)**

## 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 6.5120 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 Tipranavirin Current Clinical Practice

**Daniel R. Kuritzkes, MD**
- Director of AIDS ResearchBrigham and Woman’s HospitalDivision of AIDS
- Associate Professor of MedicineHarvard Medical SchoolBoston, MA

## Conclusions

- Burkhard Blank, MD
- Senior Vice President
- Medicine and Drug Regulatory Affairs

## TipranavirConclusions

**24-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 option**
**for PI treatment-experienced patients**

## TPV Development ProgramOngoing Studies

- RESIST-1, RESIST-2
- Treatment-naïve adults
- Pediatrics
- Emergency use, expanded access

## TPV Development ProgramPlanned 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

## 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.”

## May 19, 2005

**Antiviral Drugs Advisory Committee****APTIVUS****®**** (****tipranavir) Capsules**