1 bosentan therapy for pulmonary arterial hypertension isaac kobrin, md head of clinical development...

1

Bosentan TherapyBosentan Therapyfor Pulmonaryfor Pulmonary

Arterial HypertensionArterial Hypertension

Isaac Kobrin, MDIsaac Kobrin, MDHead of Clinical DevelopmentHead of Clinical DevelopmentActelion PharmaceuticalsActelion Pharmaceuticals

9001.01

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AdvisorsAdvisors

PAHPAH Lewis J Rubin, MD Lewis J Rubin, MD University of California San Diego University of California San Diego

Preclin / toxPreclin / tox R Michael McClain, PhD R Michael McClain, PhD Consultant in Toxicology Consultant in Toxicology

Clin pharm Clin pharm Malcolm Rowland, PhD Malcolm Rowland, PhD University of Manchester University of Manchester

HepatologyHepatology Willis C Maddrey, MD Willis C Maddrey, MD UT Southwestern Medical Center UT Southwestern Medical Center

Hematology Hematology Jerry L Spivak, MD Jerry L Spivak, MD Johns Hopkins University Johns Hopkins University

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Bosentan Therapy for PAHBosentan Therapy for PAH

Rationale for ET receptor antagonismRationale for ET receptor antagonism

Preclinical observationsPreclinical observations

Clinical pharmacologyClinical pharmacology

Clinical program:Clinical program:– Efficacy in patients with PAH Efficacy in patients with PAH – Overall safety and tolerability Overall safety and tolerability – Specific safety issuesSpecific safety issues

Drug-induced liver injury (Dr W Maddrey)Drug-induced liver injury (Dr W Maddrey)

Risk / benefit assessment (Dr L Rubin)Risk / benefit assessment (Dr L Rubin)9003.01

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Belongs to a family of 21-amino acid peptidesBelongs to a family of 21-amino acid peptides

Synthesized and secreted by endothelial cellsSynthesized and secreted by endothelial cells

Acts via 2 receptors:Acts via 2 receptors:

– ETETAA, vascular smooth muscle cells (SMC), vascular smooth muscle cells (SMC)

– ETETBB, vascular SMC, endothelial cells, fibroblasts, vascular SMC, endothelial cells, fibroblasts

Induces vasoconstriction, fibrosis, hypertrophyInduces vasoconstriction, fibrosis, hypertrophyand hyperplasiaand hyperplasia

Increases vascular permeabilityIncreases vascular permeability

Endothelin-1 (ET-1)Endothelin-1 (ET-1)

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Rationale for ET Receptor Rationale for ET Receptor Antagonism in PAHAntagonism in PAH

In patients with PAH:In patients with PAH:– Plasma ET-1 levels are increased, and levels Plasma ET-1 levels are increased, and levels

correlate with disease severitycorrelate with disease severity– Increased ET-1 immuno-reactivity in lung Increased ET-1 immuno-reactivity in lung

vasculature (plexiform lesions)vasculature (plexiform lesions)

Blockade of ET-1 activity is expected to prevent Blockade of ET-1 activity is expected to prevent its detrimental effectsits detrimental effects

ET receptor antagonists are effective in animal ET receptor antagonists are effective in animal models of pulmonary hypertension models of pulmonary hypertension

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BosentanBosentan

Specific, low MW, Specific, low MW, competitive ET-receptor competitive ET-receptor antagonistantagonist

Inhibits the effects of ET-1Inhibits the effects of ET-1by inhibiting its bindingby inhibiting its bindingto both ETto both ETAA and ET and ETBB

receptorsreceptors

N

N

N

N

OOH

O

NHS

O O

O

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Preclinical ObservationsPreclinical ObservationsRelated to PAHRelated to PAH

Pulmonary hypertensionPulmonary hypertension– Chronic hypoxiaChronic hypoxia– MonocrotalineMonocrotaline

Pulmonary fibrosisPulmonary fibrosis– BleomycinBleomycin

Pulmonary inflammationPulmonary inflammation– SephadexSephadex– Oleic acidOleic acid

Bosentan was studied in models of:

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Preclinical ObservationsPreclinical ObservationsRelated to PAHRelated to PAH

The main effects of bosentan included:The main effects of bosentan included:

Decrease in pulmonary artery pressureDecrease in pulmonary artery pressure

Decreases in pulmonary vascular hypertrophyDecreases in pulmonary vascular hypertrophyand right ventricular hypertrophyand right ventricular hypertrophy

Decreases in pulmonary fibrosisDecreases in pulmonary fibrosisand inflammationand inflammation

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Preclinical ObservationsPreclinical ObservationsRelevant to Human SafetyRelevant to Human Safety

Teratogenicity Teratogenicity

Decreased RBC parametersDecreased RBC parameters

Liver injuryLiver injury

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Preclinical ObservationsPreclinical ObservationsTesticular ChangesTesticular Changes

In a 2-year rat study, an increased incidenceIn a 2-year rat study, an increased incidenceof slight testicular tubular atrophy was observedof slight testicular tubular atrophy was observed

– Not observed in a 2-year mouse studyNot observed in a 2-year mouse study

The overall pattern and findings were not typical The overall pattern and findings were not typical of drug-induced testicular toxicityof drug-induced testicular toxicity

No effect on sperm count, motility or male No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses fertility in rats treated with oral bosentan at doses up to 50 times the recommended human doseup to 50 times the recommended human dose

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Pharmacokinetic Pharmacokinetic CharacteristicsCharacteristics

Dose proportional up to 600 mg (single dose)Dose proportional up to 600 mg (single dose)and 500 mg/day (multiple doses)and 500 mg/day (multiple doses)

Absorption: tAbsorption: tmaxmax at 3.5 hours at 3.5 hours

No relevant food effectNo relevant food effect

Oral bioavailability: approximately 50%Oral bioavailability: approximately 50%

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Pharmacokinetic Pharmacokinetic CharacteristicsCharacteristics

Terminal elimination half-life: 5.4 hoursTerminal elimination half-life: 5.4 hours

Protein binding: 98% (mainly albumin)Protein binding: 98% (mainly albumin)

Steady state reached within 3 - 5 daysSteady state reached within 3 - 5 days

Age, gender, race, body weight and renal Age, gender, race, body weight and renal function appear not to have a relevant effectfunction appear not to have a relevant effecton PK propertieson PK properties

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Metabolism and ExcretionMetabolism and Excretion

Eliminated mainly by hepatic metabolismEliminated mainly by hepatic metabolismand subsequent biliary excretionand subsequent biliary excretion

Metabolic pathways: CYP3A4 and CYP2C9 Metabolic pathways: CYP3A4 and CYP2C9

– Ketoconazole, a 3A4 inhibitor, led to a 2-fold Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposureincrease in bosentan exposure

– Inhibition of 2C9 is not expected to exert a Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole greater effect than ketoconazole

CsA, a nonspecific inhibitor of transporters, CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposuremarkedly increased bosentan exposure

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Influence on Drug MetabolismInfluence on Drug Metabolism

In vitro In vitro bosentanbosentan– Does not inhibit CYP1A2, 2C9, 2C19, 2D6Does not inhibit CYP1A2, 2C9, 2C19, 2D6

or 3A4or 3A4– Induces CYP2C9, 2C19 and 3A4Induces CYP2C9, 2C19 and 3A4

In vivo In vivo bosentanbosentan

– Decreases exposure to CYP2C9 and 3A4 Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV)substrates by 30-60% (HV)

– Reduced efficacy of CYP2C9 and 3A4 substrates Reduced efficacy of CYP2C9 and 3A4 substrates should be consideredshould be considered

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Warfarin DDI: Clinical Relevance Warfarin DDI: Clinical Relevance AC-052-352AC-052-352

Clinical experience in PAH patientsClinical experience in PAH patients(34 placebo and 59 bosentan patients) (34 placebo and 59 bosentan patients)

– No change in warfarin doseNo change in warfarin dose(BL vs end of treatment)(BL vs end of treatment)

– No change in INR (BL vs end of treatment)No change in INR (BL vs end of treatment)

– No difference in warfarin dose changesNo difference in warfarin dose changesduring treatment vs placeboduring treatment vs placebo

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Efficacy in PAH PatientsEfficacy in PAH Patients

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Open-label, long-termOpen-label, long-termAC-052-354AC-052-354(Ongoing)(Ongoing)Bos = 200Bos = 200

OverallOverallN = 245N = 245

Placebo-controlledPlacebo-controlledAC-052-351AC-052-351

Pbo = 11, Bos = 21Pbo = 11, Bos = 21

Open-label, long-termOpen-label, long-termAC-052-353AC-052-353(Ongoing)(Ongoing)Bos = 29Bos = 29

Placebo-controlledPlacebo-controlledAC-052-352AC-052-352

Pbo = 69, Bos = 144Pbo = 69, Bos = 144

PAH Studies for Efficacy PAH Studies for Efficacy EvaluationEvaluation

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Study DesignsStudy DesignsPlacebo-controlled StudiesPlacebo-controlled Studies

1616

BLBL Period 1 – EvaluationPeriod 1 – Evaluation Period 2 – Follow-upPeriod 2 – Follow-up

44Week 0Week 0 1212 2828

ScreenScreen

PlaceboPlacebo

Bosentan 125 mg bidBosentan 125 mg bid

PlaceboPlacebo

62.5 mg62.5 mgbidbid

AC-052-351AC-052-351

AC-052-352AC-052-352 62.5 mg62.5 mgbidbid


ScreenScreen

PlaceboPlacebo


PlaceboPlacebo

62.5 mg62.5 mgbidbid

11ºº Endpoints Endpoints

(Variable Period 2)(Variable Period 2)

(Fixed Period 2 for pts(Fixed Period 2 for pts

who participated)who participated)

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Patient Allocation to Periods 1 and 2 Patient Allocation to Periods 1 and 2 AC-052-351AC-052-351

Aug 99 Jan 00 Apr 00

Period 1(12 weeks)

Period 2(variable)

P1P1

P32P32

Randomization Primary Endpoint Final Endpoint

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Patient Allocation to Periods 1 and 2Patient Allocation to Periods 1 and 2AC-052-352AC-052-352

July 00 Dec 00 Mar 01

Period 1(16 weeks)

Randomization Primary Endpoint

Period 2(fixed 12 weeks)

Sep 00

Final Endpoint

P1P1

P48P48

P213P213

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Males or females Males or females 12 years old 12 years old

PAH due to PPH or secondary to sclerodermaPAH due to PPH or secondary to sclerodermaor other connective tissue diseasesor other connective tissue diseases

WHO functional class III - IVWHO functional class III - IV

Baseline 6-min walk test Baseline 6-min walk test 150 m and 150 m and 450/500 m 450/500 m

Baseline hemodynamicsBaseline hemodynamics– Mean PAP Mean PAP >> 25 mmHg 25 mmHg– PVR PVR >> 240 dyn 240 dyn••sec/cmsec/cm55

– PCWP PCWP < < 15 mmHg15 mmHg

Main Inclusion CriteriaMain Inclusion Criteria

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Main Exclusion CriteriaMain Exclusion Criteria

PAH due to other causes (eg, congenital HD, PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…)HIV, cirrhosis, thromboembolic, COPD…)

SSc/PAH with mod / severe interstitial fibrosisSSc/PAH with mod / severe interstitial fibrosis

Systolic BP Systolic BP << 85 mmHg 85 mmHg

ALT / AST ALT / AST >> 3 x ULN 3 x ULN

Hb / Hct Hb / Hct >> 30% below the LLN 30% below the LLN

PAH treatment modified within 1 monthPAH treatment modified within 1 monthof screening (excluding anticoagulants)of screening (excluding anticoagulants)

Received epoprostenol within 3 monthsReceived epoprostenol within 3 monthsof screeningof screening

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BosBos(n = 144)(n = 144)

21:7921:79

49 49 16 16

71 71 20 20

77:8:1577:8:15

55:4555:45

PboPbo(n = 11)(n = 11)

0:1000:100

47 47 1414

87 87 1818

82:18:082:18:0

82:1882:18

M:F (%)M:F (%)

Age (years)Age (years)

Weight (kg)Weight (kg)

Race (% W:B:O)Race (% W:B:O)

US / Non-US (%) US / Non-US (%)

19:8119:81

52 52 12 12

86 86 23 23

76:14:1076:14:10

81:1981:19

22:7822:78

47 47 1616

74 74 1818

86:1:1386:1:13

56:4456:44

BosBos(n = 21)(n = 21)

PboPbo(n = 69)(n = 69)

Percent or mean Percent or mean SD SD

AC-052-351AC-052-351 AC-052-352AC-052-352

DemographicsDemographics

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90:1090:10

2.5 2.5 2.9 2.9

71712323 6 6

100:0100:0

3.0 3.0 2.8 2.8

9191 9 9 ——

WHO class (% III:IV)WHO class (% III:IV)

Time from Diag (yrs)Time from Diag (yrs)

Etiology of PAH (%)Etiology of PAH (%) PPH PPH SSc/PAH SSc/PAH Other Other

100:0100:0

1.7 1.7 1.4 1.4

81811919——

94:694:6

2.3 2.3 4.0 4.0

707020201010


Baseline CharacteristicsBaseline Characteristics

AC-052-351AC-052-351 AC-052-352AC-052-352

BosBos(n = 144)(n = 144)

PboPbo(n = 11)(n = 11)

BosBos(n = 21)(n = 21)

PboPbo(n = 69)(n = 69)

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55 55 16 16

1014 1014 678 678

2.4 2.4 0.8 0.8

9.2 9.2 3.9 3.9

9.8 9.8 5.9 5.9

56 56 11 11

942 942 430 430

2.5 2.5 1.0 1.0

8.3 8.3 3.3 3.3

9.9 9.9 4.1 4.1

54 54 13 13

896 896 425 425

2.4 2.4 0.7 0.7

9.3 9.3 2.4 2.4

9.7 9.7 5.6 5.6

53 53 17 17

880 880 540 540

2.4 2.4 0.7 0.7

9.2 9.2 4.1 4.1

8.9 8.9 5.1 5.1

Mean Mean SD SD

Mean PAP (mmHg)Mean PAP (mmHg)

PVR (dynPVR (dyn··secsec//cmcm55))

CI (L/min/mCI (L/min/m22))

PCWP (mmHg)PCWP (mmHg)

Mean RAP (mmHg) Mean RAP (mmHg)

Baseline HemodynamicsBaseline Hemodynamics

AC-052-351AC-052-351 AC-052-352AC-052-352

BosBos(n = 144)(n = 144)

PboPbo(n = 11)(n = 11)

BosBos(n = 21)(n = 21)

PboPbo(n = 69)(n = 69)

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8282

91 91

5555

99

99

Anti-thrombotics (%)Anti-thrombotics (%)

DiureticsDiuretics

Calcium antagonistsCalcium antagonists

Cardiac glycosidesCardiac glycosides

OxygenOxygen

7171

8686

5252

1414

2929

7373

5151

5252

1919

33 33

7070

5454

4444

1919

2929

Main Concomitant Medications Main Concomitant Medications for PAHfor PAH

BosBos(n = 144)(n = 144)

PboPbo(n = 11)(n = 11)

BosBos(n = 21)(n = 21)

PboPbo(n = 69)(n = 69)

AC-052-351AC-052-351 AC-052-352AC-052-352

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Patient DispositionPatient DispositionAC-052-351AC-052-351

N = 32N = 32

n = 9n = 9

n = 8n = 8

n = 8n = 8

n = 21n = 21

n = 21n = 21

n = 21n = 21

RandomizedRandomizedITT/ SafetyITT/ Safety

CompletedCompletedPeriod 1Period 1


To open labelTo open label(AC-052-353)(AC-052-353)

1 w/d1 w/d

2 w/d2 w/d

BosBos125 mg bid125 mg bid

n = 21n = 21

PlaceboPlacebon = 11n = 11

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N = 214N = 214

n = 69n = 69

n = 63n = 63

n = 62n = 62


n = 70n = 70

n = 70n = 70

n = 67n = 67

n = 67n = 67

RandomizedRandomized

ITT/SafetyITT/Safety

6 w/d6 w/d

1 w/d1 w/d


Bos Bos 125 mg bid125 mg bid

n = 75n = 75

n = 74n = 74

n = 71n = 71

n = 71n = 71

3 w/d3 w/d 3 w/d3 w/dCompletedCompletedPeriod 1 Period 1

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Primary EndpointPrimary Endpoint

6-minute walk distance at end of Period 16-minute walk distance at end of Period 1

Secondary EndpointsSecondary Endpoints

Time to clinical worseningTime to clinical worsening

– DeathDeath

– Hospitalization due to PAH Hospitalization due to PAH

– Discontinuation due to worsening PAHDiscontinuation due to worsening PAH

– Start of epoprostenolStart of epoprostenol

– Lung transplantation / septostomyLung transplantation / septostomy

Efficacy ParametersEfficacy Parameters

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Change in Borg dyspnea index Change in Borg dyspnea index

Change in WHO functional classChange in WHO functional class

Change in pulmonary hemodynamicsChange in pulmonary hemodynamics(mean PAP, PVR, CI, mean RAP)(mean PAP, PVR, CI, mean RAP)

Increase in therapy for PAH (Period 1)Increase in therapy for PAH (Period 1)

Efficacy ParametersEfficacy Parameters

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Statistical AnalysesStatistical AnalysesPrimary EndpointPrimary Endpoint

All bosentan vs placebo: ITT populationAll bosentan vs placebo: ITT population

– AC-052-351: Student’s t-testAC-052-351: Student’s t-test

– AC-052-352: Mann-Whitney U-testAC-052-352: Mann-Whitney U-test

Management of patients with no valid assessment Management of patients with no valid assessment at the end of Period 1:at the end of Period 1: Due to worsening PAH or death: walk test = 0 mDue to worsening PAH or death: walk test = 0 m

– AC-052-351: 1 placebo ptAC-052-351: 1 placebo pt

– AC-052-352: 3 placebo, 2 bosentan 125 mg bid ptsAC-052-352: 3 placebo, 2 bosentan 125 mg bid pts

Due to other reasons: last value carried forwardDue to other reasons: last value carried forward

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6-minute Walk Test6-minute Walk TestMean Treatment EffectMean Treatment Effect

Treatment difference (meters)Treatment difference (meters)2020 2020 4040 6060 8080 100100 12012000 140140

BosBosPboPbo

125 mg bid125 mg bid 21211111AC-052-351AC-052-351

125 mg bid125 mg bid

AC-052-352AC-052-352

74746969

250 mg bid250 mg bid 70706969

125/250 mg bid125/250 mg bid 1441446969

Mean (95% CL)Mean (95% CL)

75.9 (12.5, 139.2)75.9 (12.5, 139.2)

34.6 (6.2, 63.1)34.6 (6.2, 63.1)

54.3 (27.3, 81.4)54.3 (27.3, 81.4)

44.2 (21.4, 67.0)44.2 (21.4, 67.0) P = 0.0002P = 0.0002

P = 0.0205P = 0.0205

(P = 0.0001)(P = 0.0001)

(P = 0.0107)(P = 0.0107)

9028.02

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Robustness of ResultsRobustness of ResultsPrimary ParameterPrimary Parameter

AC-052-351AC-052-351

Mann-Whitney U-testMann-Whitney U-testPer-protocol populationPer-protocol populationFirst 150 patients First 150 patients Pts w/o Wk-16 endpointPts w/o Wk-16 endpoint Carry forwardCarry forward Zero substitutionZero substitution Pbo CF, bos zero Pbo CF, bos zero Pbo exclude, bos zeroPbo exclude, bos zero

0.0190.019 0.021*0.021*

——

0.0410.041——————

AC-052-352AC-052-352

(0.0002)(0.0002)0.00110.00110.00630.0063

0.0002 0.0002 0.00080.00080.00540.00540.01760.0176

PP value value

* Identical to ITT population

9029.01

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-100

20

40

60

Change in Walk DistanceChange in Walk DistanceDuring Period 1During Period 1

Placebo (n = 11)Placebo (n = 11)

Bosentan 125 mg bidBosentan 125 mg bid(n = 21)(n = 21)

-100

20

40

60

Ch

ang

e in

Wal

k D

ista

nce

(m

)C

han

ge

in W

alk

Dis

tan

ce (

m)

BLBL 44 88 16161212Weeks Weeks

AC-052-352AC-052-352

AC-052-351AC-052-351

Mean Mean SEM SEM62.5 mg bid62.5 mg bid 125 or 250 mg bid125 or 250 mg bid

BosentanBosentan125/250 mg bid125/250 mg bid(n = 144)(n = 144)

PlaceboPlacebo(n = 69)(n = 69)

9030.01

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Change in Walk Distance by DoseChange in Walk Distance by DoseDuring Period 1 inDuring Period 1 in AC-052-352AC-052-352

Bosentan 250 mg bidBosentan 250 mg bid (n = 70)(n = 70)


Mean Mean SEM SEM62.5 mg bid62.5 mg bid 125 or 250 mg bid125 or 250 mg bid

BosentanBosentan125 mg bid125 mg bid(n = 74)(n = 74)

-10-10

00

2020

4040

6060

BLBL 44 88 16161212

Weeks Weeks Ch

ang

e in

Wal

k D

ista

nce

(m

)C

han

ge

in W

alk

Dis

tan

ce (

m)

9031.02

36

Walk Test in SubpopulationsWalk Test in SubpopulationsMean Treatment Effect (AC-052-352)Mean Treatment Effect (AC-052-352)

BosBosPboPbo

All patientsAll patients

GenderGender Males MalesFemalesFemales

AgeAge 12 – 20 yrs 12 – 20 yrs21 – 40 yrs21 – 40 yrs41 – 60 yrs41 – 60 yrs

>> 60 yrs 60 yrs

WeightWeight << 70 kg 70 kg 70 kg70 kg

RaceRace White WhiteOtherOther

6969

15155454

66151533331515

29294040

59591010

144144

3030114114

77313171713535

77776767

1111113333

2020 2020 4040 6060 8080 100100 12012000Treatment difference (meters)Treatment difference (meters)

…

9032.01

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BosBosPboPbo

2020 2020 4040 6060 8080 100100 12012000

All patientsAll patients

WHO classWHO class III IIIIVIV

Etiology Etiology PPH PPHSSc/PHTSSc/PHT

Time from Time from < 421 days< 421 days 421 days421 days

Congenital Congenital YesYes

NoNo

6969

6565 44

48481414

40402929

226666

144144

1301301414

1021023333

66667777

1111133133

diagnosisdiagnosis

heart diseaseheart disease

…

…

138.5

…

9033.01 Treatment difference (meters)Treatment difference (meters)

38


2020 2020 4040 6060 8080 100100 12012000

LocationLocation

BL walk testBL walk test

Mean PAPMean PAP

Mean RAPMean RAP

CICI

USUSNon-USNon-US

<< 345 m 345 m 345 m345 m

<< 52 mmHg 52 mmHg 52 mmHg52 mmHg

<< 8 mmHg 8 mmHg 8 mmHg8 mmHg

<< 2.3 L/min/m 2.3 L/min/m22

2.3 L/min/m2.3 L/min/m22

All patientsAll patients 6969

39393030

27274242

37373232

32323535

31313737

144144

79796565

79796565

67677777

66667777

75756969

BosBosPboPbo

9034.01 Treatment difference (meters)Treatment difference (meters)

39

Change in Borg Dyspnea IndexChange in Borg Dyspnea IndexMean Treatment EffectMean Treatment Effect

Treatment difference (score)Treatment difference (score)00112233 0.50.50.50.51.51.52.52.53.53.5

BosBosPboPbo

125 mg bid125 mg bid 21211111AC-052-351AC-052-351

125 mg bid125 mg bid

AC-052-352AC-052-352

74746969

250 mg bid250 mg bid 70706969

125/250 mg bid125/250 mg bid 1441446969


1.6 (1.6 (3.1, 0.0)3.1, 0.0)

0.4 (0.4 (1.1, 0.3)1.1, 0.3)

0.9 (0.9 (1.6, 1.6, 0.2)0.2)

0.6 (0.6 (1.2, 1.2, 0.1)0.1)

9035.02

40

Per

cen

t E

ven

t-fr

eeP

erce

nt

Eve

nt-

free

WeeksWeeks00 44 88 1212 1616 2020 2424 2828

pp < 0.01 < 0.01

5050

7575

100100BosentanBosentan125/250 mg bid125/250 mg bid

PlaceboPlacebo

pp < 0.01 < 0.01

00

Time to Clinical WorseningTime to Clinical WorseningUp to Treatment EndUp to Treatment End

AC-052-352AC-052-352

pp = 0.03 = 0.03

5050

7575

100100

00

AC-052-351AC-052-351

1441446969

1421426868

31311010

1411416363

1381386262

1031034848

252577

131333

BosentanBosentan125 mg bid125 mg bid

PlaceboPlacebo

21211111

21211111

7711

21211010

212188

121244

6611

2211

9036.02

41

Per

cen

t E

ven

t-fr

eeP

erce

nt

Eve

nt-

free

WeeksWeeks00 44 88 1212 1616 2020 2424 2828

5050

7575

100100

00

pp = 0.01 = 0.01p < 0.03

Time to Clinical Worsening by DoseTime to Clinical Worsening by DoseUp to Treatment End (AC-052-352)Up to Treatment End (AC-052-352)

BosentanBosentan

747470706969

727270706868

181813131010

717170706363

707068686262

555548484848

14141111

77

776633

Bos 125Bos 125Bos 250 Bos 250 PlaceboPlacebo

PlaceboPlacebo

9037.01

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Pbo Pbo (n = 69) (n = 69)

Clinical Worsening*Clinical Worsening*

DeathDeath

Hospitalization for PAHHospitalization for PAH

D/C for worsening PAHD/C for worsening PAH

Receipt of epoprostenolReceipt of epoprostenol

*Patients may fall into >1 category *Patients may fall into >1 category No cases of lung transplantation or septostomy No cases of lung transplantation or septostomy

14 (20.3) 14 (20.3)

2 (2.9) 2 (2.9)

9 (13.0) 9 (13.0)

6 (8.7) 6 (8.7)

3 (4.3)3 (4.3)

9 (6.3)9 (6.3)

1 (0.7)1 (0.7)

6 (4.2)6 (4.2)

5 (3.5)5 (3.5)

4 (2.8)4 (2.8)

BosBos(n = 144) (n = 144)

Pbo Pbo (n = 11) (n = 11)

BosBos(n = 21) (n = 21)

00

00

00

00

00

3 (27.3)3 (27.3)

00

3 (27.3)3 (27.3)

3 (27.3)3 (27.3)

3 (27.3)3 (27.3)

AC-052-351 AC-052-351 AC-052-352 AC-052-352

Incidence of Clinical WorseningIncidence of Clinical WorseningTo End of Period 2To End of Period 2

9038.01

43

Pbo Pbo (n = 69) (n = 69)

ImprovedImproved

Treatment effectTreatment effect

95% CL95% CL

BosBos(n = 144) (n = 144)

Pbo Pbo (n = 11) (n = 11)

BosBos(n = 21) (n = 21)

43%43%9%9%

AC-052-351 AC-052-351 AC-052-352 AC-052-352

Improvement in WHO ClassImprovement in WHO ClassEnd of Period 1End of Period 1

42%42%30%30%

Treatment effect of both studies combinedTreatment effect of both studies combined 14.9% (1.3%, 27.0%) 14.9% (1.3%, 27.0%)

33.8%33.8%

5.6%, 58.0%5.6%, 58.0%

11.9%11.9%

2.9%, 25.2%2.9%, 25.2%

9039.01

44

Change in WHO ClassChange in WHO ClassAC-052-351 and AC-052-352AC-052-351 and AC-052-352

Worsened 1 class (%)Worsened 1 class (%)

No changeNo change

Improved 1 classImproved 1 class

Improved 2 classesImproved 2 classes

Mann-Whitney U-testMann-Whitney U-test

00

5757

4343

00

66

6464

3030

00

22

5656

3838

44

PboPbo(n = 11)(n = 11)

Change from BLChange from BLto end of Period 1to end of Period 1

BosBos(n = 21)(n = 21)

1818

7373

99

00

PboPbo(n = 69)(n = 69)

BosBos(n = 144)(n = 144)

PP = 0.019 = 0.019 PP = 0.042 = 0.042

AC-052-351 AC-052-351 AC-052-352 AC-052-352

9040.01

45

1212 88 66 44 22 00 221010

Mean PAP (mmHg)Mean PAP (mmHg)

PVR (dynPVR (dyn••sec/cmsec/cm55))

Cardiac IndexCardiac Index (L/min/m(L/min/m22))

PCWP (mmHg)PCWP (mmHg)

Mean RAP (mmHg)Mean RAP (mmHg)


6.7 (6.7 (11.9, 11.9, 1.5)1.5)

415 (415 (608, 608, 221)221)

1.02 (0.65, 1.39)1.02 (0.65, 1.39)

3.8 (3.8 (7.3, 7.3, 0.3)0.3)

6.2 (6.2 (9.6, 9.6, 2.7)2.7)

600600 400400 300300 200200 100100 00 100100500500

Placebo = 10Placebo = 10Bos 125 mg bid = 20Bos 125 mg bid = 20

0.250.25 0.50.5 11 1.51.500

Changes in HemodynamicsChanges in HemodynamicsChange to Week 12 (AC-052-351)Change to Week 12 (AC-052-351)

Placebo-corrected treatment differencePlacebo-corrected treatment difference9041.01

46

% Pts with % Pts with 1 increase 1 increase

Treatment effectTreatment effect 95% CL 95% CL

% Pts with % Pts with 2 increases 2 increases

Treatment effectTreatment effect 95% CL 95% CL

BosentanBosentan(n = 144)(n = 144)

PlaceboPlacebo(n = 69)(n = 69)

22.222.2

11.111.1

29.029.0

18.818.8

Period 1 was 16 weeksPeriod 1 was 16 weeks

Increase in Therapy for PAHIncrease in Therapy for PAHAC-052-352 (Period 1)AC-052-352 (Period 1)

6.86.8 19.5, 7.119.5, 7.1

7.77.7 18.1, 4.718.1, 4.7

9042.01

47

Patient Allocation to Periods 1 and 2 Patient Allocation to Periods 1 and 2 AC-052-351AC-052-351

Aug 99 Jan 00 Apr 00

Period 1(12 weeks)

Period 2(variable)

P1P1

P32P32

Randomization Primary Endpoint Final Endpoint

9845.01

48


N = 32N = 32

n = 9n = 9

n = 8n = 8

n = 8n = 8

n = 21n = 21

n = 21n = 21

n = 21n = 21

RandomizedRandomizedITT/ SafetyITT/ Safety




1 w/d1 w/d

2 w/d2 w/d


n = 21n = 21


9023.01

49

Patient Allocation to Periods 1 and 2Patient Allocation to Periods 1 and 2AC-052-352AC-052-352

July 00 Dec 00 Mar 01

Period 1(16 weeks)

Randomization Primary Endpoint

Period 2(fixed 12 weeks)

Sep 00

Final Endpoint

P1P1

P48P48

P213P213

9846.01

50

Disposition of Pts Scheduled for Period 2Disposition of Pts Scheduled for Period 2 AC-052-352AC-052-352


N = 48N = 48

n = 11n = 11

n = 8n = 8


n = 16n = 16

n = 15n = 15

n = 12n = 12

RandomizedRandomized

CompletedCompletedPeriod 2 Period 2

EnteredEnteredPeriod 2Period 2

3 w/d3 w/d

1 w/d1 w/d

Bos Bos 125 mg bid125 mg bid

n = 19n = 19

n = 18n = 18

n = 13n = 13

5 w/d5 w/d 3 w/d3 w/d

1 w/d1 w/d2 w/d2 w/d

9025.01

51

Maintenance of EfficacyMaintenance of Efficacy Walk TestWalk Test Up to 28 WeeksUp to 28 Weeks

5050

7575

100100

00

AC-052-351AC-052-351BosentanBosentan125 mg bid125 mg bid

n = 21n = 21

n = 20n = 20

n = 6n = 6

2525

WeeksWeeks

AC-052-352AC-052-352

5050

7575

100100

00

2525

00 44 88 1212 1616 2020 2424 2828

BosentanBosentan125/250 mg bid125/250 mg bid(n = 35)(n = 35)

PlaceboPlacebo(n = 13)(n = 13)C

han

ge

fro

m B

asel

ine

(met

ers)

Ch

ang

e fr

om

Bas

elin

e (m

eter

s)

9493.01

Mean SEM

52

BosentanBosentan62.5 mg bid62.5 mg bid Bosentan 125 mg bidBosentan 125 mg bid

1 - 4 weeks1 - 4 weeks


Bosentan 62.5 mg bidBosentan 62.5 mg bid

AssessmentsAssessments– Walk test at Week 4Walk test at Week 4– WHO class each 6 monthsWHO class each 6 months

Patients Patients – 8 / 11 ex-placebo8 / 11 ex-placebo– 21 / 21 ex-bosentan21 / 21 ex-bosentan

3/31/01 cut off3/31/01 cut off

Open-label ExtensionOpen-label ExtensionAC-052-353AC-052-353

9043.01

53

Baseline (end of 351)Baseline (end of 351)

Change to Week 4*Change to Week 4*

393.8 393.8 37.9 37.9

22.5 22.5 14.3 14.3

Mean Mean SEM in meters SEM in meters

Ex-placeboEx-placebo(n = 8)(n = 8)

Ex-bosentanEx-bosentan(n = 21)(n = 21)

438.9 438.9 14.2 14.2

3.0 3.0 9.2 9.2

* * Treatment in AC-052-351 still blinded for 26 of 29 patientsTreatment in AC-052-351 still blinded for 26 of 29 patients

6-minute Walk Distance6-minute Walk DistanceOpen-label Extension Study AC-052-353Open-label Extension Study AC-052-353

9044.01

54

Class I (n)Class I (n)

Class IIClass II

Class IIIClass III

Class IVClass IV

00

00

2929

00

11

1212

1515

11

11

1111

1616

11

Start of Start of AC-052-351AC-052-351 6 months6 months 1 year1 year

Open-label bosentan Open-label bosentan

WHO class WHO class

WHO Functional ClassWHO Functional ClassOpen-label Extension Study AC-052-353Open-label Extension Study AC-052-353

29 patients entered the open-label study

9045.01

55

Bosentan 125 and 250 mg bid (vs placebo):Bosentan 125 and 250 mg bid (vs placebo):

Increased exercise capacityIncreased exercise capacity

– Consistent in all subpopulationsConsistent in all subpopulations

Improved dyspnea on exerciseImproved dyspnea on exercise

Improved WHO functional classImproved WHO functional class

Efficacy ConclusionsEfficacy Conclusions

9046.01

56

Efficacy ConclusionsEfficacy Conclusions

Improved pulmonary hemodynamics: Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAPcardiac index, mean PAP, PVR and mean RAP(125 mg bid)(125 mg bid)

Decreased risk of clinical worseningDecreased risk of clinical worsening

With extended treatment:With extended treatment:

Clinical benefits maintained; no evidenceClinical benefits maintained; no evidencefor tolerancefor tolerance

9047.01

57

9048.01

58

Safety and TolerabilitySafety and Tolerability

9049.01

59

Bosentan Therapeutic StudiesBosentan Therapeutic StudiesSafety DatabaseSafety Database

9050.01

Therapeutic StudiesTherapeutic StudiesN = 972N = 972

PAHPAHN = 252N = 252

BD14884BD148842000 mg/d2000 mg/d

PC, DB (n = 7)PC, DB (n = 7)

AC-052-351AC-052-351250 mg/d250 mg/d

PC, DB (n = 32)PC, DB (n = 32)AC-052-353AC-052-353

250 mg/d250 mg/dOL (n = 29)OL (n = 29)

AC-052-352AC-052-352250/500 mg/d250/500 mg/d

PC, DB (n = 213)PC, DB (n = 213)AC-052-354AC-052-354

250 mg/d250 mg/dOL (n = 200)OL (n = 200)

60


9051.01

CHFCHFN = 447N = 447



BC15064/part IBC15064/part I1000 mg/d1000 mg/dOL (n = 7)OL (n = 7)

NC15462NC154621000 mg/d1000 mg/d

PC, DB (n = 370) PC, DB (n = 370)

BC15064/part IIBC15064/part II2000 mg/d2000 mg/d

PC, DB (n = 36)PC, DB (n = 36)

NC15018NC150182000 mg/d2000 mg/d

PC, DB (n = 34)PC, DB (n = 34)

NC15464BNC15464B250 mg/d250 mg/d

OL (n = 86)OL (n = 86)

BD14884BD148842000 mg/d2000 mg/d

PC, DB (n = 7)PC, DB (n = 7)

AC-052-351AC-052-351250 mg/d250 mg/d

PC, DB (n = 32)PC, DB (n = 32)

ENABLEENABLE250 mg/d250 mg/d

PC, DB (n = 1613)PC, DB (n = 1613)

AC-052-353AC-052-353250 mg/d250 mg/d

OL (n = 29)OL (n = 29)AC-052-352AC-052-352

250/500 mg/d250/500 mg/dPC, DB (n = 213)PC, DB (n = 213)

AC-052-354AC-052-354250 mg/d250 mg/d

OL (n = 200)OL (n = 200)

61


9052.01


HTNHTNN = 243N = 243




NC15462NC154621000 mg/d1000 mg/d

PC, DB (n = 370) PC, DB (n = 370)


PC, DB (n = 36)PC, DB (n = 36)

NC15018NC150182000 mg/d2000 mg/d

PC, DB (n = 34)PC, DB (n = 34)

NC15464BNC15464B250 mg/d250 mg/d

OL (n = 86)OL (n = 86)

NC15020NC15020100-2000 mg/d100-2000 mg/d

PC, DB (n = 243)PC, DB (n = 243)

BD14884BD148842000 mg/d2000 mg/d

PC, DB (n = 7)PC, DB (n = 7)

AC-052-351AC-052-351250 mg/d250 mg/d

PC, DB (n = 32)PC, DB (n = 32)


PC, DB (n = 1613)PC, DB (n = 1613)

AC-052-353AC-052-353250 mg/d250 mg/d

OL (n = 29)OL (n = 29)AC-052-352AC-052-352


AC-052-354AC-052-354250 mg/d250 mg/d

OL (n = 200)OL (n = 200)

62


HTNHTNN = 243N = 243

SAHSAHN = 30N = 30




NC15462NC154621000 mg/d1000 mg/d

PC, DB (n = 370) PC, DB (n = 370)


PC, DB (n = 36)PC, DB (n = 36)

NC15018NC150182000 mg/d2000 mg/d

PC, DB (n = 34)PC, DB (n = 34)

NC15464BNC15464B250 mg/d250 mg/d

OL (n = 86)OL (n = 86)

NC15020NC15020100-2000 mg/d100-2000 mg/d

PC, DB (n = 243)PC, DB (n = 243)

NN15031NN150311500 mg/d1500 mg/d

PC, SB (n = 30)PC, SB (n = 30)

BD14884BD148842000 mg/d2000 mg/d

PC, DB (n = 7)PC, DB (n = 7)

AC-052-351AC-052-351250 mg/d250 mg/d

PC, DB (n = 32)PC, DB (n = 32)


PC, DB (n = 1613)PC, DB (n = 1613)

AC-052-353AC-052-353250 mg/d250 mg/d

OL (n = 29)OL (n = 29)AC-052-352AC-052-352



AC-052-354AC-052-354250 mg/d250 mg/d

OL (n = 200)OL (n = 200)9053.01

63

Subjects in the DatabaseSubjects in the Database

Pharmacology (23 studies)Pharmacology (23 studies)

Therapeutic trialsTherapeutic trials

8 Placebo-controlled8 Placebo-controlled

3 Open-label (2 extensions)3 Open-label (2 extensions)

ENABLE (blinded)ENABLE (blinded)

155155

288288

3131

PlaceboPlacebo BosentanBosentan

434434

677677

91911 : 11 : 1

AllAll

571571

965965

122122

16131613

About 1522 bosentan-treated patients About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) givenAdditional 62 PAH patients (ex-placebo) given

bosentan in AC-052-354bosentan in AC-052-354

9054.01

64

Subjects in the DatabaseSubjects in the Database88 Placebo-controlled StudiesPlacebo-controlled Studies

Indication [n (%)]Indication [n (%)] PAHPAH CHF CHF HTN HTN SAH SAHTreatmentTreatment Placebo Placebo Bos 100 mg/d Bos 100 mg/d Bos 250-500 mg/dBos 250-500 mg/d Bos 1000-1500 mg/dBos 1000-1500 mg/d Bos 2000 mg/dBos 2000 mg/d

(28.8)(28.8)(51.0)(51.0)

(17.0) (17.0) (3.1) (3.1)

(100)(100)

(25.0) (25.0) (43.3)(43.3)

(28.7) (28.7) (3.1) (3.1)

(7.4)(7.4)(31.6)(31.6)(45.8)(45.8)(15.2)(15.2)

PlaceboPlacebo (N = 288) (N = 288)

BosentanBosentan (N = 677) (N = 677)

83 83 147 147

49 4999

288288————————

169 169 293 293 194 194

21 21

——5050

214214310310103103

9055.01

65

Exposure to BosentanExposure to BosentanOverall and Placebo-controlled StudiesOverall and Placebo-controlled Studies

11 Therapeutic Studies11 Therapeutic Studies

120012001000100080080060060040040020020000

DaysDays

00

2525

5050

7575

100100

Pe

rce

nt

of

Pa

tien

tsP

erc

en

t o

f P

ati

ents

All bosentan doses (N = 715)All bosentan doses (N = 715)Mean (SD): 168 Mean (SD): 168 271 d 271 d

8 Placebo-controlled Studies8 Placebo-controlled Studies

DaysDays

Pe

rce

nt

of

Pa

tien

tsP

erc

en

t o

f P

ati

ents

4 weeks 526 (73.6%)4 weeks 526 (73.6%)3 months 352 (49.2%)3 months 352 (49.2%)6 months 141 (19.7%)6 months 141 (19.7%)1 year 88 (12.3%)1 year 88 (12.3%)3 years 28 (3.9%)3 years 28 (3.9%)

2002001001000000

2525

5050

7575

100100 All bosentan doses (N = 677)All bosentan doses (N = 677)

Placebo (N = 288)Placebo (N = 288)Mean (SD):Mean (SD): 101 101 61 d 61 d

Mean (SD): 85 Mean (SD): 85 64 d 64 d

5050 150150

9056.01

66

Gender (% M:F)Gender (% M:F)

Age (years)Age (years)

Weight (kg)Weight (kg)

Race (% W:B:O)Race (% W:B:O)

US / Non-US (%)US / Non-US (%)

PlaceboPlacebo(N = 288)(N = 288)

57:4357:43

57 57 14 14

77 77 15 15

90:4:790:4:7

32:6832:68

61:3961:39

57 57 13 13

78 78 17 17

89:6:689:6:6

28:7228:72

BosentanBosentan(N = 677)(N = 677)


Patient DemographicsPatient Demographics8 Placebo-controlled studies8 Placebo-controlled studies

9057.01

67

Flushing (%)Flushing (%)Leg edema / edemaLeg edema / edemaAbnormal hepatic funcAbnormal hepatic funcHeadache Headache AnemiaAnemia

% with % with 1 AE 1 AE


1.7 1.7 2.72.7

2.1 2.1 12.812.8

1.01.0

76.476.4

With a placebo-subtracted difference of With a placebo-subtracted difference of 2% 2%

6.6 6.6 7.47.45.95.9

15.815.83.43.4

78.178.1


4.94.94.6 4.6 3.83.83.03.02.42.4

1.71.7

Placebo-Placebo-subtractedsubtracted

Treatment-emergent AEsTreatment-emergent AEs88 Placebo-controlled StudiesPlacebo-controlled Studies

9058.01

68

Cardiac failureCardiac failure

DyspneaDyspnea

Aggravated PAHAggravated PAH

Angina pectoris/Angina pectoris/ chest pain chest pain

SyncopeSyncope

HypotensionHypotension

Postural hypotensionPostural hypotension

DizzinessDizziness

All were more frequent among placebo-treated All were more frequent among placebo-treated than bosentan-treated patientsthan bosentan-treated patients

Abdominal pain / nausea / vomitingAbdominal pain / nausea / vomiting

AEs of Specific InterestAEs of Specific Interest8 Placebo-controlled Studies8 Placebo-controlled Studies

9059.01

69

Increased incidence of worsening HF duringIncreased incidence of worsening HF during11stst month of treatment in CHF patients related to: month of treatment in CHF patients related to:

– Starting dose (125 and 250 mg bid)Starting dose (125 and 250 mg bid)– Speed of up-titration (weekly to 500 mg bid)Speed of up-titration (weekly to 500 mg bid)

Overall incidence of hospitalization for HF was Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo significantly lower with bosentan vs placebo

PlaceboPlacebo BosentanBosentan

Worsening Heart FailureWorsening Heart Failure

Overall incidenceOverall incidence

64 (22.2%) 120 (17.7%)64 (22.2%) 120 (17.7%)

60 (40.8%) 114 (38.9%) 60 (40.8%) 114 (38.9%)

PC studies (288/677)PC studies (288/677) CHF studies (147/293)CHF studies (147/293)

9060.01

REACH-1 (NC15462)REACH-1 (NC15462)

70

Abnormal hepatic func (%)Abnormal hepatic func (%)Leg edema / edema Leg edema / edema FlushingFlushingNasopharyngitisNasopharyngitisHypotensionHypotension

% with % with 1 AE 1 AE


2.52.58.88.85.05.07.57.53.83.8

93.893.8

With a placebo-subtracted difference of With a placebo-subtracted difference of 2% 2%

8.58.513.913.9

9.19.110.910.9

6.76.7

94.594.5


6.06.05.25.24.14.13.43.42.92.9

0.70.7


Most Frequent (Most Frequent ( 5%) Treatment-emergent AEs 5%) Treatment-emergent AEsAC-052-351 and AC-052-352AC-052-351 and AC-052-352

9061.01

71

Aggravated PAHAggravated PAH

Cardiac failureCardiac failure

DyspneaDyspnea

CoughCough

DizzinessDizziness

2% more frequent on placebo2% more frequent on placebo

Abdominal painAbdominal pain

Nausea/vomiting Nausea/vomiting

GastritisGastritis

InfluenzaInfluenza

Limb painLimb pain

Most Frequent (Most Frequent ( 5%) Treatment-emergent AEs 5%) Treatment-emergent AEsAC-052-351 and AC-052-352AC-052-351 and AC-052-352

9062.01

72

Abnormal hepatic func [n (%)]Abnormal hepatic func [n (%)]

HeadacheHeadache

Pts with Pts with 1 AE 1 AE


2 (0.7)2 (0.7)

2 (0.7)2 (0.7)

27 (9.4)27 (9.4)

28 (4.1)28 (4.1)

8 (1.2)8 (1.2)

75 (11.1)75 (11.1)


AEs (AEs ( 1.0%) Leading to Withdrawal 1.0%) Leading to Withdrawal8 Placebo-controlled Studies8 Placebo-controlled Studies

9063.01

73



Abnormal hepatic func [n (%)]Abnormal hepatic func [n (%)]Aggravated PAHAggravated PAHCardiac failure Cardiac failure SyncopeSyncope

Pts with Pts with 1 AE 1 AE

Occurring in > 1 patient per treatment groupOccurring in > 1 patient per treatment group

3 (1.8)3 (1.8)2 (1.2)2 (1.2)2 (1.2)2 (1.2)

00

9 (5.5)9 (5.5)

006 (7.5)6 (7.5)1 (1.3)1 (1.3)2 (2.5)2 (2.5)

8 (10.0)8 (10.0)

AEs Leading to WithdrawalAEs Leading to WithdrawalAC-052-351 and AC-052-352AC-052-351 and AC-052-352

9064.01

74

Cardiac failure [n (%)]Cardiac failure [n (%)]

Sudden deathSudden death

Cardiac arrestCardiac arrest

Myocardial infarctionMyocardial infarction

Total deathsTotal deaths


1 (0.3)1 (0.3)

5 (1.7)5 (1.7)

00

00

15 (5.2)15 (5.2)

6 (0.9)6 (0.9)

3 (0.4)3 (0.4)

3 (0.4)3 (0.4)

3 (0.4)3 (0.4)

31 (4.6)31 (4.6)


Reasons for Death (Reasons for Death ( 3 3 patients)patients)


9065.01

75

Cardiac failure [n (%)]Cardiac failure [n (%)]Aggravated PHTAggravated PHTPneumoniaPneumoniaPulmonary hemorrhagePulmonary hemorrhageSepsisSepsis

Total deathsTotal deaths


002 (2.5)2 (2.5)

000000

2 (2.5)2 (2.5)

2 (1.2)2 (1.2)00

1 (0.6)1 (0.6)1 (0.6)1 (0.6)1 (0.6)1 (0.6)

4 (2.4)4 (2.4)


All deaths occurring during the study or within 28 days of treatment endAll deaths occurring during the study or within 28 days of treatment end

Reasons for DeathReasons for DeathAC-052-351 and AC-052-352AC-052-351 and AC-052-352

9066.01

76

Change from BLChange from BL Pulse rate (bpm)Pulse rate (bpm) SBP (mmHg)SBP (mmHg) DBP (mmHg)DBP (mmHg)

IncidenceIncidence SBP < 80 mmHgSBP < 80 mmHg AE hypotensionAE hypotension


1.0 1.0 1.1 1.14.2 4.2 1.4 1.4 3.3 3.3 1.0 1.0


Mean change Mean change SEM or percent SEM or percent


0.2 0.2 0.5 0.5

3.1 3.1 0.7 0.73.0 3.0 0.4 0.4


0.3 0.3 0.7 0.72.4 2.4 1.0 1.0 0.4 0.4 0.7 0.7

PC StudiesPC Studies AC-052-351 + 352AC-052-351 + 352

3.3 3.3 1.5 1.53.8 3.8 1.8 1.8 0.7 0.7 1.2 1.2

Vital SignsVital Signs

2.8%2.8%7.6%7.6%

0.8%0.8%6.8%6.8%

00

3.8%3.8%

0.6%0.6%6.7%6.7%

9067.01

77

Evidence for Rebound?Evidence for Rebound?

Experience limited to 22 PAH patients Experience limited to 22 PAH patients – 5 pts had treatment discontinued after dose 5 pts had treatment discontinued after dose

reductionreduction– 7 pts had treatment interrupted for 2-14 days7 pts had treatment interrupted for 2-14 days– 10 pts had open-label treatment discontinued 10 pts had open-label treatment discontinued

PAH-related adverse experiencesPAH-related adverse experiences– 1 pt with aggravated PAH (29 days after d/c)1 pt with aggravated PAH (29 days after d/c)

No evidence in hypertensive or CHF patientsNo evidence in hypertensive or CHF patients

9068.01

78

Outcomes in PAH Patients Outcomes in PAH Patients Started on EpoprostenolStarted on Epoprostenol

Ex-placeboEx-placebon = 8n = 8

5 pts improved5 pts improved1 death1 death2 pts worse2 pts worse

Concomitant Concomitant bosentanbosentan

n = 6n = 6

Ex-bosentanEx-bosentann = 8n = 8

5 pts improved5 pts improved2 deaths2 deaths1 pt worse1 pt worse

5 pts improved5 pts improved1 death1 death

9071.01

79

Overall exposure to bosentanOverall exposure to bosentan– 29 patients: 21 of 21 ex-bosentan29 patients: 21 of 21 ex-bosentan

8 of 11 ex-placebo 8 of 11 ex-placebo– 485 485 97 days (range 105 – 595 days) 97 days (range 105 – 595 days)– 28 patients with 28 patients with 1 year 1 year

7 patients with 7 patients with 1.5 years 1.5 years

Outcomes:Outcomes:– No deathsNo deaths– 1 d/c for worsening PAH (epoprostenol)1 d/c for worsening PAH (epoprostenol)– 4 patients up-titrated to 250 mg bid4 patients up-titrated to 250 mg bid

(after 348 – 548 days of treatment)(after 348 – 548 days of treatment)

Long-term ExperienceLong-term ExperienceOpen-label Extension Study AC-052-353Open-label Extension Study AC-052-353

9069.01

80

Long-term ExperienceLong-term ExperienceOpen-label Extension Study AC-052-354Open-label Extension Study AC-052-354

Overall exposure to bosentanOverall exposure to bosentan– 200 patients: 138 of 144 ex-bosentan 200 patients: 138 of 144 ex-bosentan

62 of 69 ex-placebo 62 of 69 ex-placebo – 171 171 73 days (range 25 – 321 days) 73 days (range 25 – 321 days)– 100 patients with 100 patients with 6 months 6 months

13 patients with 13 patients with 9 months 9 months

Outcomes:Outcomes:– 2 deaths (pulmonary hemorrhage)2 deaths (pulmonary hemorrhage)– 2 d/c for worsening PAH (epoprostenol)2 d/c for worsening PAH (epoprostenol)– 6 d/c for elevated ALT/AST6 d/c for elevated ALT/AST– 4 d/c for AE/administrative reasons4 d/c for AE/administrative reasons

9070.01

81

00

Overall ExposureOverall ExposurePAH PatientsPAH Patients

9090 180180 270270

4040

00May 31, 2001 cut offMay 31, 2001 cut off

360360 540540 630630

100100

6060

DaysDays

8080

Per

cen

t o

f P

atie

nts

2020

450450

BosentanBosentan

> 3 months 191 (81.3%)> 3 months 191 (81.3%)> 6 months 128 (54.5%)> 6 months 128 (54.5%)> 9 months 41 (17.4%)> 9 months 41 (17.4%)>12 months 28 (11.9%)>12 months 28 (11.9%)>18 months 12 (5.1%)>18 months 12 (5.1%)

137.2 patient-years137.2 patient-years

N = 235N = 235

9072.01

82

00

SurvivalSurvivalAC-052-351, AC-052-352 and OL ExtensionsAC-052-351, AC-052-352 and OL Extensions

0.250.25 0.50.5 0.750.75

8585

00

Fitted exponentialFitted exponentialdistribution (distribution ( = 0.05) = 0.05)

1.01.0 1.251.25 1.51.5

100100

9090

YearsYears

9595

Per

cen

t S

urv

ivo

rs

235235 190190 125125 4040 2929 2121 1010

At risk:At risk:

9074.01

83

No relevant difference between bosentan and No relevant difference between bosentan and placebo in SAEs placebo in SAEs

No relevant changes in ECG parametersNo relevant changes in ECG parametersor treatment-emergent ECG findings or treatment-emergent ECG findings

No relevant changes in laboratory tests except:No relevant changes in laboratory tests except:

– Decreases in RBC parameters Decreases in RBC parameters – Increases in liver enzymesIncreases in liver enzymes

Additional Safety ObservationsAdditional Safety Observations

9075.01

84

Decreases in Hemoglobin Decreases in Hemoglobin ConcentrationConcentration

9076.01

85

Preclinical ObservationsPreclinical ObservationsDecreases in HemoglobinDecreases in Hemoglobin

Mild (7–13%) decreases in Hb concentrationMild (7–13%) decreases in Hb concentrationin rats and dogsin rats and dogs

No evidence for:No evidence for:

– Hemolysis or immuno-allergic reactionHemolysis or immuno-allergic reaction– Bone marrow toxicityBone marrow toxicity– BleedingBleeding

Evidence for increased plasma volumeEvidence for increased plasma volumewith hemodilution in ratswith hemodilution in rats

9077.01

86

Hemoglobin Conc (g/dl)Hemoglobin Conc (g/dl) Chg to end of treatmentChg to end of treatment Chg to lowest valueChg to lowest value

% of Patients with% of Patients with Decrease of Decrease of 1.0 g/dl 1.0 g/dl Value < LLNValue < LLN Marked decrease (LL)Marked decrease (LL) LL and < 10.0 g/dlLL and < 10.0 g/dl

0.780.780.77 0.77

27.827.8 7.57.5 3.13.1 00

0.140.140.550.55

29.029.024.424.4 2.62.6 2.22.2


0.920.921.321.32

56.856.8 32.032.0 5.65.6 2.22.2


Incidence of Decreased Hb ConcIncidence of Decreased Hb Conc8 Placebo-controlled Studies8 Placebo-controlled Studies


LL = < 11.0 g/dl and >15% decrease from baselineLL = < 11.0 g/dl and >15% decrease from baseline

9078.01

87



0.960.961.09 1.09

34.834.813.813.8 1.81.8 1.21.2

0.010.010.480.48

30.430.4 8.98.9 1.31.3 1.31.3



0.960.961.571.57

65.265.2 22.722.7 3.03.0 2.42.4


Incidence of Decreased Hb ConcIncidence of Decreased Hb ConcAC-052-351 and AC-052-352AC-052-351 and AC-052-352


9079.01

88



1.021.021.12 1.12

35.535.514.614.6 2.32.3 1.11.1

0.410.410.440.44

14.014.0 3.23.2 00 00

HTNHTN(N = 231)(N = 231)

PAHPAH(N = 248)(N = 248)

0.910.910.870.87

36.536.5 13.513.5 5.05.0 0.30.3

CHFCHF(N = 405)(N = 405)

Incidence of Decreased Hb ConcIncidence of Decreased Hb ConcPlacebo-corrected IncidencePlacebo-corrected Incidence


9080.01

89

Among PAH Patients with AnemiaAmong PAH Patients with Anemia

No evidence for increase in bilirubinNo evidence for increase in bilirubin

No associated decrease in WBCs or plateletsNo associated decrease in WBCs or platelets

No increase in eosinophils above the ULNNo increase in eosinophils above the ULN

No premature withdrawal due to anemiaNo premature withdrawal due to anemia

Blood transfusions in 4 patients (2.4%)Blood transfusions in 4 patients (2.4%)

– 1 epistaxis, 2 GI bleeding, and 1 anemia1 epistaxis, 2 GI bleeding, and 1 anemia

– All 8 PC studies:All 8 PC studies: 1.8% on bosentan1.8% on bosentan1.0% on placebo1.0% on placebo

9081.01

90

Time to OccurrenceTime to OccurrenceDecreases in HemoglobinDecreases in Hemoglobin

8800 1616 2424 3232 WeeksWeeks

Pe

rce

nt

of

Pa

tien

ts a

t R

isk

Pe

rce

nt

of

Pa

tien

ts a

t R

isk

Marked decreaseMarked decrease( ( 15% and 15% and << 11 g/dl) 11 g/dl)

Marked decreaseMarked decrease( ( 15% and 15% and << 10 g/dl) 10 g/dl)

Decrease of Decrease of 1 g/dl 1 g/dl

Bosentan (N = 636) Bosentan (N = 636) Placebo (N = 271)Placebo (N = 271)

2020

1010

002020

1010

00

00

100100

5050


9082.01

91

-5

-4

-3

-2

-1

0

1

2

3

4

5

Change in Hb ConcentrationChange in Hb ConcentrationNC15462 and NC15464BNC15462 and NC15464B

Ch

ang

e fr

om

Bas

elin

eC

han

ge

fro

m B

asel

ine

Hb

(g

/dl)

Hb

(g

/dl)

Bosentan (n = 29)Bosentan (n = 29) 500 mg bid 500 mg bid


BLBL 33 441212 2626 BLBL 1212WeeksWeeks WeeksWeeks

Median and 25Median and 25thth and 75 and 75thth percentiles percentiles

Bosentan (n = 29)Bosentan (n = 29)


NC15462 (REACH-1)NC15462 (REACH-1) NC15464B (open label)NC15464B (open label)

9083.01

92

-4

-3

-2

-1

0

1

2

3

4

Change in Hb ConcentrationChange in Hb ConcentrationAC-052-352AC-052-352

BLBL 44 1616

Median and 25Median and 25thth and 75 and 75thth percentiles percentiles

88 1212WeeksWeeks



Ch

ang

e fr

om

Bas

elin

eC

han

ge

fro

m B

asel

ine

Hb

(g

/dl)

Hb

(g

/dl)

9084.01

93

Unlikely ReasonsUnlikely ReasonsDecrease in HemoglobinDecrease in Hemoglobin

Hemolysis:Hemolysis:– No increase in bilirubinNo increase in bilirubin– No increase in reticulocytes or MCVNo increase in reticulocytes or MCV

Bone marrow toxicity:Bone marrow toxicity:– No concomitant marked decreases in WBC No concomitant marked decreases in WBC

or platelet countsor platelet counts– Normal bone marrow evaluations (2 cases)Normal bone marrow evaluations (2 cases)

Bleeding tendency:Bleeding tendency:– No evidence for bleeding in most casesNo evidence for bleeding in most cases

9085.01

94

Possible MechanismsPossible MechanismsDecrease in HemoglobinDecrease in Hemoglobin

Hemodilution / fluid shiftHemodilution / fluid shift– Preclinical evidence for increased plasma Preclinical evidence for increased plasma

volumevolume– Compatible with clinical pictureCompatible with clinical picture– Compatible with mechanism of actionCompatible with mechanism of action

– VasodilationVasodilation– Decreased capillary permeabilityDecreased capillary permeability

Decrease in elevated erythropoetin levelsDecrease in elevated erythropoetin levels

9086.01

95

Risk to the patient is smallRisk to the patient is small

Hb concentration should be evaluatedHb concentration should be evaluatedafter 1 and 3 months of treatment and quarterly after 1 and 3 months of treatment and quarterly thereafterthereafter

Cases of marked decrease in Hb concentration Cases of marked decrease in Hb concentration should be further evaluated and/or treated,should be further evaluated and/or treated,based on clinical judgmentbased on clinical judgment

Risk ManagementRisk ManagementDecrease in HemoglobinDecrease in Hemoglobin

9087.01

96

Increases inIncreases inLiver AminotransferasesLiver Aminotransferases

9088.01

97

Preclinical ObservationsPreclinical Observations

Evidence for cholestasisEvidence for cholestasis

– Increase in plasma bile salts and alk phosIncrease in plasma bile salts and alk phos

No evidence for:No evidence for:

– Reactive or toxic metabolites Reactive or toxic metabolites – Immuno-allergic reaction Immuno-allergic reaction – Centrolobular necrosisCentrolobular necrosis– Mitochondrial toxicityMitochondrial toxicity

Competitive inhibition of bile salt excretionCompetitive inhibition of bile salt excretion(Bsep), which can lead to accumulation(Bsep), which can lead to accumulationof bile salts and hepatocellular lysisof bile salts and hepatocellular lysis

9089.01

98

20002000

PAH (%) PAH (%)

CHF CHF

HTN HTN

All All

— —

4.24.2

10.010.0

6.96.9

——

15.815.8

11.411.4

14.514.5

12.712.7

13.813.8

6.96.9

11.211.2

AllAll250/500250/500 1000/15001000/1500

12.712.7

— —

4.34.3

10.910.9

100 100

——

——

2.12.1

2.12.1

Bosentan Dose (mg/d)Bosentan Dose (mg/d)

Incidence on placebo was approximately 2%Incidence on placebo was approximately 2%

Elevated ALT/AST > 3 x ULN by DoseElevated ALT/AST > 3 x ULN by DoseSafety DatabaseSafety Database

Database Database

9090.01

99

88

PAH (N = 165) PAH (N = 165)

Others (N = 493)Others (N = 493)

All (N = 658)All (N = 658)

ENABLE (N ENABLE (N 807)* 807)*

4.24.2

3.93.9

4.04.0

2.82.8

1.81.8

3.23.2

2.92.9

2.02.0

12.712.7

10.810.8

11.211.2

8.68.6

>>3 - 3 - << 5 5 5 - 5 - << 8 8

6.76.7

3.73.7

4.44.4

3.83.8

* Percentages assume all events occur on bosentan, as data are still blinded* Percentages assume all events occur on bosentan, as data are still blinded

ALT / AST (x ULN)ALT / AST (x ULN)

Severity of Elevated ALT/ASTSeverity of Elevated ALT/ASTSafety DatabaseSafety Database

AllAllDatabase (%) Database (%)

9091.01

100

Bosentan (mg bid)Bosentan (mg bid)

125125(N = 95)(N = 95)

AE abn hepatic func [n (%)]AE abn hepatic func [n (%)]

ALT/AST > 3 x ULNALT/AST > 3 x ULNALT/AST > 8 x ULNALT/AST > 8 x ULN

Transient casesTransient cases At target doseAt target dose With dose reduction With dose reduction

DiscontinuedDiscontinued

10 (14.3)10 (14.3)

10 (14.3)10 (14.3) 5 (7.1)5 (7.1)

442222

33

4 (4.2)4 (4.2)

11 (11.6)11 (11.6) 2 (2.1)2 (2.1)

887711

00

250250(N = 70)(N = 70)

Elevated AminotransferasesElevated AminotransferasesAC-052-351 and AC-052-352AC-052-351 and AC-052-352

9092.01

101

Time CourseTime CourseElevated AminotransferasesElevated Aminotransferases

Gradual over several weeksGradual over several weeks

Normalized or reduced to < 2 x ULN during Normalized or reduced to < 2 x ULN during continued treatment (transient)continued treatment (transient)

– 70% (8/11) with bosentan 125 mg bid (PAH)70% (8/11) with bosentan 125 mg bid (PAH)– 40% (4/10) with bosentan 250 mg bid (PAH)40% (4/10) with bosentan 250 mg bid (PAH)– 16% (6/38) with bosentan 500 mg bid (CHF)16% (6/38) with bosentan 500 mg bid (CHF)

Complete resolution after treatment cessationComplete resolution after treatment cessation

9093.01

102

Safety databaseSafety database

AC-052-354AC-052-354

ENABLE ENABLE

3 – 643 – 64

18 – 5618 – 56

10 – 4410 – 44

RangeRange(days)(days)

3333

66

2323

NumberNumberof casesof cases

26 26 13 13

32 32 13 13

23 23 10 10

Mean Mean SD SD(days)(days)

Time following treatment end depended on time of evaluationTime following treatment end depended on time of evaluation

97% of elevations were resolved within 8 weeks97% of elevations were resolved within 8 weeks

Time to ResolutionTime to ResolutionALT/AST Returned to Baseline or < 2 x ULNALT/AST Returned to Baseline or < 2 x ULN

9094.01

103

Predisposing FactorsPredisposing FactorsIncidence of Elevated ALT/AST > 3 x ULNIncidence of Elevated ALT/AST > 3 x ULN

ALT/AST > 3 x ULNALT/AST > 3 x ULN

No effect of age or genderNo effect of age or gender

With With FactorFactor W/oW/o Factor FactorPredisposing factorPredisposing factor

ALT/AST > ULN at BLALT/AST > ULN at BL (n = 133, 521) (n = 133, 521)

Alk phos > ULN at BLAlk phos > ULN at BL (n = 83, 572) (n = 83, 572)

Concomitant glibenclamideConcomitant glibenclamide (n = 31, 213) (n = 31, 213)

10.0%10.0%

11.4%11.4%

13.3%13.3%

16.5%16.5%

10.8%10.8%

27.5%27.5%

9095.01

104

Time to First OccurrenceTime to First OccurrenceElevated Liver AminotransferasesElevated Liver AminotransferasesP

erce

nt

of

Pat

ien

ts a

t R

isk

BosentanPlacebo

40

20

0

0

40

20

8 Placebo-controlledStudies

AC-052-352

BosentanPlacebo

80 16 24 32

Weeks

(N = 144) (N = 68)

(N = 658) (N = 280)

9096.01

105

00

Time to First OccurrenceTime to First OccurrenceElevated Liver AminotransferasesElevated Liver Aminotransferases

1212 2424 3636 4848

2020

1010

00

BosentanBosentan (N (N 807) 807)

69 cases (8.6%)69 cases (8.6%)assuming all on bosentanassuming all on bosentan

6060 7272 8484 9696

4040

3030

WeekWeek

ENABLEENABLE

Per

cen

t o

f P

atie

nts

at

Ris

k

9097.01

106

Associated SymptomsAssociated SymptomsElevated Liver AminotransferasesElevated Liver Aminotransferases

Pts with symptomsPts with symptoms Nausea/vomiting (n)Nausea/vomiting (n) Abdominal painAbdominal pain FeverFever Jaundice/bili > 3xULNJaundice/bili > 3xULN

*Assuming all cases on bosentan*Assuming all cases on bosentan

9 / 749 / 74 33 22 44 11

PC StudiesPC Studies(N = 677)(N = 677)

2 / 52 / 52211001 1

OL StudiesOL Studies(N = 122)(N = 122)

11 / 6911 / 694466221 1

ENABLEENABLE(N = 807*)(N = 807*)

9098.01

107

Type of Liver InjuryType of Liver InjuryCouncil for Intl Org of Medical ScienceCouncil for Intl Org of Medical Science

Cholestatic Cholestatic ((ratio ratio 2 2))

Hepatocellular Hepatocellular ((ratio ratio 5) 5)

Mixed Mixed ((ratio ratio >>2, 2, << 5) 5)

Type of InjuryType of Injury

Ratio =Ratio =

* The ULN, respectively* The ULN, respectively

ALT / 30 U/L*ALT / 30 U/L*

Alk Phos / 95 U/L*Alk Phos / 95 U/L*

9099.01

108

Type of Liver InjuryType of Liver InjuryCouncil for Intl Org of Medical ScienceCouncil for Intl Org of Medical Science

Total number (%) of casesTotal number (%) of cases

Cholestatic Cholestatic ((ratio ratio 2 2))

Hepatocellular Hepatocellular ((ratio ratio 5) 5)

Mixed Mixed ((ratio ratio >>2, 2, << 5) 5)

67 (100)67 (100)

3 (4.5)3 (4.5)

25 (37.3)25 (37.3)

39 (58.2)39 (58.2)

ENABLEENABLE(N = 807(N = 807††))

74 (100)74 (100)

7 (9.5)7 (9.5)

34 (45.9)34 (45.9)

33 (44.6)33 (44.6)

PC StudiesPC Studies(N = 658)(N = 658)Type of InjuryType of Injury

* The ULN, respectively* The ULN, respectively† † Assuming all cases are on bosentanAssuming all cases are on bosentan

ALT / 30 U/L*ALT / 30 U/L*

Alk Phos / 95 U/L*Alk Phos / 95 U/L*Ratio =Ratio =

9100.01

109

MechanismMechanismElevated AminotransferasesElevated Aminotransferases

Not yet fully elucidatedNot yet fully elucidated

Competitive inhibition of bile salt excretion Competitive inhibition of bile salt excretion may be a contributory factormay be a contributory factor

No evidence for immuno-allergic reaction No evidence for immuno-allergic reaction – During treatmentDuring treatment– At reintroductionAt reintroduction

9101.01

110

Risk AssessmentRisk AssessmentHyman Zimmerman’s SuggestionsHyman Zimmerman’s Suggestions

Increased risk of acute liver failure in patientsIncreased risk of acute liver failure in patientswith predominantly hepatocellular disease:with predominantly hepatocellular disease:


Clinical jaundice (bilirubin > 3 x ULN)Clinical jaundice (bilirubin > 3 x ULN)

May be associated with small changesMay be associated with small changesin alkaline phosphatasein alkaline phosphatase

Estimated that 10% of patients who have drug-Estimated that 10% of patients who have drug-induced liver injury will develop acute liver failureinduced liver injury will develop acute liver failure

9102.01

111

Mean Mean SD (yrs) SD (yrs) (Range)(Range)Pts (%) treatedPts (%) treated > 3 months> 3 months > 6 months> 6 months > 9 months> 9 months >12 months>12 months >18 months>18 months >24 months>24 months

PAH PAH StudiesStudies

(N = 235)(N = 235)

0.58 0.58 0.37 0.37 (0.07 – (0.07 – 1.71)1.71)

0.87 0.87 1.161.16

(0 – 4.11)(0 – 4.11)

183 (68.5)183 (68.5) 95 (35.6)95 (35.6) 71 (26.6)71 (26.6) 61 (22.8)61 (22.8) 49 (18.4)49 (18.4) 39 (14.6)39 (14.6)

NC15462NC15462NC15464BNC15464B(N = 267)(N = 267)

1.13 1.13 0.480.48

(0 – 1.93)(0 – 1.93)

1483 (91.9)1483 (91.9)1386 (85.9)1386 (85.9)1316 (81.6)1316 (81.6)1079 (66.9)1079 (66.9) 412 (25.5)412 (25.5)

——

ENABLE*ENABLE*(N = 1613)(N = 1613)

Long-term ExposureLong-term Exposureto Bosentanto Bosentan

191 (81.3)191 (81.3)128 (54.5)128 (54.5) 41 (17.4)41 (17.4) 28 (11.9)28 (11.9)

12 (5.1)12 (5.1)

——* Treatment still blinded; about half on bosentan

9512.01

112

Risk Assessment with BosentanRisk Assessment with Bosentan

Among the 1522 bosentan-treated patients:Among the 1522 bosentan-treated patients:

No cases of acute liver failure No cases of acute liver failure

3 pts have had ALT/AST and bilirubin > 3 x ULN3 pts have had ALT/AST and bilirubin > 3 x ULNand also had alk phosphatase 2-3 x ULNand also had alk phosphatase 2-3 x ULN

– 1 in AC-052-352 (250 mg bid)1 in AC-052-352 (250 mg bid)– 1 in NC15464B (open-label 125 mg bid)1 in NC15464B (open-label 125 mg bid)– 1 in ENABLE (blinded treatment)1 in ENABLE (blinded treatment)

All 3 had complete resolution within 24-64 daysAll 3 had complete resolution within 24-64 daysof treatment cessation (based on evaluation date)of treatment cessation (based on evaluation date)

9103.01

113

Clinical PictureClinical PictureElevated AminotransferasesElevated Aminotransferases

Overall incidence of 11.2%Overall incidence of 11.2%

Incidence and severity are dose relatedIncidence and severity are dose related

Onset mainly during the first 16 weeksOnset mainly during the first 16 weeksof treatmentof treatment

Gradual increase over several weeksGradual increase over several weeks

Transient in 50% of casesTransient in 50% of cases

9104.01

114

Clinical PictureClinical PictureElevated AminotransferasesElevated Aminotransferases

Typically asymptomaticTypically asymptomatic

Associated with elevated alkaline phosphataseAssociated with elevated alkaline phosphatasein about 50% of casesin about 50% of cases

Infrequently associated with elevated bilirubinInfrequently associated with elevated bilirubin(> 3 x ULN)(> 3 x ULN)

Rapid and complete resolution with treatment Rapid and complete resolution with treatment cessationcessation

No evidence for continued liver injuryNo evidence for continued liver injury

9105.01

115

Is the Risk of Increased Liver Is the Risk of Increased Liver Aminotransferases Manageable?Aminotransferases Manageable?

PAH patients are very compliant and havePAH patients are very compliant and havea close relationship with their physicians a close relationship with their physicians

Recommendations:Recommendations:– Monthly monitoring for first 6 months and Monthly monitoring for first 6 months and

quarterly thereafterquarterly thereafter– Monitoring can be incorporated into the Monitoring can be incorporated into the

routine management of these patients routine management of these patients (INR/chemistries)(INR/chemistries)

9106.01

116

– Guidelines for treatment modificationGuidelines for treatment modification– Reduce or interrupt treatment:Reduce or interrupt treatment:

ALT/AST > 3 and < 5 x ULNALT/AST > 3 and < 5 x ULN– Stop treatment: ALT/AST > 5 x ULN, or Stop treatment: ALT/AST > 5 x ULN, or

increase in ALT/AST associated with increase in ALT/AST associated with symptoms of liver injury, or bilirubinsymptoms of liver injury, or bilirubin> 3 x ULN> 3 x ULN

– Education of physicians, nurses, pharmacistsEducation of physicians, nurses, pharmacists– Information to patients, directly via drug Information to patients, directly via drug

distribution and through patient organizations distribution and through patient organizations

Is the Risk of Increased Liver Is the Risk of Increased Liver Aminotransferases Manageable?Aminotransferases Manageable?

9107.01

117

Starting dose: bosentan 62.5 mg bid (4 weeks)Starting dose: bosentan 62.5 mg bid (4 weeks)

Target dose:Target dose:

No dose adjustment needed for most subgroupsNo dose adjustment needed for most subgroups

Not recommended for:Not recommended for:– Pts with moderate to severe liver impairmentPts with moderate to severe liver impairment– Pts with ALT/AST > 3 x ULN at baselinePts with ALT/AST > 3 x ULN at baseline– Pts on glibenclamide or cyclosporin APts on glibenclamide or cyclosporin A– Pregnant womenPregnant women

Recommended DosagesRecommended Dosages

9108.01

bosentan 125 mg bidbosentan 125 mg bid

118

Treatment with bosentan is associated with:Treatment with bosentan is associated with:

Improvement in all clinical and hemodynamic Improvement in all clinical and hemodynamic efficacy measuresefficacy measures

Reduction in risk of clinical worseningReduction in risk of clinical worsening

Good tolerabilityGood tolerability

Potential risks related to:Potential risks related to:– Modest decrease in Hb concentrationModest decrease in Hb concentration– Increase incidence of elevated liver enzymesIncrease incidence of elevated liver enzymes

Both can be managed by appropriate monitoring Both can be managed by appropriate monitoring and education and education

Overall SummaryOverall Summary

9109.01

119

Risk Related to Elevated Liver Risk Related to Elevated Liver AminotransferasesAminotransferases

Willis C Maddrey, MDWillis C Maddrey, MDExecutive VP for Clinical Affairs Executive VP for Clinical Affairs UT Southwestern Medical CenterUT Southwestern Medical Center and Aston Ambulatory Care Ctr and Aston Ambulatory Care Ctr

9110.01

120

Signals of Drug-induced Signals of Drug-induced HepatotoxicityHepatotoxicity

Major: Development of acute liver failureMajor: Development of acute liver failure Onset of clinically apparent jaundice Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, Appearance of ascites, encephalopathy, coagulopathy coagulopathy

Intermediate: ALT > 8 x ULNIntermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 5 x ULN ALT > 3 x ULN ALT > 3 x ULN

Minor: Any elevation in ALT (< 3 x ULN)Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient in an asymptomatic patient

9111.01

121

Relevance of Elevated Liver Relevance of Elevated Liver AminotranferasesAminotranferases

Inexact correlations with injury Inexact correlations with injury

Important role of associated signs and symptomsImportant role of associated signs and symptoms

> 3 x ULN equal to inflammation on liver biopsy> 3 x ULN equal to inflammation on liver biopsy

> 5 x ULN triggers considerably heightened > 5 x ULN triggers considerably heightened awareness and follow-up (treatment awareness and follow-up (treatment withdrawal should be considered) withdrawal should be considered)

Drugs associated with liver injury tend to haveDrugs associated with liver injury tend to havea signature patterna signature pattern

9112.01

122

Drug-induced Hepatocellular JaundiceDrug-induced Hepatocellular JaundiceZimmerman Observations / RuleZimmerman Observations / Rule

In patients with drug-induced hepatoxicity whoIn patients with drug-induced hepatoxicity whohave elevated aminotransferase levels (> 3 x ULN),have elevated aminotransferase levels (> 3 x ULN),clinical jaundice (bilirubin > 3 mg/dl), and aclinical jaundice (bilirubin > 3 mg/dl), and arelatively little change in alkaline phosphatase,relatively little change in alkaline phosphatase,there is an approximately 10% mortality rate.there is an approximately 10% mortality rate.

Drugs studied:Drugs studied: Isoniazid ~10%Methyldopa ~10%Tienilic acid ~10%

9114.01

123

Bosentan-induced HepatotoxicityBosentan-induced Hepatotoxicity

Injury – hepatocellular or mixedInjury – hepatocellular or mixed

Incidence of elevated ALT/ASTIncidence of elevated ALT/AST– 11.2% with > 3 x ULN11.2% with > 3 x ULN– 0.6% with > 20 x ULN0.6% with > 20 x ULN

Onset usually (> 90%) within 16 weeksOnset usually (> 90%) within 16 weeks

All elevations resolved upon drug withdrawalAll elevations resolved upon drug withdrawal(97% within 8 weeks) (97% within 8 weeks)

No cases of acute liver failureNo cases of acute liver failure9115.01

124

Risk ReductionRisk ReductionBosentan Monitoring GuidelinesBosentan Monitoring Guidelines

Determination of biochemical tests of liver:Determination of biochemical tests of liver:

PretreatmentPretreatment

Monthly for 6 monthsMonthly for 6 months

Quarterly thereafterQuarterly thereafter

Discontinue treatment if:Discontinue treatment if:


Increased ALT/AST is associatedIncreased ALT/AST is associatedwith symptoms of liver injurywith symptoms of liver injury

9116.01

125

9117.01

126

Risks vs. BenefitsRisks vs. Benefits

Lewis J Rubin, MDLewis J Rubin, MDProfessor of MedicineProfessor of MedicineDirector of PulmonaryDirector of Pulmonary and Critical Care Medicine and Critical Care MedicineUniv of California, San DiegoUniv of California, San Diego

9118.01

127

Benefits of Bosentan Treatment Benefits of Bosentan Treatment

Treatment with oral bosentan is associated with:Treatment with oral bosentan is associated with:

Improvement in 6-min walk testImprovement in 6-min walk test

Improvement in dyspnea score during exerciseImprovement in dyspnea score during exercise

Improvement in WHO functional classImprovement in WHO functional class

Delay in time to clinical worseningDelay in time to clinical worsening

Improvement in hemodynamic parametersImprovement in hemodynamic parameters

Maintenance of treatment effect, with no evidence Maintenance of treatment effect, with no evidence for tolerancefor tolerance

9123.01

128

Risks with Bosentan TreatmentRisks with Bosentan Treatment

Treatment with bosentan is associated with:Treatment with bosentan is associated with:

Decreases in hemoglobin concentrationDecreases in hemoglobin concentration

Increased incidence of elevated liver Increased incidence of elevated liver aminotransferasesaminotransferases

9125.01

129

Elevated Liver Elevated Liver AminotransferasesAminotransferases

Have been characterizedHave been characterized

Have been quantifiedHave been quantified– IncidenceIncidence– Degree of severityDegree of severity

Can be monitoredCan be monitoredwithin PAH treatment paradigmwithin PAH treatment paradigm

9126.01

130

Risks / Benefits ConclusionRisks / Benefits Conclusion

Treatment with bosentan produces clinically Treatment with bosentan produces clinically meaningful benefits that substantially meaningful benefits that substantially outweigh its characterized risks. outweigh its characterized risks.

Oral bosentan fulfills an unmet medical need Oral bosentan fulfills an unmet medical need in patients with PAH. in patients with PAH.

9128.01

1 bosentan therapy for pulmonary arterial hypertension isaac kobrin, md head of clinical development...

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pulmonary vascular hypertrophy

pah rationale

disease severity increased

pah overall safety

bosentan specific

main effects of bosentan