Boehringer Ingelheim

boehringer ingelheim pharmaceuticals, inc.

Tipranavir

Anti-viral Drugs advisory committee (AVDAC)

Briefing document

NDA 21-814

April 19, 2005

available for public disclosure without redaction

TABLE OF CONTENTS

List of abbreviations...................................................................... 6

SUMMARY.................................................................................................. 8

1. INTRODUCTION.............................................................................. 13

2. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY.......... 15

3. MICROBIOLOGY............................................................................. 21

3.1 Mechanism Of Action.............................................................................. 21

3.2 Antiviral Activity In Vitro.................................................................. 21

4. OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM......... 23

4.1 EARLY DEVELOPMENT.................................................................................. 23

4.2 DOSE-FINDING TRIAL.................................................................................... 23

4.3 PHASE III PIVOTAL TRIAL PROGRAM....................................................... 25

4.3.1 Trial design.............................................................................................. 25

4.3.2 Trial design issues................................................................................... 28

4.3.2.1 Choice of comparator PI............................................................. 28

4.3.2.2 Open-label study design.............................................................. 29

4.3.2.3 Resistance status of study cohort................................................. 30

4.3.2.4 RESIST study amendments and relevant protocol deviations........ 31

4.3.2.5 Non-inferiority testing.................................................................. 32

4.4 ADDITIONAL CLINICAL DATA..................................................................... 33

5. CLINICAL PHARMACOLOGY........................................................ 35

5.1 Clinical Pharmacokinetics................................................................ 35

5.1.1 Demographic subpopulations.................................................................. 37

5.1.2 Absorption, distribution, metabolism, elimination (ADME).................. 38

5.1.2.1 Absorption................................................................................. 38

5.1.2.2 Distribution................................................................................. 40

5.1.2.3 Metabolism................................................................................. 40

5.1.2.4 Excretion.................................................................................... 41

5.1.3 Drug interactions..................................................................................... 42

5.1.3.1 Effect on tipranavir...................................................................... 42

5.1.3.2 Interactions with reverse transcriptase inhibitors........................... 43

5.1.3.3 Interactions with protease inhibitors............................................. 45

5.1.3.4 Interactions with non-ARV medications....................................... 46

5.1.3.5 Potential drug interactions............................................................ 48

5.1.4 Hepatic or renal impairment................................................................... 53

5.2 Pharmacokinetic Conclusions......................................................... 54

6. EFFICACY......................................................................................... 55

6.1 Early Clinical Data................................................................................. 55

6.2 Dose Selection (BI 1182.52)....................................................................... 56

6.3 Efficacy results of pivotal, active-controlled trials (RESIST Trials)............................................................................................................................... 59

6.3.1 Study population...................................................................................... 59

6.3.1.1 Baseline genotypic resistance....................................................... 62

6.3.1.2 Baseline phenotypic resistance..................................................... 63

6.3.2 Pre-selection of comparator PI and enfuvirtide..................................... 64

6.3.2.1 Stratification by pre-selected PI and enfuvirtide use...................... 64

6.3.2.2 Use of new vs. ongoing or susceptible vs. resistant
comparator PIs........................................................................... 67

6.3.3 Differences between RESIST studies.................................................... 67

6.3.4 Patient disposition................................................................................... 68

6.3.5 Analysis of treatment response: primary and secondary endpoints..... 69

6.3.5.1 Treatment response..................................................................... 69

6.3.5.2 Response by pre-selected PI strata............................................. 72

6.3.5.3 Viral load change from baseline at 24 weeks (FAS population).... 74

6.3.5.4 Virologic response (< 400 and < 50 copies/mL) and immunologic response at 24 weeks (FAS population)........................................................................ 76

6.3.5.5 New onset of AIDS events......................................................... 78

6.3.6.... Impact of active background antiretroviral drugs................................. 78

6.3.7.... Impact of baseline viral load and CD4+ count....................................... 82

6.3.8 Sensitivity analyses................................................................................. 83

6.4 Efficacy RESULTS IN SPECIAL POPULATIONS..................................... 84

6.5 EFFICACY CONCLUSIONS.............................................................................. 87

7. RESISTANCE.................................................................................... 88

7.1 Development Of Tipranavir Resistance In Vitro................... 88

7.2 Clinical Resistance (In Vivo).............................................................. 88

7.3 GENOTYPIC SCORES....................................................................................... 89

7.3.1 Key protease mutations (HIV protease codons 33, 82, 84 and 90)...... 90

7.3.2 Tipranavir score...................................................................................... 91

7.3.3 FDA protease gene mutations................................................................ 92

7.4 Relationship of Genotype to Phenotype..................................... 92

7.5 Impact of Genotype on Virologic Response.............................. 94

7.6 Impact of Phenotype on Virologic Response........................... 97

7.7 Predictors OF VIRAL Load RESPONSE at 24 Weeks..................... 99

7.8 RESISTANCE Conclusions...................................................................... 100

8. SAFETY............................................................................................ 101

8.1 EXPOSURE........................................................................................................ 101

8.2 SAFETY DATA FROM EARLY CLINICAL TRIALS................................... 101

8.3 CLINICAL SAFETY DATA OF PIVOTAL, ACTIVE-CONTROLLED TRIALS (RESIST-1 AND RESIST-2)................................................................................................ 103

8.3.1 Exposure and disposition...................................................................... 105

8.3.2 Adverse Events in RESIST trials......................................................... 106

8.3.3 Serious adverse events......................................................................... 108

8.3.4 Adverse events leading to discontinuation of treatment..................... 110

8.3.5 Exploratory analyses of medically selected terms.............................. 111

8.4 LABORATORY EVALUATIONS OF PIVOTAL, ACTIVE-CONTROLLED TRIALS (RESIST-1 AND RESIST-2)............................................................................................. 114

8.4.1.... Overview of DAIDS Grade 3 and 4 Laboratory Adnormalities in the Safety Update................................................................................................................ 114

8.4.2.... Hepatic Transaminase Elevations in the Safety Update..................... 115

8.4.2.1 Evaluation of ALT and/or AST Abnormalities............................ 115

8.4.2.2 Multivariable Analysis for Risk of LFT Elevations...................... 117

8.4.2.3 Actions Taken with LFT Abnormalities...................................... 118

8.4.2.4 Clinical Hepatic Adverse Events................................................ 120

8.4.2.5 Summary of Hepatic Findings.................................................... 121

8.4.3.... Fasting Lipid Elevations....................................................................... 122

8.4.3.1 Triglyceride Elevations.............................................................. 122

8.4.3.2 Cholesterol Elevations............................................................... 124

8.5 mortality and aids progression.................................................. 125

8.5.1.... Deaths in all TPV Trials....................................................................... 125

8.5.2.... AIDS Progression Events in RESIST Trials....................................... 126

8.5.3 Deaths in RESIST trials....................................................................... 127

8.5.4.... Adjustment for Exposure in RESIST Trials........................................ 127

8.5.5.... Analysis of Patients who Rolled over to Trial BI 1182.17 from the CPI/r arm of RESIST Trials and Died...................................................................................... 129

8.5.6.... Contrast of Deaths in the rollover study: Patients from RESIST Clinical Program compared to Patients from other TPV Trials....................................... 130

8.5.7 Review of hepatic deaths...................................................................... 131

8.5.8.... Summary of Deaths............................................................................... 134

8.6 Safety results in special populations....................................... 135

8.6.1.... Long-term safety from rollover Trial BI 1182.17................................ 135

8.6.2.... Pediatric Trial BI 1182.14..................................................................... 137

8.6.3.... Emergency Use and Expanded Access Programs............................... 138

8.6.4.... Safety in Women and Minorities.......................................................... 140

8.7 safety conclusions................................................................................ 141

9. OVERALL Conclusions........................................................... 142

10. PLANS FOR COMPLETING REQUIREMENTS FOR TRADITIONAL APPROVAL...................................................................................... 148

APPENDIX 1 NONCLINICAL PHARMACOLOGY AND TOXICOLOGY 149

Appendix 1.1 Overview................................................................................... 149

Appendix 1.2 General and Safety Pharmacology........................ 150

Appendix 1.3 Absorption, Distribution, Metabolism, and Excretion 151

Appendix 1.4 Toxicology.............................................................................. 152

Appendix 1.4.1 Single dose toxicity studies (acute toxicity)......................... 152

Appendix 1.4.2 Chronic studies...................................................................... 153

Appendix 1.4.3 TPV-ritonavir co-administration studies.............................. 154

Appendix 1.4.4 Genotoxicity studies............................................................. 157

Appendix 1.4.5 Reproduction toxicology....................................................... 157

Appendix 1.4.6 Other toxicity........................................................................ 158

APPENDIX 2 TPV Clinical Trial Program........................... 161

Appendix 2.1 Biopharmaceutic Studies............................................... 161

Appendix 2.2 Human Pharmacokinetic Studies.............................. 164

Appendix 2.3 Human Pharmacodynamic Studies........................... 172

Appendix 2.4 Clinical Efficacy and Safety Studies...................... 174

Appendix 3 DRUG INTERACTIONS.............................................. 182

Appendix 4 FATAL EVENTS IN RESIST TRIALS........................ 185

List of abbreviations

AE Adverse event

ALT Alanine aminotransferase

APV Amprenavir

ARV Antiretroviral (agent)

BI Boehringer Ingelheim

BID Twice a day

BLQ Below limit of quantitation

CD4+ Cluster of differentiation 4 (antigen marker on T-lymphocytes)

CI Confidence interval

CPI/r Comparator protease inhibitor with ritonavir

C_12h Plasma concentration of drug at 12 hours

EFV Efavirenz

ENF Enfuvirtide, also referred to as T-20

EAP Expanded Access Program

EUP Emergency Use Program (BI Trial 1182.58)

FAS Full analysis set

FC Fold-change

GSS Genotypic sensitivity score

HAART Highly active antiretroviral therapy

HFC Hard filled capsule

HIV Human immunodeficiency virus

IC₅₀ Concentration of drug required to produce 50% inhibition

IDV Indinavir

ITT Intent-to-treat (population)

IQR Interquartile range; 25^th percentile and 75^th percentile around median

KM Kaplan Meier probability

LOCF Last observation carried forward

LPV Lopinavir

mg Milligram

mL Milliliter

mm³ Cubic millimeter

N Number of patients

NCC Non-completer considered censored

NCF Non-completer considered failure

NRTI Nucleoside reverse transcriptase inhibitor

NNRTI Non-nucleoside reverse transcriptase inhibitor

OBR Optimized background regimen

OLSS Open-Label Safety Study

OR Odds ratio

OT On treatment

p Probability

PBMC Peripheral blood mononuclear cells

PCR Polymerase chain reaction

PEY Person exposure years

PI Protease inhibitor

PK Pharmacokinetics

PPS Per protocol set

P&U Pharmacia and Upjohn

RESIST-1 Randomized Evaluation of Strategic Intervention in multi-drug resistant patients with Tipranavir [BI Trial 1182.12]

RESIST-2 Randomized Evaluation of Strategic Intervention in multi-drug resistant patients with Tipranavir [BI Trial 1182.48]

RNA Ribonucleic acid

RR Relative risk

RTV Ritonavir

SAE Serious adverse event

SCS Summary of Clinical Safety

SEC Soft elastic capsule

SEDDS Self-emulsifying drug delivery system

SQV Saquinavir

SQV/r Saquinavir with ritonavir

SOC System organ class

TPV Tipranavir

TPV/r Tipranavir co-administered with ritonavir

TR Treatment response

μM Micromole

VL Viral load

WT Wild type

SUMMARY

Highly Active Antiretroviral Therapy (HAART) has had a marked impact on the course of the HIV epidemic in the developed world. These potent antiretroviral combination therapies are able to effectively suppress viral replication and are associated with reconstitution of the immune system. However, non-adherence to HAART regimens and increased transmission of drug-resistant HIV-1 are common problems in the clinic, and this has led to the development of a large patient population with multi-drug resistant HIV-1 infection. Each of the major classes of antiretroviral agents (ARVs) is affected by resistance, including protease inhibitors (PI). As a result, novel therapeutic agents are needed to construct active regimens for PI-experienced patients to reduce viral replication and decrease HIV-related morbidity and mortality. Tipranavir (TPV) is a non-peptidic protease inhibitor active against the majority of protease inhibitor resistant HIV-1 seen in clinical practice. Both a soft gelatin capsule and a liquid formulation have been developed to meet the clinical needs of HIV-positive patients. The subject of this document is the capsule formulation only (NDA 21-814). Tipranavir helps to address a continued unmet clinical need for new drugs to treat patients with multidrug resistant HIV-1.

Patients in the tipranavir clinical development program demonstrated multi-drug resistance with varying degrees of cross-resistance to the currently available PIs. In this briefing document, we present 2- and 24-week data demonstrating the antiviral activity of tipranavir, co-administered with low-dose ritonavir (TPV/r), in PI-experienced patients with established PI-resistant viruses.

As of 30 September 2004, the cut-off date for the Safety Update, a total of 3,367 HIV-positive patients have been treated with TPV/r. In the clinical trial database, 1,870 of these patients have been treated with TPV/r representing 1,760 patient-years of exposure. Nearly half of the patients (47%) have been treated for ≥48 weeks with a maximum exposure of 5 years. 1,411 patients have been treated with the TPV/r 500/200 mg dose with 1,206 having received this to-be-marketed dose for at least 24 weeks.

The ongoing RESIST^{^[1]} trial program, which compares TPV/r to a ritonavir-boosted comparator PI (CPI/r) on an optimized background regimen (OBR), is one of the largest programs undertaken in a PI-experienced population. Comparator PIs in the RESIST trials include ritonavir-boosted lopinavir, indinavir, saquinavir, and amprenavir. The intrinsic activity of TPV/r is demonstrated by the ≥ 1 log₁₀ reduction observed at 2 weeks after the initiation of TPV/r therapy. After 24 weeks of treatment (interim analysis), TPV/r had superior antiviral activity compared to CPI/r as shown below:

Overview of Week 24 efficacy endpoints - combined RESIST trials

	TPV/r + OBR N=582	CPI/r + OBR N=577	p-value
Median baseline viral load	4.83	4.82
Median baseline CD4+ count	155	158

Treatment Response (confirmed > 1 log₁₀VL decrease)	41%	19%	<0.0001
Median HIV VL change from baseline (log₁₀ copies/mL)	-0.80	-0.25	<0.0001
HIV VL < 400 copies/mL	34%	15%	<0.0001
HIV VL < 50 copies/mL	24%	9%	<0.0001
Median increase in CD4+ cell count (cells/mm³)	34	4	<0.0001

At 24 weeks, TPV/r had superior virological and immunological responses which were associated with a non-significant decrease in AIDS progression events in patients with PI‑resistant HIV-1. The 24‑week responses were of greater magnitude when TPV/r is combined with other active antiretroviral agents, for example enfuvirtide.

It has been shown that TPV must be co-administered with low-dose ritonavir to achieve adequate drug levels. Patients taking TPV/r generally achieve plasma concentrations that are many-fold above the protein-adjusted IC₉₀ for the majority of PI-resistant HIV-1 strains in the clinic. Despite being an inducer of the cytochrome P450 isoenzyme 3A (CYP3A) when given alone, TPV when combined with 200 mg of ritonavir produces a net inhibition of CYP3A. The pharmacokinetic drug interactions for most non-antiretroviral concomitant medications are similar to other ritonavir-boosted PIs.

Drug levels for ritonavir-boosted lopinavir, saquinavir, and amprenavir were significantly reduced when combined with TPV/r, therefore these combinations are not recommended. Protease inhibitor levels for novel dual PI regimens containing TPV/r cannot be predicted without formal drug interaction studies possibly due to the mixed patterns of inhibition and induction of CYP pathways seen with these drug combinations.

While reductions in plasma concentrations of abacavir and zidovudine have been observed when they are combined with TPV/r, the clinical relevance of these changes has not been established and no dose adjustment can be recommended at this time.

We have undertaken an extensive evaluation of the resistance profile of TPV/r and have defined the genotypic and phenotypic correlates associated with treatment response. The best correlations of the antiviral activity of TPV/r with a genotypic score were obtained with (1) the key mutations in the HIV-1 protease at positions 33, 82, 84, and 90, and (2) a tipranavir score derived from correlation of mutations in HIV-1 protease to viral phenotype and viral load responses seen in the Phase II and III programs. Based on these analyses, it takes 3 key mutations and > 4 TPV-score mutations to produce decreased TPV susceptibility (> 3-fold wild-type) in vitro or decreased antiviral responses in the clinic. High level resistance (> 10-fold wild type) usually requires all 4 key mutations or > 7 TPV-score mutations which are uncommon in clinical HIV-1 isolates from treatment-experienced patients. These in vitro and clinical data confirm that there is a high genetic barrier to resistance with TPV.

Many of the mutations which are associated with decreased susceptibility to TPV have not been associated with drug resistance to currently available PIs. While one or more mutations at protease codons 33, 82, 84, 90 can produce high level resistance to currently available PIs, it takes at least three of these mutations produce reduced susceptibility to TPV/r. The predominant emerging mutations with virologic failure in PI-experienced patients receiving TPV/r are 33F/I/V, 82T/L, and 84V; the drug resistance pattern which will result from treatment of drug naïve patients is not yet established.

The types and rates of adverse events (AEs) and serious AEs reported for TPV/r in the RESIST trials are similar to CPI/r and are consistent with AEs associated with the use of other ritonavir-boosted PIs except for increased rates of Grade 3/4 elevations in ALT/AST, cholesterol and triglycerides which were more common with TPV/r than with CPI/r. The hepatic events were generally asymptomatic and most patients were successfully continued on treatment. These laboratory abnormalities can be managed with routine monitoring except in patients with chronic Hepatitis B or C co‑infection or elevated baseline LFTs where increased monitoring of LFTs is recommended.

There was a nonsignificant difference in fatalities between the TPV/r and CPI/r arms of the RESIST trials at 24 weeks (p=0.64). The types and rate of fatalities in the TPV/r development program are consistent with what has been described for patients with advanced HIV disease. There have been a limited number of cases of clinical hepatitis or death due to hepatic failure in the TPV development program, primarily in patients with advanced HIV disease taking multiple concomitant medications. A causal relationship to TPV/r could not be established.

In summary, tipranavir, co-administered with low-dose ritonavir, is a novel HIV protease inhibitor which retains significant antiviral activity in the face of multiple PI mutations. Regimens containing TPV/r in the RESIST population of patients with highly PI-resistant viruses had superior virologic and immunologic activity at 24 weeks compared with the CPI/r‑based regimens. Genotypic resistance testing can assist in the selection of drugs to combine with TPV/r and in determination of which patients are most likely to benefit from a TPV/r-based regimen. Similar to other ritonavir-boosted PIs, pharmacokinetic interactions between TPV/r and other drugs metabolized by CYP3A should be expected. The net effect of TPV/r is CYP3A inhibition. Finally, the safety profile of TPV/r is similar to other ritonavir-boosted PIs in a PI-experienced population, except for increased rates of ALT/AST, cholesterol and triglyceride elevations which were seen for the TPV/r arms in the RESIST trials.

The use of TPV/r-based regimens in treatment-experienced patients with PI-resistant HIV-1 helps to meet a large unmet clinical need. The balance of the benefits and risks of drug regimens containing tipranavir co-administered with low-dose ritonavir supports the indication for use in PI treatment-experienced patients with HIV-1 infection.

1. INTRODUCTION

With the introduction of the new class of HIV protease inhibitors (PI) in the mid-1990s, the Highly Active Antiretroviral Therapy (HAART) era began. This was associated with dramatic decreases in HIV-related morbidity and mortality and subsequent prolongation of the course of HIV infection.^{^[2]} However, the first PIs were associated with poor bioavailability, complex dosing demands, and/or significant GI intolerability. These factors led to development of PI resistance, treatment failure, and an understanding of the importance of treatment adherence.

The second wave of protease inhibitor development focused on making agents that were easier to tolerate, had an improved and more forgiving pharmacokinetic profile, and could overcome established PI drug resistance. These newer agents to varying degrees have fulfilled this need. However, concurrent resistance to reverse transcriptase inhibitors developed during this period to the point where many antiretroviral-experienced patients have evolved significant three-class HIV drug resistance. This population of patients harbouring multi-drug resistant HIV represents a growing difficult to treat group.^{^[3]}

Tipranavir is a novel non-peptidic HIV protease inhibitor that was developed with the specific goal of being able to overcome broad PI cross-resistance. It belongs to the class of 4‑hydroxy‑5,6‑dihydro‑2‑pyrone sulfonamides. The chemical name of tipranavir is 2-Pyridinesulfonamide, N-[3-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl). Its molecular formula is C₃₁H₃₃F₃N₂O₅S with a corresponding molecular weight of 602.7 (Figure 1: 1).

Figure 1: 1 Structural formula of tipranavir

Early in vitro studies showed that viral isolates cross-resistant to most of the commercially available PIs retained susceptibility to tipranavir.^{^[4]} The IC90 for multi-drug resistant clinical HIV isolates ranged from 0.31-0.86 µM, and most clinical HIV isolates had a serum-adjusted IC90of ≤ 2 µM. This is in contrast to an IC90 of 0.18 µM for WT HIV-1 in PBMC.

Although the number of new AIDS diagnoses and deaths has fallen since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990’s, many HIV-positive patients have not had adequate responses to the regimens, cannot tolerate the toxic effects, or have difficulty complying with treatment regimens that involve large numbers of pills. Up to 50% of patients fail their initial regimens, and there is an increasing population of patients infected with drug-resistant HIV-1 strains who need new agents with improved resistance profiles compared to those of existing ARVs.^{^[5]} Thus, the initial tipranavir clinical development program focused on the study of PI-experienced patients in need of new therapy.

Phase II and III clinical trials in patients with a PI-resistant HIV-1 have confirmed that tipranavir has potent antiviral activity. Thus, tipranavir represents a significant advance in the treatment armamentarium for clinicians treating drug-resistant HIV-1 infection.

2. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY

General/Safety pharmacology studies were performed with TPV to assess effects on the cardiovascular, central nervous, pulmonary, renal, and gastrointestinal (GI) systems. These studies indicated that the drug was well-tolerated, with some effects noted in the renal and GI systems. Studies to investigate effects on the cardiovascular system showed an inhibitory effect in vitro on the HERG-associated potassium channel (IC50 = 2.9 µM; U02-1175), but no changes were noted in the guinea pig papillary muscle assay at similar concentrations, nor were any effects noted on QTc prolongation in the ECGs of conscious dogs following single administration of up to 160 mg/kg. Overall, these results suggest that TPV has little potential to prolong the QTc interval. No evidence of cardiovascular effects was noted in toxicity studies of up to 26 weeks in dogs with TPV/r or up to 39 weeks in dogs with TPV, and no prolongation of the QTc interval has been observed in multiple clinical studies.

Pharmacokinetic studies in humans have demonstrated the requirement for RTV co‑administration with TPV treatment in order to achieve and maintain required plasma levels of TPV for anti-viral activity. In humans, TPV is primarily metabolized by CYP3A and is a substrate for Pgp. The boosting effect of RTV on TPV plasma levels noted in humans is also observed in animals. However, the boosting effect seen in nonclinical species does not fully reflect that observed in humans, as there can be distinct species differences in CYP450 and Pgp selectivities. RTV co-administration resulted in an increase in TPV systemic exposure in all nonclinical species: mice (12- to 22-fold), rats (6‑to 7-fold), dogs (3‑to 13‑fold), and monkeys (2-fold). In rats and dogs, co‑administration of RTV resulted in a 4- to 5-fold decrease in clearance of TPV, consistent with inhibition of drug-metabolizing enzymes by RTV. In toxicity studies in animals at higher dose levels the boosting effect of RTV is lower in magnitude, perhaps due to a saturation of the boosting mechanism. In humans, in contrast, the boosting effect is more pronounced with co-administration of RTV (200 mg) with TPV (500 mg) at the proposed human dose level resulting in a 45-fold increase in Cmin, a 4-fold increase in Cmax, and an 11-fold increase in overall systemic exposure (). RTV is clearly increasing plasma concentrations of TPV by inhibiting metabolism, as the levels of metabolites in rats and humans are negligible following RTV co‑administration.

It has been noted in toxicity studies that TPV exposure in animals, even at the highest dose levels tested, is approximately equivalent to or only slightly above that achieved at the human dose level of 500 mg/200 mg TPV/r BID. Toxicity testing on TPV commenced with TPV administered as a singular entity. Once it was recognized that TPV was to be co‑administered with RTV in humans to achieve therapeutic plasma levels, co‑administration studies in animals were initiated to investigate the toxicity of the two compounds given concurrently and to increase plasma levels of TPV in animals. Co-administration of TPV with RTV does increase plasma levels of TPV in animals, notably at lower dose levels. However, this effect diminishes at higher dose levels, and does not reach the magnitude of the boosting effect that is achieved in humans. Rats in a 26-week TPV study administered 400 mg/kg/day TPV were exposed to maximum plasma concentrations of 90/209 µM in males/females and plasma exposure levels of 910/2320 µM·h (M/F). No total exposure was calculated in the 26-week TPV/r study, but plasma levels measured 8 hours after TPV administration ranged from 180 to 334 µM at the highest dose level tested of 1200/320 mg/kg/day TPV/r. Highest exposure in dogs was achieved in a 39‑week study at a dose level of 320 mg/kg/day TPV where Cmax and AUC values of 114 µM and 1155 µM·h (sexes combined), respectively, were achieved. These are in contrast to plasma levels reached at the human therapeutic dose level of 500/200 mg BID TPV/r, where a Cmax of 103 µM and an AUC0-24 of 1542 µM·h were achieved.

Toxicities seen in repeat-dose studies in rats and dogs are not considered to preclude chronic administration of TPV to the intended patient population, even in view of their observance at plasma levels equivalent to or below human exposure. The reasons for this are primarily their reversibility, manageability, species specificity, and correlation with species-specific hepatic enzyme-inducing effects of TPV in the rodent. Primary target organs identified in rats and dogs included the liver and GI tract. Co-administration of TPV and RTV in rats and dogs revealed only signs of toxicity or target organ effects evident when each compound was administered alone. More importantly, co‑administration did not exacerbate the toxicity of either drug.

Changes in the GI tract in nonclinical studies have included emesis, soft stools, diarrhea, and/or excessive salivation post-dosing. Excessive salivation after TPV administration was attributed to the bitter taste of TPV, which animals were exposed to during gavage administration.

In rats and dogs, TPV plasma levels declined with repeated dosing relative to Day 1, indicative of enzyme induction. This was supported by increases in CYP450 isoforms CYP3A and CYP2B in both species, increases in smooth endoplasmic reticulum, increased liver weights, and hepatocellular hypertrophy. These increases in enzyme levels in animals are considered an adaptive response to exposure to a xenobiotic and not evidence of toxicity. Hepatic effects of TPV were dose-related, and reversible with discontinuation of treatment, or transient and of no clinical relevance.

Hepatic microsomal enzyme induction has resulted in secondary changes during toxicity studies in rodents. These include increased clearance of thyroid hormones with resultant increased thyroid weight and thyroid follicular hypertrophy/hyperplasia, slight increases in plasma proteins, and increases in coagulation parameters. All of these effects were found to be reversible with termination of treatment. Increases in plasma proteins are considered to reflect their increased synthesis in the liver due to enzyme induction. Thyroid effects in rats due to hepatic microsomal enzyme induction are not considered relevant to humans. Reversible increases in coagulation indices (PT and APTT), observed only in rodents administered TPV or TPV/r, were judged secondary to hepatic enzyme induction rather than a direct effect of the drug. Some increases in PT and fibrinogen were observed in mice, but not consistently, and no increases in coagulation parameters have been observed in beagle dogs. In response to these findings in rodents, monitoring of PT was performed in early clinical trials, but no increases in PT have been observed in humans.

Other hepatic changes in rodents included degeneration, vacuolation, necrosis, mineral deposition, and karyomegaly. Karyomegaly was noted at a low incidence in rats treated with TPV/r over 26-weeks. In these animals, the incidence of karyomegaly was not related to TPV dose. A much higher incidence was noted in RTV‑treated animals, and has been previously observed in rat studies on RTV performed by Abbott Laboratories. This finding is therefore an effect of RTV administration and not considered to be of concern for humans administered TPV/r, as in the combination therapy, RTV plasma levels are low. The other hepatic findings, along with elevations of ALT and AST, appeared predominantly in the mouse and were possibly related to tissue anoxia from circulatory derangements caused by hepatocellular hypertrophy. These changes were not observed in rats and dogs and may reflect a species-specific effect. Based on the disparity between species, the implications for humans are not clear. As liver function may be readily monitored, the appearance of increased ALT and AST in one species should not preclude the use of TPV in humans.

In beagle dogs, mild elevations in alkaline phosphatase in TPV or TPV/r treated groups may be related to enzyme induction, but may also be caused by an effect on the biliary system. The alkaline phosphatase increases in dogs were shown in the 26-week SEDDS safety study to be due to the hepatic isoform. Based on a lack of other findings indicating cholestasis, this change raises no concern for humans.

Testicular degeneration and/or atrophy were observed in long-term studies in rats and dogs at high dose levels. Re-evaluation of these data by an expert panel indicated that the findings in the beagle dog were within normal limits of variation. The testicular changes in rats, seen in only three animals at a high dose level, were morphologically and pathogenically unrelated and therefore not related to drug treatment. Consequently, testes are not considered to be a target organ of toxicity.

Genotoxicity studies with TPV have shown no potential for mutagenicity or clastogenicity in standard assays both in vitro and in vivo. Carcinogenicity studies are ongoing; therefore no definitive statements may be made regarding the potential for TPV to induce tumors. A lack of genotoxicity suggests that TPV would not induce tumors by a mutagenic or clastogenic mechanism. The potential effects of TPV on hepatic enzyme induction with consequent hepatic and/or thyroid tumors in rodent carcinogenicity has already been discussed and at this time are not considered to be a risk to humans taking TPV chronically.

Reproductive toxicity of TPV was assessed in standard studies in rats and rabbits. At a maximum plasma concentration in rats of 258 µM (2-fold human Cmax), no effects on spermatogenesis, estrous cycles, copulation, fertility, implantation, or early embryonic development were observed. In studies investigating exposure at the time of organogenesis, the no observed adverse effect levels (NOAEL) in rats and rabbits corresponding to exposures (AUC0-24) of 340 µM·h and 66 µM·h were determined. Maternal toxicity, embryotoxicity, and/or developmental toxicity were observed at greater exposure levels. Human exposure levels, at the recommended dose level, are above these NOAEL exposure levels in animals. Consequently, TPV should be given during pregnancy only if the benefit to the mother and the fetus outweighs the risk to the fetus. The definitive study in rabbits resulted in gross malformations at a maternally toxic dose level. These findings were judged to be due to a litter effect and not a drug effect, as marked maternal toxicity was observed at this dose level, and in a previous study at the same and higher dose levels there were no similar findings. Consequently, TPV was judged not to be a selective developmental toxicant and consequently is not teratogenic. TPV retarded pup growth in rats when administered during gestation and into the postpartum period. Distribution studies in rats administered 14C-TPV have demonstrated that radioactivity is excreted into the milk of rats. Consequently, women should be cautioned to avoid breastfeeding while taking TPV.

The immunotoxic potential of TPV was assessed in a standard assay testing the functioning of the humoral component of the immune system, the T-dependent antigen response to sheep red blood cells (sRBC). Treatment with TPV co-administered with RTV or TPV alone did not adversely affect the functional ability of the humoral component of the immune system in female CD-1 mice, as evaluated in the IgM antibody-forming cell response to the T‑dependent antigen, sRBC.

Toxicity of impurities in TPV drug substance and degradation products of TPV in drug product have been evaluated in general toxicity and genotoxicity studies, as recommended by ICH guidances Q3A(R) and Q3B(R). Impurities in TPV drug substance and drug product have been qualified at levels equal to or greater than the proposed acceptance criteria.

TPV is administered in self-emulsifying drug delivery system (SEDDS) formulations, with both the bulk fill solution and the oral solution each containing a special mixture of excipients. A 26-week safety study was designed in dogs to evaluate the toxicity of the bulk fill solution, with special attention given to the dose levels of one excipient, Cremophor EL (CrEL). CrEL is also present in the co‑administered RTV capsule formulation, as it is an excipient included in Norvir® capsules at 60 mg/mL (communication from Abbott Laboratories). Assessment of the bulk fill solution formulation in rats and dogs in toxicity studies of 13 and 26 weeks, respectively, confirm its safety at the human dose level of 500/200 mg BID TPV/r.

Literature assessment of components of the TPV oral solution indicate no toxicity concerns when used as instructed. Levels of propylene glycol (PG) in the TPV oral solution co‑administered with RTV oral solution are considered safe when administered to adults and children greater than 2 years of age. Due to the low levels of the PG-metabolizing enzyme alcohol dehydrogenase expressed by young livers, caution must be exercised when administering this combination to infants or children less than 2 years of age when administering TPV oral and RTV oral solutions along with other prescription and/or non‑prescription medications containing propylene glycol and/or ethanol. Due to the presence of Vitamin E TPGS in the TPV oral solution, Vitamin E supplementation should not be taken along with the oral solution since the Vitamin E content of this product exceeds the Recommended Daily Intake. Due to anticoagulant effects of high dose levels of Vitamin E, the possibility exists that this excipient could exacerbate coagulation defects in individuals who are deficient in Vitamin K or are receiving anticoagulant therapy and suggests that caution is warranted.

The nonclinical evaluation of TPV/r has confirmed the safety, efficacy, and bioavailability of TPV for its use in man for the treatment of HIV.

3. MICROBIOLOGY

In the course of the development of tipranavir, numerous in vitro and in vivo studies have been conducted to examine its antiviral activity. Particular focus has been on viral isolates containing mutations (and the patients who harbor these) that confer protease inhibitor resistance. These studies have shown that susceptibility to tipranavir is often maintained despite the development of broad cross-resistance to currently available PIs. In addition, in vitro passage experiments have shown that selection of mutations that confer resistance is slow; ongoing studies in antiretroviral naïve patients should help define whether or not there is a signature mutation that confers resistance to tipranavir.

3.1 Mechanism Of Action

Tipranavir is a non-peptidic protease inhibitor (NPPI) of HIV belonging to the class of 4‑hydroxy‑5,6‑dihydro‑2‑pyrone sulfonamides. In enzymatic assays, TPV demonstrates potent inhibition of the cleavage of a peptidic substrate by the HIV-1 protease with an inhibition constant (Ki) of 8.9 ± 6.8 pM. Using the same assay, TPV also inhibits the activities of HIV-2 protease (Ki < 1 µM) and of mutant HIV-1 proteases carrying the mutations V82A (Ki = 3 nM) or V82F/I84V (Ki = 0.25 µM). Selectivity for the HIV protease was demonstrated by high Ki values against the human aspartyl proteases pepsin (Ki = 2 µM), cathepsin D (Ki = 15 µM), and cathepsin E (Ki = 9 µM). Therefore, TPV is both a potent and a selective inhibitor of the HIV protease.

3.2 Antiviral Activity In Vitro

Tipranavir inhibits the replication of laboratory strains and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC₅₀) ranging from 0.03 to 0.07 µM (18-42 ng/mL). Tipranavir is also effective at inhibiting the replication of M-tropic strains of HIV (EC_{90 ADA}= 0.75 uM, 452 ng/mL and EC_90
DGV= 0.3 µM, 180 ng/mL) and at inhibiting the extracellular accumulation of the p24 capsid protein from H-9 cells chronically infected with HIV-1 IIIB (EC₅₀ of 0.39 µM, 235 ng/mL). Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-fold in conditions where human serum is present. When used in combination with other antiretrovirals, tipranavir shows synergy to additivity with the NRTI zidovudine, the NNRTI delavirdine and the PI ritonavir. Activities ranging from synergy to slight antagonism were reported when tipranavir was used in combination with other currently available ARV drugs. No evidence of strong antagonism was seen in any of the drugs combined with TPV, and these data have been recently confirmed by additional analyses of mixed drug cell cultures for all currently available PIs.

A large subset of isolates from PI-experienced patients entering the pivotal Phase III RESIST trials were evaluated for the presence of phenotypic susceptibility to commercially available PIs and TPV. Analyses using these samples are presented in Section 7 on TPV resistance.

4. OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM

4.1 EARLY DEVELOPMENT

Tipranavir was discovered by Pharmacia and Upjohn (P&U) and licensed for development by Boehringer Ingelheim (BI) in 2000. The initial development of tipranavir conducted by P&U involved optimizing the soft gelatin capsule SEDDS formulation and characterizing the ritonavir-boosting effect, so as to address issues of bioavailability and plasma exposure typical for PIs.

At BI, the TPV clinical development program was initially focused on PI-experienced patients, as this group has the greatest unmet medical needs. To provide additional data on the possible use of TPV/r in other populations, studies in pediatric and treatment naïve adult patients are ongoing.

Overall, through 30 September 2004^{^[6]}, 3,367 HIV-positive patients and 769 HIV-negative volunteer subjects have been exposed to TPV/r.

Early open-label, dose ranging studies (BI 1182.3, 1182.2 and 1182.4) demonstrated that tipranavir reduces viral load in HIV-positive patients with variable levels of treatment experience (naïve, single- and multiple-PI-experienced). However, these trials failed to determine the optimal TPV/r dose, thus a Phase II dose-defining study was designed (BI 1182.52).

4.2 DOSE-FINDING TRIAL

BI 1182.52 was the definitive dose-finding study that evaluated three TPV/r doses (TPV/r 500/100, 500/200, and 750/200 given twice daily). The doses chosen for testing in this study were based on data from the Phase I and II trial program and were considered the three best doses for possible further study in the Phase III program.

The study was conducted in patients very similar to those studied in the Phase III RESIST trials. All patients were triple ARV class, two PI-based regimen-experienced and had baseline viral isolates with at least one primary protease mutation (30N, 46I/L, 48V, 50V, 82A/L/F/T, 84V and 90M), with not more than 2 mutations among 82L/T, 84V or 90M. The presence of a primary protease mutation was required to support adherence to the previous treatment regimen. The specific primary protease mutations selected were drawn from a mutation list that had been used in a number of prior clinical trials including the Genotypic Antiretroviral Resistance Testing (GART) and Multiple Drug Resistance (MDR-HIV) studies.^{^[7]} The requirement to have no more than 2 mutations among 82L/T, 84V and 90M was based on in vitro TPV resistance selection studies, HIV-1 isolates from early Phase II TPV/r trials and a large panel of highly PI-resistant clinical isolates.^{^[8]}

BI 1182.52 was a double-blind study with three TPV/r doses: TPV/r 500/100 mg, TPV/r 500/200 mg and TPV/r 750/200 mg, all given twice daily with a genotypically optimized background regimen (OBR) that was individually chosen by investigators. The first 2 weeks of the study were the functional monotherapy phase, in which patients changed the PI they were taking at entry to one of the three TPV/r doses, but maintained the same OBR. The antiviral effect observed in the first 2 weeks was likely due to TPV/r, thereby allowing critical analyses of the activity of the three doses. The study also tested the PK and safety of the three doses.

Based on a composite of optimal safety, PK and antiviral activity against PI-resistant viruses, the TPV/r 500/200 mg dose group was selected for study in Phase III trials. In addition, BI 1182.52 confirmed that patients with virus containing three or more mutations at HIV protease positions 33, 82, 84 or 90 were unlikely to obtain a durable response to TPV/r or the alternative boosted PIs available. These data were discussed with the FDA at an End-of-Phase II meeting prior to the initiation of the Phase III trial program.

4.3 PHASE III PIVOTAL TRIAL PROGRAM

4.3.1 Trial design

The Phase III Trials (BI 1182.12 [RESIST-1] and BI 1182.48 [RESIST-2]) are ongoing, large, randomized, open-label, multicenter trials designed to evaluate the efficacy and safety of TPV/r in comparison to ritonavir-boosted comparator PIs (CPI/r). Similar to the Phase IIB dose-finding study, patients in the RESIST trials were triple ARV class, two PI-based regimen experienced with HIV RNA ³1,000 copies/mL at baseline. The study was originally designed for 48 weeks, but has now been extended for up to five years of follow up.

Genotyping was conducted at screening for the study and patients had to demonstrate at least one primary protease mutation (30N, 46I/L, 48V, 50V, 82A/L/F/T, 84V or 90M), with not more than 2 mutations at codons 33, 82, 84 or 90. Patients screening for the RESIST studies with 3 or more of these key mutations were eligible for the companion dual-booted PI study, BI 1182.51.

Both the general design of the tipranavir development program and the protocols in the Phase III program (BI 1182.12, 1182.48, and 1182.51) were reviewed with the FDA and important design elements were agreed upon. The RESIST studies also received a Special Protocol Assessment prior to initiation.

Figure 4.3.1: 1 General design of the tipranavir Phase II—III development program

The genotypic inclusion requirement in both BI 1182.52 and in the RESIST trials was based on the need to test a documented PI-experienced patient population for proof of the efficacy of TPV/r in these treatment-experienced patients. Patients were required to have at least one primary mutation to demonstrate that they had taken and failed a PI-containing regimen with sufficient adherence to select for a mutation. Importantly, any one of the mutations on the list would have been insufficient to develop resistance to all of the 4 comparator PIs used in RESIST.

In earlier in vitro and clinical data (BI 1182.52), the presence of multiple mutations at protease codons 33^{^[9]}, 82, 84, or 90 had been associated with reduced VL responses to TPV/r and shown to produce high level resistance to currently available PIs (specifically LPV, IDV, SQV, and APV). By allowing a maximum of two mutations at positions 33, 82, 84, or 90, patients who had clear evidence of PI resistance but still had a sufficient chance to respond to either study arm were selected for the RESIST trials.

Since it was anticipated that patients with three or more mutations at codons 33, 82, 84, or 90 would be unlikely to achieve a durable 1 log₁₀ response with either TPV/r or any of the CPI/r treatments, a dual boosted PI companion study (BI 1182.51) was designed. The objective of this study was to evaluate the PK, safety and preliminary efficacy of a dual-boosted PI regimen containing TPV in patients with 3 or 4 mutations at codons 33, 82, 84, or 90.

To ensure that both arms of the RESIST trials had a balanced number of patients with similar characteristics, the OBR had to be pre-selected prior to randomization. Specifically, using baseline genotyping results and patient treatment history, investigators had to pre-select the PI their patients would receive if they were randomized to the CPI/r arm. In addition, investigators had to pre-select the OBR and decide whether they would choose enfuvirtide as part of the OBR.

Following the selection of the preferred PI and the OBR, patients in the RESIST trials were then randomized 1:1 to either TPV/r or to the comparator arm (CPI/r) Patients in the CPI/r would receive the PI that had been pre-selected (lopinavir [LPV], indinavir [IDV], saquinavir [SQV] or amprenavir [APV]). Importantly, the randomizations were stratified according to both the pre-selected PI and on whether or not they intended to use enfuvirtide.

It was intended that all patients receive the best possible treatment available. If the patient's treatment history and genotype indicated that the PI that was part of the screening regimen was the best option for the patient (an ‘ongoing PI’), this could be the pre-selected PI chosen by the investigator for the RESIST trial.

In general, the designs of the two RESIST trials are similar except for the timing of the interim trial endpoints, the statistical hypotheses, and the resistance testing methods used. The primary endpoint for both trials is treatment response after 48 weeks. As defined in the protocol, the analysis for accelerated approval submission was to be performed at Week 24.

In the two RESIST studies, the key efficacy endpoint for the 24-week analysis was ‘treatment response,’ a composite endpoint of the proportion of patients with two consecutive viral load measurements ³1 log10 below baseline without evidence of: confirmed virological failure to < 1 log10 reduction, introduction of a new ARV (for reasons other than toxicity or intolerance to a background drug), permanent discontinuation of study drug, loss to follow-up, or death.

It is the 24-week interim analyses of the RESIST studies that form the foundation of the data provided in the TPV NDA package submitted for accelerated approval.

4.3.2 Trial design issues

4.3.2.1 Choice of comparator PI

The comparator arm treatments in the RESIST studies were selected as an “optimized standard of care.” Following the 1:1 randomization, patients could be treated with any of four RTV-boosted comparator PIs along with an OBR. The choice of both the comparator PI and the OBR was made prior to randomization by each investigator and was based on individual treatment history and the screening genotype data provided. As noted above, the objective of the pre‑randomization selection of all medications was to ensure balance between the two treatment arms, to provide the optimal treatment response for patients who were randomized to the comparator arm, and to eliminate a potential source of bias.

If needed, investigators were offered the use of an external panel of resistance experts to assist with drug selection (as needed) and to optimize the PI treatments chosen for use in the CPI/r arm. The use of enfuvirtide was allowed if it was pre‑declared prior to randomization and could be made available from the start of treatment. The randomization was stratified on both the choice of comparator PI and the use of enfuvirtide.

The use of a single RTV-boosted PI in the comparator arm (e.g., LPV/r) would have simplified the study analyses and allowed for blinding, and BI carefully considered this approach. BI concluded that the limitations of this approach outweighed the benefits. First, the trial would have been very slow to enroll; if there had been just one PI option in the CPI/r arm, patients and investigators might have considered the trial less attractive since that CPI/r option may not have been optimal for their treatment. Second, use of a single RTV-boosted PI in the CPI/r arm would have limited the amount of comparative data in this treatment-experienced population. Third, patients in the comparator arm would not necessarily be taking an “optimized standard of care” regimen, and a large number of comparator arm drop-outs might have resulted that could have invalidated the study efficacy endpoints. Finally, providing the best possible individualized option for each patient who randomized to the comparator arm appeared to be the most ethical approach for such patients since this optimized the opportunity for a treatment response in the CPI/r arm.

4.3.2.2 Open-label study design

BI recognizes the advantages of conducting pivotal registrational trials in a randomized, double-blind study design. However, the open-label design of the two RESIST trials allowed the use of the best possible RTV-boosted PI for patients randomized to the CPI/r arm. Using blinded drug supplies in the study would have required patients to take more capsules and this might have reduced patient adherence in both treatment arms; this would have also required a complex, time-consuming set of blinded drug supply agreements between five different pharmaceutical companies. The open-label nature of the RESIST studies was discussed with the FDA and concurrence was achieved on these important design elements.

To help overcome potential biases in this open‑label study design, BI took multiple precautions. First, an objectively defined composite primary endpoint—one log viral load reduction from baseline—was chosen which would be unlikely to be subject to bias. Second, the conservative intent-to-treat, non-completer considered failure approach has been used for the primary analysis, and multiple sensitivity analyses have been performed^{^[10]}. Third, investigators were required to pre-select both the CPI/r and OBR to be used. Finally, BI statistical, data management, and clinical teams were internally blinded to individual patient treatment assignment during the conduct of the study until after database lock. In spite of these precautions, BI was aware that the open-label study design might have a higher rate of discontinuations in the comparator arm since patients were knowingly not receiving TPV/r, a potentially preferred treatment option.

It is important to note that patients in the comparator arm could leave the study after Week 8 if they had confirmed virologic failure in order to receive TPV treatment outside of the RESIST program (in the BI 1182.17 long-term safety follow-up study). To reduce the number of patients who might not strictly adhere to the comparator arm treatments, all RESIST investigators were required to carefully document virologic failure and to provide confirmed comparator PI plasma concentrations prior to patients being able to receive TPV in BI 1182.17. Due to the subjective nature of adverse event reporting, patients leaving the comparator arm of RESIST for safety reasons were not considered for participation in BI 1182.17.

4.3.2.3 Resistance status of study cohort

The RESIST study population was chosen as a representative sample of patients with PI treatment-experience who demonstrated PI resistance.

Prior to patient randomization in the two RESIST studies, the study protocol was amended (Amendment 2) to allow investigators to pre-select a comparator PI that was interpreted as “resistant” on the baseline genotype report.

This important protocol amendment was necessary because initial genotype reports indicated that 57.4-73.8% of patients had resistance to the selected PI, making it impossible to enroll eligible patients and complete the trial within a reasonable time period. Patients with pan-resistance to available PIs and very limited treatment options would at least have a 50% chance of receiving TPV/r. Additional considerations included the knowledge that the genotype report gives an interpretation of resistance primarily based on unboosted PIs, while RTV-boosted PIs were exclusively used in the comparator PI arm. BI encouraged investigators to review the actual mutations listed on the resistance report (in addition to the interpretation) and to make use of the expert resistance consultant panel^{^[11]}. Finally, BI recognized the importance of providing TPV/r to patients in the RESIST studies if they had virologic failure on the CPI/r arm, and this was made available through BI 1182.17, the long term rollover trial.

4.3.2.4 RESIST study amendments and relevant protocol deviations

There were six RESIST protocol amendments by the time of the 24-week interim analysis. These amendments did not fundamentally change the study objectives, nor did their implementation have a clinically relevant impact on patients participating in the study (with the exception of Amendment 2). The primary goals of each amendment are described in the following paragraph.

Amendment 1 was implemented prior to the start of patient treatment to allow the use of tenofovir in Canada, where the drug previously had not been commercially available. As noted above, Amendment 2 (as discussed above) was implemented prior to the start of patient treatment to allow the entry of patients who had a baseline genotypic interpretation indicating ‘resistance’ to all of the available PIs^{^[12]},^{^[13]}. Amendment 3 was implemented in the first several weeks of the study to provide protocol clarifications where the language might have been subject to misinterpretation, and to provide guidelines for the management of vomiting. Amendment 4 was implemented in the first three months of the study to create a separate pharmacokinetic sub-study of women. Amendment 5 was implemented in the eighth month of the study to extend the study to 96 weeks from the originally planned 48 weeks. Amendment 6 was implemented after the data cut-off for the 24‑week analysis to correct a DAIDS adverse event severity grading scale that had been erroneously included in the protocol.

The relevant protocol deviations were broadly characterized in the trial protocols and specified in more detail in the trial statistical analysis plans. Final decisions about relevant protocol violations were made independently by the trial teams in the blinded report planning meetings held for each study, and these take place prior to internal unblinding of the data base. It is important to point out that each trial team was permitted to make their own decisions about relevant protocol deviations and reconciliations between the two RESIST study teams was not required. During the review process by the international TPV project team, relevant protocol deviations were re-assessed using the same fundamental criteria as used by each individual trial. As a result, a modified per-protocol set was derived that is slightly smaller than the per-protocol set report analyzed at 24 weeks in the individual RESIST clinical trial reports. This modified per-protocol set reduces the TPV/r group by six patients and the CPI/r group by 14 patients, leaving no substantive impact on the conclusion of superiority for the TPV/r arm.

4.3.2.5 Non-inferiority testing

For the pre-planned analyses at 24 weeks, both RESIST clinical trial protocols had planned to use a test of non-inferiority of TPV/r to CPI/r, followed by a test of superiority of TPV/r to CPI/r if non-inferiority was confirmed. Both tests were to be performed by the calculation of the same 95% confidence interval for the differences in response rates, taking into account the stratified randomization in the two arms of the trials.

The test of non-inferiority was originally included in the protocol statistical analysis plans because the control group was expected to show a response rate comparable to that of the TPV/r arm, at least in a large sub-group of the participating patients who would have viruses sensitive to both TPV and their chosen CPI. However, after Amendment #2 was implemented and it was recognized from the analysis of the composition of the trial population and the response rate of the CPI/r group, it became obvious that the response rate in the CPI/r group was incompatible with a response of a fully active control arm. As a result, BI concluded that a demonstration of non-inferiority was insufficient to demonstrate the antiviral efficacy of TPV/r and that a demonstration of superiority was required.

4.4 ADDITIONAL CLINICAL DATA

In support of the RESIST pivotal program, further extensive clinical data have been generated. These include an initial study of the impact of TPV in very highly treatment experienced patients, too resistant for participation in the RESIST trials (BI 1182.51).

In addition, a large amount of data on the resistance profile of TPV, evaluating the clinical impact of TPV resistance on treatment response and identifying predictors of TPV treatment response, has been generated, providing a resistance profile database superior to that of any currently available ARV.

In parallel, an extensive and highly detailed analysis and characterization of the pharmacokinetic and drug interaction profile of TPV/r has been performed.

At the time of NDA submission, data on 37 pediatric patients with up to four weeks of TPV/r exposure was available. This 48-week, 100-patient pediatric study in HIV-infected children and adolescents between 2 and 18 years of age now has been fully accrued and will be the subject of a future efficacy supplement.

Finally, a Phase III study of TPV/r versus LPV/r in antiretroviral naïve patients has recently completed enrolment.

All studies in the TPV development program have used standard research approaches to design, conduct, and analysis that are consistent with other ARV drug development programs. A listing of all 39 clinical trials conducted in support of TPV may be found in Appendix 2.

5. CLINICAL PHARMACOLOGY

5.1 Clinical Pharmacokinetics

To achieve effective tipranavir plasma concentrations using a twice-daily (BID) dosing regimen, co-administration of tipranavir with low-dose ritonavir twice-daily is essential. Ritonavir acts by inhibiting hepatic cytochrome P450 3A (CYP 3A), the intestinal P‑glycoprotein (Pgp) efflux pump, and possibly intestinal cytochrome P450 3A as well. As demonstrated in a dose‑ranging evaluation in 113 HIV-negative healthy male and female volunteers (BI 1182.5), ritonavir increases tipranavir AUC0-12h, Cmax and Cmin by decreasing its clearance.

Tipranavir 500 mg, co-administered with low-dose ritonavir 200 mg (TPV/r 500/200 mg), BID for 21 days was associated with a 48-fold increase in the geometric mean morning steady-state trough plasma concentrations of tipranavir as compared with tipranavir 500 mg given BID without ritonavir for 11 days (Figure 5.1: 1).

Figure 5.1: 1 Steady state plasma tipranavir concentrations on the 11^th-day of 500 mg BID administration without ritonavir (open circles) and following the addition of 200 mg ritonavir BID for 14 days (closed circles)

Given alone, TPV induces hepatic CYP 3A and RTV inhibits CYP 3A. To understand the net effect of coadministration of tipranavir and ritonavir on hepatic CYP 3A, a single 200 mg dose of ritonavir co-administered with 500 mg tipranavir was studied using an erythromycin breath test (ERMBT).

Tipranavir rapidly induced CYP 3A when given alone. When ritonavir was added the expected inhibitory effect on CYP 3A was predominant. This net inhibition of CYP 3A for the TPV/r combination was nearly complete on Study Day 1. Following withdrawal of drug administration, CYP 3A activity returned to baseline levels by Study Day 3, likely due to hepatic enzyme turnover.

These data confirm that tipranavir and ritonavir must be taken together and doses should not be missed. Patients should be cautioned to take their tipranavir and ritonavir together as prescribed and to not run out of the booster drug, ritonavir. Full hepatic enzyme inhibition is necessary to deliver adequate exposure to tipranavir.

The recommended dose of tipranavir is 500 mg (two 250 mg capsules or 5 mL of oral solution), co-administered with 200 mg ritonavir (low-dose ritonavir), twice daily. Steady state is attained in patients after 7 days of dosing. TPV/r exhibits linear pharmacokinetics at steady state and the half-life is 6.0 hours in HIV‑positive patients. Trough concentrations 60‑fold above the protein-adjusted IC₅₀ for protease inhibitor-resistant HIV-1 clinical isolates (i.e., IQ ³ 60) are achieved at doses of TPV/r 500/200 mg, and have been associated with a 1 log₁₀ viral load reduction in clinical studies of treatment-experienced patients.

5.1.1 Demographic subpopulations

Demographic subpopulations were also analyzed. For example, evaluation of steady-state plasma trough tipranavir concentrations at 10-14 h after dosing from the RESIST studies demonstrated that there was no change in median trough tipranavir concentrations as age increased for either gender through 65 years of age. The trend of consistent trough tipranavir concentrations with increasing age through 80 years for men was supported.

In addition, females generally had higher tipranavir concentrations than males. After 4 weeks of TPV/r 500 mg/200 mg BID, the median plasma trough concentration of tipranavir was 43.9 mM for females and 31.1 mM for males.

Finally, white males generally had more variability in tipranavir concentrations than black males, but the median concentration and the range making up the majority of the data are comparable between the races. Table 5.1.1: 1 summarizes pharmacokinetic parameters by gender and HIV status.

Table 5.1.1: 1 Population pharmacokinetic assessment by gender and HIV status

Pharmacokinetic parameter

HIV+ patients

HIV- subjects