Bosentan Therapy for Pulmonary Arterial Hypertension

1
Bosentan Therapyfor PulmonaryArterial
Hypertension
Isaac Kobrin, MD Head of Clinical
Development Actelion Pharmaceuticals
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Advisors

• PAH Lewis J Rubin, MD University of
  California San Diego
• Preclin / tox R Michael McClain,
  PhD Consultant
  in Toxicology
• Clin pharm Malcolm Rowland, PhD
  University of Manchester
• Hepatology Willis C Maddrey, MD
  UT Southwestern Medical Center
• Hematology Jerry L Spivak, MD Johns
  Hopkins University

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Bosentan Therapy for PAH

• Rationale for ET receptor antagonism
• Preclinical observations
• Clinical pharmacology
• Clinical program
• Efficacy in patients with PAH
• Overall safety and tolerability
• Specific safety issues
• Drug-induced liver injury (Dr W Maddrey)
• Risk / benefit assessment (Dr L Rubin)

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Endothelin-1 (ET-1)

• Belongs to a family of 21-amino acid peptides
• Synthesized and secreted by endothelial cells
• Acts via 2 receptors
• ETA, vascular smooth muscle cells (SMC)
• ETB, vascular SMC, endothelial cells, fibroblasts
• Induces vasoconstriction, fibrosis,
  hypertrophyand hyperplasia
• Increases vascular permeability

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Rationale for ET Receptor Antagonism in PAH

• In patients with PAH
• Plasma ET-1 levels are increased, and levels
  correlate with disease severity
• Increased ET-1 immuno-reactivity in lung
  vasculature (plexiform lesions)
• Blockade of ET-1 activity is expected to prevent
  its detrimental effects
• ET receptor antagonists are effective in animal
  models of pulmonary hypertension

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Bosentan

• Specific, low MW, competitive ET-receptor
  antagonist
• Inhibits the effects of ET-1by inhibiting its
  bindingto both ETA and ETB receptors

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Preclinical ObservationsRelated to PAH
Bosentan was studied in models of

• Pulmonary hypertension
• Chronic hypoxia
• Monocrotaline
• Pulmonary fibrosis
• Bleomycin
• Pulmonary inflammation
• Sephadex
• Oleic acid

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Preclinical ObservationsRelated to PAH

• The main effects of bosentan included
• Decrease in pulmonary artery pressure
• Decreases in pulmonary vascular hypertrophyand
  right ventricular hypertrophy
• Decreases in pulmonary fibrosisand inflammation

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Preclinical ObservationsRelevant to Human Safety

• Teratogenicity
• Decreased RBC parameters
• Liver injury

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Preclinical ObservationsTesticular Changes

• In a 2-year rat study, an increased incidenceof
  slight testicular tubular atrophy was observed
• Not observed in a 2-year mouse study
• The overall pattern and findings were not typical
  of drug-induced testicular toxicity
• No effect on sperm count, motility or male
  fertility in rats treated with oral bosentan at
  doses up to 50 times the recommended human dose

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Pharmacokinetic Characteristics

• Dose proportional up to 600 mg (single dose)and
  500 mg/day (multiple doses)
• Absorption tmax at 3.5 hours
• No relevant food effect
• Oral bioavailability approximately 50

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Pharmacokinetic Characteristics

• Terminal elimination half-life 5.4 hours
• Protein binding 98 (mainly albumin)
• Steady state reached within 3 - 5 days
• Age, gender, race, body weight and renal function
  appear not to have a relevant effecton PK
  properties

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Metabolism and Excretion

• Eliminated mainly by hepatic metabolismand
  subsequent biliary excretion
• Metabolic pathways CYP3A4 and CYP2C9
• Ketoconazole, a 3A4 inhibitor, led to a 2-fold
  increase in bosentan exposure
• Inhibition of 2C9 is not expected to exert a
  greater effect than ketoconazole
• CsA, a nonspecific inhibitor of transporters,
  markedly increased bosentan exposure

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Influence on Drug Metabolism

• In vitro bosentan
• Does not inhibit CYP1A2, 2C9, 2C19, 2D6or 3A4
• Induces CYP2C9, 2C19 and 3A4
• In vivo bosentan
• Decreases exposure to CYP2C9 and 3A4 substrates
  by 30-60 (HV)
• Reduced efficacy of CYP2C9 and 3A4 substrates
  should be considered

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Warfarin DDI Clinical Relevance AC-052-352

• Clinical experience in PAH patients(34 placebo
  and 59 bosentan patients)
• No change in warfarin dose(BL vs end of
  treatment)
• No change in INR (BL vs end of treatment)
• No difference in warfarin dose changesduring
  treatment vs placebo

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Efficacy in PAH Patients
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PAH Studies for Efficacy Evaluation
Overall N 245
Placebo-controlled AC-052-352 Pbo 69, Bos 144
Placebo-controlled AC-052-351 Pbo 11, Bos 21
Open-label, long-term AC-052-354 (Ongoing) Bos
200
Open-label, long-term AC-052-353 (Ongoing) Bos
29
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Study DesignsPlacebo-controlled Studies
Bosentan 125 mg bid
AC-052-351
62.5 mgbid
(Variable Period 2)
Placebo
Screen
Placebo
Bosentan 250 mg bid
62.5 mgbid
AC-052-352
(Fixed Period 2 for pts who participated)
Bosentan 125 mg bid
62.5 mgbid
Screen
Placebo
Placebo
1º Endpoints
4
28
16
12
Week 0
BL
Period 1 Evaluation
Period 2 Follow-up
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Patient Allocation to Periods 1 and 2 AC-052-351
Period 1 (12 weeks)
Period 2 (variable)
Randomization
Primary Endpoint
Final Endpoint
P1
P32
Apr 00
Aug 99
Jan 00
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Patient Allocation to Periods 1 and 2AC-052-352
Period 1 (16 weeks)
Period 2 (fixed 12 weeks)
Randomization
Primary Endpoint
Final Endpoint
P1
P48
P213
Mar 01
July 00
Dec 00
Sep 00
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Main Inclusion Criteria

• Males or females ? 12 years old
• PAH due to PPH or secondary to sclerodermaor
  other connective tissue diseases
• WHO functional class III - IV
• Baseline 6-min walk test ? 150 m and ? 450/500 m
• Baseline hemodynamics
• Mean PAP gt 25 mmHg
• PVR gt 240 dynsec/cm5
• PCWP lt 15 mmHg

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Main Exclusion Criteria

• PAH due to other causes (eg, congenital HD, HIV,
  cirrhosis, thromboembolic, COPD)
• SSc/PAH with mod / severe interstitial fibrosis
• Systolic BP lt 85 mmHg
• ALT / AST gt 3 x ULN
• Hb / Hct gt 30 below the LLN
• PAH treatment modified within 1 monthof
  screening (excluding anticoagulants)
• Received epoprostenol within 3 monthsof screening

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Demographics
AC-052-352
AC-052-351
Bos (n 144)
Pbo (n 69)
Pbo (n 11)
Bos (n 21)
2179 49 ? 16 71 ? 20 77815 5545
0100 47 ? 14 87 ? 18 82180 8218
MF () Age (years) Weight (kg) Race ( WBO) US
/ Non-US ()
1981 52 ? 12 86 ? 23 761410 8119
2278 47 ? 16 74 ? 18 86113 5644
Percent or mean ? SD
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Baseline Characteristics
AC-052-352
AC-052-351
Bos (n 144)
Pbo (n 69)
Pbo (n 11)
Bos (n 21)
9010 2.5 ? 2.9 7123 6
1000 3.0 ? 2.8 91 9
WHO class ( IIIIV) Time from Diag
(yrs) Etiology of PAH () PPH SSc/PAH
Other
1000 1.7 ? 1.4 8119
946 2.3 ? 4.0 702010
Percent or mean ? SD
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Baseline Hemodynamics
AC-052-352
AC-052-351
Bos (n 144)
Pbo (n 69)
Pbo (n 11)
Bos (n 21)
55 ? 16 1014 ? 678 2.4 ? 0.8 9.2 ? 3.9
9.8 ? 5.9
56 ? 11 942 ? 430 2.5 ? 1.0 8.3 ? 3.3 9.9 ? 4.1
54 ? 13 896 ? 425 2.4 ? 0.7 9.3 ? 2.4 9.7 ? 5.6
53 ? 17 880 ? 540 2.4 ? 0.7 9.2 ? 4.1 8.9 ? 5.1
Mean PAP (mmHg) PVR (dynsec/cm5) CI
(L/min/m2) PCWP (mmHg) Mean RAP (mmHg)
Mean ? SD
9021.01
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Main Concomitant Medications for PAH
AC-052-352
AC-052-351
Bos (n 144)
Pbo (n 69)
Pbo (n 11)
Bos (n 21)
82 91 55 9 9
Anti-thrombotics () Diuretics Calcium
antagonists Cardiac glycosides Oxygen
71 86 52 14 29
73 51 52 19 33
70 54 44 19 29
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Patient DispositionAC-052-351
N 32
Bos125 mg bidn 21
RandomizedITT/ Safety
Placebon 11
2 w/d
CompletedPeriod 1
n 9
n 21
1 w/d
CompletedPeriod 2
n 8
n 21
To open label(AC-052-353)
n 8
n 21
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Patient DispositionAC-052-352
N 214
Bos250 mg bidn 70
Bos 125 mg bidn 75
Placebon 69
Randomized
1 w/d
ITT/Safety
n 69
n 70
n 74
6 w/d
3 w/d
3 w/d
CompletedPeriod 1
n 63
n 67
n 71
To open label(AC-052-354)
n 62
n 67
n 71
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Efficacy Parameters

• Primary Endpoint
• 6-minute walk distance at end of Period 1
• Secondary Endpoints
• Time to clinical worsening
• Death
• Hospitalization due to PAH
• Discontinuation due to worsening PAH
• Start of epoprostenol
• Lung transplantation / septostomy

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Efficacy Parameters

• Change in Borg dyspnea index
• Change in WHO functional class
• Change in pulmonary hemodynamics(mean PAP, PVR,
  CI, mean RAP)
• Increase in therapy for PAH (Period 1)

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Statistical AnalysesPrimary Endpoint

• All bosentan vs placebo ITT population
• AC-052-351 Students t-test
• AC-052-352 Mann-Whitney U-test

• Management of patients with no valid assessment
  at the end of Period 1
• Due to worsening PAH or death walk test 0 m
• AC-052-351 1 placebo pt
• AC-052-352 3 placebo, 2 bosentan 125 mg bid pts
• Due to other reasons last value carried forward

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6-minute Walk TestMean Treatment Effect
Bos
Pbo
Mean (95 CL)
AC-052-351
P 0.0205
125 mg bid
75.9 (12.5, 139.2)
21
11
AC-052-352
P 0.0002
125/250 mg bid
144
69
44.2 (21.4, 67.0)
74
69
(P 0.0107)
125 mg bid
34.6 (6.2, 63.1)
250 mg bid
70
69
54.3 (27.3, 81.4)
(P 0.0001)
140
?20
20
40
60
80
100
120
0
Treatment difference (meters)
9028.02
33
Robustness of ResultsPrimary Parameter
P value
AC-052-351
AC-052-352
Mann-Whitney U-test Per-protocol population First
150 patients Pts w/o Wk-16 endpoint Carry
forward Zero substitution Pbo CF, bos zero
Pbo exclude, bos zero
0.019 0.021 0.041
(0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.01
76
Identical to ITT population
9029.01
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Change in Walk DistanceDuring Period 1
Bosentan 125 mg bid (n 21)
AC-052-351
60
40
20
Placebo (n 11)
0
-10
Change in Walk Distance (m)
AC-052-352
60
Bosentan125/250 mg bid (n 144)
40
20
Placebo (n 69)
0
-10
Mean ? SEM
62.5 mg bid
125 or 250 mg bid
9030.01
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Change in Walk Distance by DoseDuring Period 1
in AC-052-352
Bosentan 250 mg bid (n 70)
Bosentan125 mg bid (n 74)
Change in Walk Distance (m)
Placebo (n 69)
Mean ? SEM
9031.02
36
Walk Test in SubpopulationsMean Treatment Effect
(AC-052-352)
Bos
Pbo

• All patients
• Gender Males
• Females
• Age 12 20 yrs
• 21 40 yrs
• 41 60 yrs
• gt 60 yrs
• Weight lt 70 kg
• ? 70 kg
• Race White
• Other

• 69
• 15
• 54
• 6
• 15
• 33
• 15
• 29
• 40
• 59
• 10

• 144
• 30
• 114
• 7
• 31
• 71
• 35
• 77
• 67
• 111
• 33

?20
20
40
60
80
100
120
0
Treatment difference (meters)
9032.01
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Walk Test in SubpopulationsMean Treatment Effect
(AC-052-352)
Bos
Pbo

• All patients
• WHO class III
• IV
• Etiology PPH
• SSc/PHT
• Time from
• lt 421 days
• ? 421 days
• Congenital
• Yes
• No

• 69
• 65
• 4
• 48
• 14
• 40
• 29
• 2
• 66

• 144
• 130
• 14
• 102
• 33
• 66
• 77
• 11
• 133

138.5

diagnosis
heart disease


?20
20
40
60
80
100
120
0
Treatment difference (meters)
9033.01
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Walk Test in SubpopulationsMean Treatment Effect
(AC-052-352)
Bos
Pbo
All patients

• US
• Non-US
• lt 345 m
• ? 345 m
• lt 52 mmHg
• ? 52 mmHg
• lt 8 mmHg
• ? 8 mmHg
• lt 2.3 L/min/m2
• ? 2.3 L/min/m2

• 69
• 39
• 30
• 27
• 42
• 37
• 32
• 32
• 35
• 31
• 37

• 144
• 79
• 65
• 79
• 65
• 67
• 77
• 66
• 77
• 75
• 69

• Location
• BL walk test
• Mean PAP
• Mean RAP
• CI

?20
20
40
60
80
100
120
0
Treatment difference (meters)
9034.01
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Change in Borg Dyspnea IndexMean Treatment Effect
Bos
Pbo
Mean (95 CL)
AC-052-351
125 mg bid
?1.6 (?3.1, 0.0)
21
11
AC-052-352
125/250 mg bid
144
69
?0.6 (?1.2, ?0.1)
74
69
125 mg bid
?0.4 (?1.1, 0.3)
250 mg bid
70
69
?0.9 (?1.6, ?0.2)
0
?1
?2
?3
0.5
?0.5
?1.5
?2.5
?3.5
Treatment difference (score)
9035.02
40
Time to Clinical WorseningUp to Treatment End
Bosentan125 mg bid
100
p 0.03
AC-052-351
75
Placebo
21 11
2111
71
2110
218
124
61
21
50
0
Percent Event-free
100
Bosentan125/250 mg bid
AC-052-352
p lt 0.01
p lt 0.01
75
Placebo
14469
14268
3110
14163
13862
10348
257
133
50
0
Weeks
9036.02
41
Time to Clinical Worsening by DoseUp to
Treatment End (AC-052-352)
100
Bosentan
p 0.01
p lt 0.03
75
Percent Event-free
Placebo
74 70 69
72 7068
18 1310
71 7063
70 6862
55 4848
14 117
7 63
50
0
0
4
8
12
16
20
24
28
Weeks
9037.01
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Incidence of Clinical WorseningTo End of Period 2
AC-052-351
AC-052-352
Pbo (n 69)
Bos (n 144)
Pbo (n 11)
Bos (n 21)
Clinical Worsening Death Hospitalization for
PAH D/C for worsening PAH Receipt of
epoprostenol
14 (20.3) 2 (2.9) 9 (13.0) 6
(8.7) 3 (4.3)
9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8)
0 0 0 0 0
3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3)
Patients may fall into gt1 category No cases of
lung transplantation or septostomy
9038.01
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Improvement in WHO ClassEnd of Period 1
AC-052-351
AC-052-352
Pbo (n 69)
Bos (n 144)
Pbo (n 11)
Bos (n 21)
Improved Treatment effect 95 CL
43
9
42
30
33.8 ?5.6, 58.0
11.9 ?2.9, 25.2
Treatment effect of both studies combined 14.9
(1.3, 27.0)
9039.01
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Change in WHO ClassAC-052-351 and AC-052-352
AC-052-351
AC-052-352
Pbo(n 69)
Bos(n 144)
Pbo(n 11)
Change from BLto end of Period 1
Bos(n 21)
Worsened 1 class () No change Improved 1
class Improved 2 classes Mann-Whitney U-test
0 57 43 0
6 64 30 0
2 56 38 4
18 73 9 0
P 0.019
P 0.042
9040.01
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Changes in HemodynamicsChange to Week 12
(AC-052-351)
Mean (95 CL)
?415 (?608, ?221)
PVR (dynsec/cm5)
?600
?400
?300
?200
?100
0
100
?500
Mean PAP (mmHg)
?6.7 (?11.9, ?1.5)
PCWP (mmHg)
?3.8 (?7.3, ?0.3)
Mean RAP (mmHg)
?6.2 (?9.6, ?2.7)
?12
?8
?6
?4
?2
0
2
?10
Cardiac Index (L/min/m2)
1.02 (0.65, 1.39)
Placebo 10 Bos 125 mg bid 20
?0.25
0.5
1
1.5
0
Placebo-corrected treatment difference
9041.01
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Increase in Therapy for PAHAC-052-352 (Period 1)
Bosentan (n 144)
Placebo (n 69)
Pts with ? 1 increase Treatment effect 95
CL Pts with ? 2 increases Treatment effect
95 CL
22.2 11.1
29.0 18.8
?6.8 ?19.5, 7.1 ?7.7 ?18.1, 4.7
Period 1 was 16 weeks
9042.01
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Patient Allocation to Periods 1 and 2 AC-052-351
Period 1 (12 weeks)
Period 2 (variable)
Randomization
Primary Endpoint
Final Endpoint
P1
P32
Apr 00
Aug 99
Jan 00
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Patient DispositionAC-052-351
N 32
Bos125 mg bidn 21
RandomizedITT/ Safety
Placebon 11
2 w/d
CompletedPeriod 1
n 9
n 21
1 w/d
CompletedPeriod 2
n 8
n 21
To open label(AC-052-353)
n 8
n 21
9023.01
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Patient Allocation to Periods 1 and 2AC-052-352
Period 1 (16 weeks)
Period 2 (fixed 12 weeks)
Randomization
Primary Endpoint
Final Endpoint
P1
P48
P213
Mar 01
July 00
Dec 00
Sep 00
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Disposition of Pts Scheduled for Period 2
AC-052-352
N 48
Bos250 mg bidn 16
Bos 125 mg bidn 19
Placebon 13
Randomized
1 w/d
1 w/d
2 w/d
EnteredPeriod 2
n 11
n 15
n 18
3 w/d
5 w/d
3 w/d
CompletedPeriod 2
n 8
n 12
n 13
9025.01
51
Maintenance of Efficacy Walk Test Up to 28 Weeks
100
AC-052-351
Bosentan125 mg bid
n 20
75
n 6
50
n 21
25
Mean ? SEM
0
Change from Baseline (meters)
100
AC-052-352
Bosentan125/250 mg bid(n 35)
75
50
25
Placebo(n 13)
0
0
4
8
12
16
20
24
28
Weeks
9493.01
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Open-label ExtensionAC-052-353
Bosentan 250 mg bid
Bosentan 62.5 mg bid
Bosentan 125 mg bid
Bosentan 62.5 mg bid
1 - 4 weeks
3/31/01 cut off

• Assessments
• Walk test at Week 4
• WHO class each 6 months

• Patients
• 8 / 11 ex-placebo
• 21 / 21 ex-bosentan

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6-minute Walk DistanceOpen-label Extension Study
AC-052-353
Ex-placebo(n 8)
Ex-bosentan(n 21)
Baseline (end of 351) Change to Week 4
393.8 ? 37.9 22.5 ? 14.3
438.9 ? 14.2 3.0 ? 9.2
Treatment in AC-052-351 still blinded for 26 of
29 patients
Mean ? SEM in meters
9044.01
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WHO Functional ClassOpen-label Extension Study
AC-052-353
Open-label bosentan
Start of AC-052-351
WHO class
6 months
1 year
Class I (n) Class II Class III Class IV
0 0 29 0
1 12 15 1
1 11 16 1
29 patients entered the open-label study
9045.01
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Efficacy Conclusions

• Bosentan 125 and 250 mg bid (vs placebo)
• Increased exercise capacity
• Consistent in all subpopulations
• Improved dyspnea on exercise
• Improved WHO functional class

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Efficacy Conclusions

• Improved pulmonary hemodynamics cardiac index,
  mean PAP, PVR and mean RAP(125 mg bid)
• Decreased risk of clinical worsening
• With extended treatment
• Clinical benefits maintained no evidencefor
  tolerance

9047.01
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9048.01
58
Safety and Tolerability
9049.01
59
Bosentan Therapeutic StudiesSafety Database
Therapeutic StudiesN 972
PAHN 252
BD148842000 mg/dPC, DB (n 7)
AC-052-351250 mg/dPC, DB (n 32)
AC-052-353250 mg/dOL (n 29)
AC-052-352250/500 mg/dPC, DB (n 213)
AC-052-354250 mg/dOL (n 200)
9050.01
60
Bosentan Therapeutic StudiesSafety Database
Therapeutic StudiesN 972
CHFN 447
PAHN 252
BC15064/part I1000 mg/dOL (n 7)
NC154621000 mg/dPC, DB (n 370)
BD148842000 mg/dPC, DB (n 7)
BC15064/part II2000 mg/dPC, DB (n 36)
NC15464B250 mg/d OL (n 86)
AC-052-351250 mg/dPC, DB (n 32)
AC-052-353250 mg/dOL (n 29)
NC150182000 mg/dPC, DB (n 34)
AC-052-352250/500 mg/dPC, DB (n 213)
ENABLE250 mg/dPC, DB (n 1613)
AC-052-354250 mg/dOL (n 200)
9051.01
61
Bosentan Therapeutic StudiesSafety Database
Therapeutic StudiesN 972
CHFN 447
HTNN 243
PAHN 252
BC15064/part I1000 mg/dOL (n 7)
NC154621000 mg/dPC, DB (n 370)
NC15020100-2000 mg/dPC, DB (n 243)
BD148842000 mg/dPC, DB (n 7)
BC15064/part II2000 mg/dPC, DB (n 36)
NC15464B250 mg/d OL (n 86)
AC-052-351250 mg/dPC, DB (n 32)
AC-052-353250 mg/dOL (n 29)
NC150182000 mg/dPC, DB (n 34)
AC-052-352250/500 mg/dPC, DB (n 213)
ENABLE250 mg/dPC, DB (n 1613)
AC-052-354250 mg/dOL (n 200)
9052.01
62
Bosentan Therapeutic StudiesSafety Database
Therapeutic StudiesN 972
CHFN 447
HTNN 243
SAHN 30
PAHN 252
BC15064/part I1000 mg/dOL (n 7)
NC154621000 mg/dPC, DB (n 370)
NC15020100-2000 mg/dPC, DB (n 243)
NN150311500 mg/dPC, SB (n 30)
BD148842000 mg/dPC, DB (n 7)
BC15064/part II2000 mg/dPC, DB (n 36)
NC15464B250 mg/d OL (n 86)
AC-052-351250 mg/dPC, DB (n 32)
AC-052-353250 mg/dOL (n 29)
NC150182000 mg/dPC, DB (n 34)
AC-052-352250/500 mg/dPC, DB (n 213)
ENABLE250 mg/dPC, DB (n 1613)
AC-052-354250 mg/dOL (n 200)
9053.01
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Subjects in the Database
Placebo
Bosentan
All
571 965 122 1613
Pharmacology (23 studies) Therapeutic trials 8
Placebo-controlled 3 Open-label (2
extensions) ENABLE (blinded)
155 288 31
434 677 91
1 1

• About 1522 bosentan-treated patients
• Additional 62 PAH patients (ex-placebo)
  givenbosentan in AC-052-354

9054.01
64
Subjects in the Database8 Placebo-controlled
Studies
Placebo (N 288)
Bosentan (N 677)
Indication n () PAH CHF HTN
SAHTreatment Placebo Bos 100 mg/d Bos
250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d
(28.8)(51.0) (17.0) (3.1) (100)
(25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (
45.8) (15.2)
83 147 49 9 288
169 293 194 21 50 214 310 103
9055.01
65
Exposure to BosentanOverall and
Placebo-controlled Studies
11 Therapeutic Studies
8 Placebo-controlled Studies
100
100
All bosentan doses (N 715)
All bosentan doses (N 677)
Mean (SD) 168 ? 271 d
Mean (SD) 85 ? 64 d
4 weeks 526 (73.6)3 months 352 (49.2)6
months 141 (19.7)1 year 88 (12.3) 3
years 28 (3.9)
Placebo (N 288)
75
75
Mean (SD) 101 ? 61 d
50
50
Percent of Patients
Percent of Patients
25
25
0
0
1200
1000
800
600
400
200
0
200
100
0
50
150
Days
Days
9056.01
66
Patient Demographics8 Placebo-controlled studies
Placebo (N 288)
Bosentan (N 677)
Gender ( MF) Age (years) Weight (kg) Race (
WBO) US / Non-US ()
6139 57 ? 13 78 ? 17 8966 2872
5743 57 ? 14 77 ? 15 9047 3268
Percent or mean ? SD
9057.01
67
Treatment-emergent AEs8 Placebo-controlled
Studies
Placebo (N 288)
Bosentan (N 677)
Placebo-subtracted
Flushing () Leg edema / edema Abnormal hepatic
func Headache Anemia with ? 1 AE
1.7 2.7 2.1 12.8 1.0 76.4
6.6 7.4 5.9 15.8 3.4 78.1
4.9 4.6 3.8 3.0 2.4 1.7
With a placebo-subtracted difference of ? 2
9058.01
68
AEs of Specific Interest8 Placebo-controlled
Studies

• Cardiac failure
• Dyspnea
• Aggravated PAH
• Angina pectoris/ chest pain

• Syncope
• Hypotension
• Postural hypotension
• Dizziness

• Abdominal pain / nausea / vomiting

All were more frequent among placebo-treated than
bosentan-treated patients
9059.01
69
Worsening Heart Failure

• Increased incidence of worsening HF during1st
  month of treatment in CHF patients related to
• Starting dose (125 and 250 mg bid)
• Speed of up-titration (weekly to 500 mg bid)
• Overall incidence of hospitalization for HF was
  significantly lower with bosentan vs placebo

REACH-1 (NC15462)
Placebo
Bosentan
Overall incidence
64 (22.2) 120 (17.7) 60 (40.8) 114 (38.9)

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

9060.01
70
Most Frequent (? 5) Treatment-emergent
AEsAC-052-351 and AC-052-352
Placebo (N 80)
Bosentan (N 165)
Placebo-subtracted
Abnormal hepatic func () Leg edema / edema
Flushing Nasopharyngitis Hypotension with ? 1
AE
2.5 8.8 5.0 7.5 3.8 93.8
8.5 13.9 9.1 10.9 6.7 94.5
6.0 5.2 4.1 3.4 2.9 0.7
With a placebo-subtracted difference of ? 2
9061.01
71
Most Frequent (? 5) Treatment-emergent
AEsAC-052-351 and AC-052-352
? 2 more frequent on placebo

• Aggravated PAH
• Cardiac failure
• Dyspnea
• Cough
• Dizziness

• Abdominal pain
• Nausea/vomiting
• Gastritis
• Influenza
• Limb pain

9062.01
72
AEs (? 1.0) Leading to Withdrawal8
Placebo-controlled Studies
Placebo (N 288)
Bosentan (N 677)
Abnormal hepatic func n () Headache Pts with ?
1 AE
2 (0.7) 2 (0.7) 27 (9.4)
28 (4.1) 8 (1.2) 75 (11.1)
9063.01
73
AEs Leading to WithdrawalAC-052-351 and
AC-052-352
Placebo (N 80)
Bosentan (N 165)
Abnormal hepatic func n () Aggravated
PAH Cardiac failure Syncope Pts with ? 1 AE
3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5)
0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0)
Occurring in gt 1 patient per treatment group
9064.01
74
Reasons for Death (? 3 patients)8
Placebo-controlled Studies
Bosentan (N 677)
Placebo (N 288)
Cardiac failure n () Sudden death Cardiac
arrest Myocardial infarction Total deaths
1 (0.3) 5 (1.7) 0 0 15 (5.2)
6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6)
9065.01
75
Reasons for DeathAC-052-351 and AC-052-352
Placebo (N 80)
Bosentan (N 165)
Cardiac failure n () Aggravated
PHT Pneumonia Pulmonary hemorrhage Sepsis Total
deaths
0 2 (2.5) 0 0 0 2 (2.5)
2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4)
All deaths occurring during the study or within
28 days of treatment end
9066.01
76
Vital Signs
PC Studies
AC-052-351 352
Bosentan(N 677)
Bosentan(N 165)
Placebo(N 80)
Placebo(N 288)
Change from BL Pulse rate (bpm) SBP (mmHg)
DBP (mmHg)Incidence SBP lt 80 mmHg AE
hypotension
?1.0 ? 1.1 ?4.2 ? 1.4 ?3.3 ? 1.0

• 0.2 ? 0.5
• 3.1 ? 0.7
• 3.0 ? 0.4

0.3 ? 0.7 ?2.4 ? 1.0 ?0.4 ? 0.7
3.3 ? 1.5 ?3.8 ? 1.8 0.7 ? 1.2
2.8 7.6
0.8 6.8
0 3.8
0.6 6.7
Mean change ? SEM or percent
9067.01
77
Evidence for Rebound?

• Experience limited to 22 PAH patients
• 5 pts had treatment discontinued after dose
  reduction
• 7 pts had treatment interrupted for 2-14 days
• 10 pts had open-label treatment discontinued
• PAH-related adverse experiences
• 1 pt with aggravated PAH (29 days after d/c)
• No evidence in hypertensive or CHF patients

9068.01
78
Outcomes in PAH Patients Started on Epoprostenol
Concomitant bosentann 6
Ex-placebon 8
Ex-bosentann 8
5 pts improved 1 death 2 pts worse
5 pts improved 2 deaths 1 pt worse
5 pts improved 1 death
9071.01
79
Long-term ExperienceOpen-label Extension Study
AC-052-353

• Overall exposure to bosentan
• 29 patients 21 of 21 ex-bosentan
  8 of 11 ex-placebo
• 485 ? 97 days (range 105 595 days)
• 28 patients with ? 1 year 7 patients with ?
  1.5 years
• Outcomes
• No deaths
• 1 d/c for worsening PAH (epoprostenol)
• 4 patients up-titrated to 250 mg bid(after 348
  548 days of treatment)

9069.01
80
Long-term ExperienceOpen-label Extension Study
AC-052-354

• Overall exposure to bosentan
• 200 patients 138 of 144 ex-bosentan
  62 of 69 ex-placebo
• 171 ? 73 days (range 25 321 days)
• 100 patients with ? 6 months 13 patients with ?
  9 months
• Outcomes
• 2 deaths (pulmonary hemorrhage)
• 2 d/c for worsening PAH (epoprostenol)
• 6 d/c for elevated ALT/AST
• 4 d/c for AE/administrative reasons

9070.01
81
Overall ExposurePAH Patients
100
Bosentan
N 235
gt 3 months 191 (81.3)gt 6 months 128
(54.5)gt 9 months 41 (17.4)gt12 months
28 (11.9) gt18 months 12 (5.1)
80
60
Percent of Patients
40
137.2 patient-years
20
May 31, 2001 cut off
0
0
90
180
270
360
540
630
450
Days
9072.01
82
SurvivalAC-052-351, AC-052-352 and OL Extensions
100
95
90
Percent Survivors
85
At risk
235
190
125
40
29
21
10
0
0
0.25
0.5
0.75
1.0
1.25
1.5
Years
9074.01
83
Additional Safety Observations

• No relevant difference between bosentan and
  placebo in SAEs
• No relevant changes in ECG parametersor
  treatment-emergent ECG findings
• No relevant changes in laboratory tests except
• Decreases in RBC parameters
• Increases in liver enzymes

9075.01
84
Decreases in Hemoglobin Concentration
9076.01
85
Preclinical ObservationsDecreases in Hemoglobin

• Mild (713) decreases in Hb concentrationin
  rats and dogs
• No evidence for
• Hemolysis or immuno-allergic reaction
• Bone marrow toxicity
• Bleeding
• Evidence for increased plasma volumewith
  hemodilution in rats

9077.01
86
Incidence of Decreased Hb Conc8
Placebo-controlled Studies
Placebo (N 269)
Bosentan (N 618)
Placebo-subtracted
Hemoglobin Conc (g/dl) Chg to end of treatment
Chg to lowest value of Patients with
Decrease of ? 1.0 g/dl Value lt LLN Marked
decrease (LL) LL and lt 10.0 g/dl
?0.78 ?0.77 27.8 7.5 3.1 0
?0.14 ?0.55 29.0 24.4 2.6 2.2
?0.92 ?1.32 56.8 32.0 5.6 2.2
LL lt 11.0 g/dl and gt15 decrease from baseline
9078.01
87
Incidence of Decreased Hb ConcAC-052-351 and
AC-052-352
Placebo (N 79)
Placebo-subtracted
Bosentan (N 161)
Hemoglobin Conc (g/dl) Chg to end of treatment
Chg to lowest value of Patients with
Decrease of ? 1.0 g/dl Value lt LLN Marked
decrease (LL) LL and lt 10.0 g/dl
?0.96 ?1.09 34.8 13.8 1.8 1.2
0.01 ?0.48 30.4 8.9 1.3 1.3
?0.96 ?1.57 65.2 22.7 3.0 2.4
LL lt 11.0 g/dl and gt15 decrease from baseline
9079.01
88
Incidence of Decreased Hb ConcPlacebo-corrected
Incidence
HTN (N 231)
PAH(N 248)
CHF (N 405)
Hemoglobin Conc (g/dl) Chg to end of treatment
Chg to lowest value of Patients with
Decrease of ? 1.0 g/dl Value lt LLN Marked
decrease (LL) LL and lt 10.0 g/dl
?1.02 ?1.12 35.5 14.6 2.3 1.1
?0.41 ?0.44 14.0 3.2 0 0
?0.91 ?0.87 36.5 13.5 5.0 ?0.3
LL lt 11.0 g/dl and gt15 decrease from baseline
9080.01
89
Among PAH Patients with Anemia

• No evidence for increase in bilirubin
• No associated decrease in WBCs or platelets
• No increase in eosinophils above the ULN
• No premature withdrawal due to anemia
• Blood transfusions in 4 patients (2.4)
• 1 epistaxis, 2 GI bleeding, and 1 anemia
• All 8 PC studies

1.8 on bosentan 1.0 on placebo
9081.01
90
Time to OccurrenceDecreases in Hemoglobin
100
8 Placebo-controlled Studies
Bosentan (N 636) Placebo (N 271)
50
Decrease of ? 1 g/dl
0
20
Marked decrease ( ?15 and lt 11 g/dl)
Percent of Patients at Risk
10
0
20
Marked decrease ( ?15 and lt 10 g/dl)
10
0
Weeks
8
0
16
24
32
9082.01
91
Change in Hb ConcentrationNC15462 and NC15464B
NC15462 (REACH-1)
NC15464B (open label)
Bosentan (n 29) 500 mg bid Placebo (n 7)
Bosentan (n 29) Bosentan (n 7) 125 mg bid
Change from BaselineHb (g/dl)
BL
3
4
12
26
BL
12
Weeks
Weeks
Median and 25th and 75th percentiles
9083.01
92
Change in Hb ConcentrationAC-052-352
Bosentan (n 120) 125 mg bid Placebo (n 53)
Change from BaselineHb (g/dl)
BL
4
16
8
12
Weeks
Median and 25th and 75th percentiles
9084.01
93
Unlikely ReasonsDecrease in Hemoglobin

• Hemolysis
• No increase in bilirubin
• No increase in reticulocytes or MCV
• Bone marrow toxicity
• No concomitant marked decreases in WBC or
  platelet counts
• Normal bone marrow evaluations (2 cases)
• Bleeding tendency
• No evidence for bleeding in most cases

9085.01
94
Possible MechanismsDecrease in Hemoglobin

• Hemodilution / fluid shift
• Preclinical evidence for increased plasma volume
• Compatible with clinical picture
• Compatible with mechanism of action
• Vasodilation
• Decreased capillary permeability
• Decrease in elevated erythropoetin levels

9086.01
95
Risk ManagementDecrease in Hemoglobin

• Risk to the patient is small
• Hb concentration should be evaluatedafter 1 and
  3 months of treatment and quarterly thereafter
• Cases of marked decrease in Hb concentration
  should be further evaluated and/or treated,based
  on clinical judgment

9087.01
96
Increases inLiver Aminotransferases
9088.01
97
Preclinical Observations

• Evidence for cholestasis
• Increase in plasma bile salts and alk phos
• No evidence for
• Reactive or toxic metabolites
• Immuno-allergic reaction
• Centrolobular necrosis
• Mitochondrial toxicity
• Competitive inhibition of bile salt
  excretion(Bsep), which can lead to
  accumulationof bile salts and hepatocellular
  lysis

9089.01
98
Elevated ALT/AST gt 3 x ULN by DoseSafety Database
Bosentan Dose (mg/d)
Database
2000
All
250/500
1000/1500
100
12.7 4.3 10.9
PAH () CHF HTN All
4.2 10.0 6.9
15.8 11.4 14.5
12.7 13.8 6.9 11.2
2.1 2.1
Incidence on placebo was approximately 2
9090.01
99
Severity of Elevated ALT/ASTSafety Database
ALT / AST (x ULN)
Database ()
?8
gt3 - lt 5
?5 - lt 8
All
PAH (N 165) Others (N 493) All (N
658) ENABLE (N ? 807)
4.2 3.9 4.0 2.8
1.8 3.2 2.9 2.0
12.7 10.8 11.2 8.6
6.7 3.7 4.4 3.8
Percentages assume all events occur on
bosentan, as data are still blinded
9091.01
100
Elevated AminotransferasesAC-052-351 and
AC-052-352
Bosentan (mg bid)
250(N 70)
125(N 95)
AE abn hepatic func n () ALT/AST gt 3 x
ULN ALT/AST gt 8 x ULN Transient cases At
target dose With dose reduction Discontinued

10 (14.3) 10 (14.3) 5 (7.1) 422 3
4 (4.2) 11 (11.6) 2 (2.1) 871 0
9092.01
101
Time CourseElevated Aminotransferases

• Gradual over several weeks
• Normalized or reduced to lt 2 x ULN during
  continued treatment (transient)
• 70 (8/11) with bosentan 125 mg bid (PAH)
• 40 (4/10) with bosentan 250 mg bid (PAH)
• 16 (6/38) with bosentan 500 mg bid (CHF)
• Complete resolution after treatment cessation

9093.01
102
Time to ResolutionALT/AST Returned to Baseline
or lt 2 x ULN
Range(days)
Numberof cases
Mean ? SD(days)
Safety database AC-052-354 ENABLE
3 64 18 56 10 44
33 6 23
26 ? 13 32 ? 13 23 ? 10
Time following treatment end depended on time of
evaluation

• 97 of elevations were resolved within 8 weeks

9094.01
103
Predisposing FactorsIncidence of Elevated
ALT/AST gt 3 x ULN
ALT/AST gt 3 x ULN
With Factor
W/o Factor
Predisposing factor
ALT/AST gt ULN at BL (n 133, 521) Alk phos gt
ULN at BL (n 83, 572) Concomitant
glibenclamide (n 31, 213)
10.0 11.4 13.3
16.5 10.8 27.5
No effect of age or gender
9095.01
104
Time to First OccurrenceElevated Liver
Aminotransferases
40
8 Placebo-controlledStudies
20
Bosentan Placebo
(N 658) (N 280)
0
Percent of Patients at Risk
40
AC-052-352
20
Bosentan Placebo
(N 144) (N 68)
0
8
0
16
24
32
Weeks
9096.01
105
Time to First OccurrenceElevated Liver
Aminotransferases
40
ENABLE
Bosentan
(N ? 807)
30
69 cases (8.6)assuming all on bosentan
Percent of Patients at Risk
20
10
0
0
12
24
36
48
60
72
84
96
Week
9097.01
106
Associated SymptomsElevated Liver
Aminotransferases
PC Studies (N 677)
OL Studies (N 122)
ENABLE (N 807)
Pts with symptoms Nausea/vomiting (n)
Abdominal pain Fever Jaundice/bili gt 3xULN
9 / 74 3 2 4 1
2 / 5 2 1 0 1
11 / 69 4 6 2 1
Assuming all cases on bosentan
9098.01
107
Type of Liver InjuryCouncil for Intl Org of
Medical Science
ALT / 30 U/L
Ratio
Alk Phos / 95 U/L
Type of Injury
Cholestatic (ratio ? 2) Hepatocellular
(ratio ? 5) Mixed (ratio gt2, lt 5)
The ULN, respectively
9099.01
108
Type of Liver InjuryCouncil for Intl Org of
Medical Science
ALT / 30 U/L
Ratio
Alk Phos / 95 U/L
ENABLE(N 807)
PC Studies(N 658)
Type of Injury
Total number () of cases Cholestatic
(ratio ? 2) Hepatocellular (ratio ? 5) Mixed
(ratio gt2, lt 5)
67 (100) 3 (4.5) 25 (37.3) 39
(58.2)
74 (100) 7 (9.5) 34 (45.9) 33
(44.6)
The ULN, respectively Assuming all cases are
on bosentan
9100.01
109
MechanismElevated Aminotransferases

• Not yet fully elucidated
• Competitive inhibition of bile salt excretion may
  be a contributory factor
• No evidence for immuno-allergic reaction
• During treatment
• At reintroduction

9101.01
110
Risk AssessmentHyman Zimmermans Suggestions

• Increased risk of acute liver failure in
  patientswith predominantly hepatocellular
  disease
• ALT/AST gt 3 x ULN
• Clinical jaundice (bilirubin gt 3 x ULN)
• May be associated with small changesin alkaline
  phosphatase
• Estimated that 10 of patients who have
  drug-induced liver injury will develop acute
  liver failure

9102.01
111
Long-term Exposureto Bosentan
PAH Studies (N 235)
NC15462NC15464B (N 267)
ENABLE(N 1613)
0.58 ? 0.37 (0.07 1.71)
0.87 ? 1.16 (0 4.11) 183 (68.5) 95 (35.6)
71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6)
1.13 ? 0.48 (0 1.93) 1483 (91.9) 1386
(85.9) 1316 (81.6) 1079 (66.9) 412 (25.5)
191 (81.3) 128 (54.5) 41 (17.4) 28
(11.9) 12 (5.1)

Mean ? SD (yrs) (Range) Pts () treated gt 3
months gt 6 months gt 9 months gt12 months
gt18 months gt24 months
Treatment still blinded about half on bosentan
9512.01
112
Risk Assessment with Bosentan

• Among the 1522 bosentan-treated patients
• No cases of acute liver failure
• 3 pts have had ALT/AST and bilirubin gt 3 x
  ULNand also had alk phosphatase 2-3 x ULN
• 1 in AC-052-352 (250 mg bid)
• 1 in NC15464B (open-label 125 mg bid)
• 1 in ENABLE (blinded treatment)
• All 3 had complete resolution within 24-64
  daysof treatment cessation (based on evaluation
  date)

9103.01
113
Clinical PictureElevated Aminotransferases

• Overall incidence of 11.2
• Incidence and severity are dose related
• Onset mainly during the first 16 weeksof
  treatment
• Gradual increase over several weeks
• Transient in 50 of cases

9104.01
114
Clinical PictureElevated Aminotransferases

• Typically asymptomatic
• Associated with elevated alkaline phosphatasein
  about 50 of cases
• Infrequently associated with elevated
  bilirubin(gt 3 x ULN)
• Rapid and complete resolution with treatment
  cessation
• No evidence for continued liver injury

9105.01
115
Is the Risk of Increased Liver Aminotransferases
Manageable?

• PAH patients are very compliant and havea close
  relationship with their physicians
• Recommendations
• Monthly monitoring for first 6 months and
  quarterly thereafter
• Monitoring can be incorporated into the routine
  management of these patients (INR/chemistries)

9106.01
116
Is the Risk of Increased Liver Aminotransferases
Manageable?

• Guidelines for treatment modification
• Reduce or interrupt treatmentALT/AST gt 3 and lt
  5 x ULN
• Stop treatment ALT/AST gt 5 x ULN, or increase in
  ALT/AST associated with symptoms of liver injury,
  or bilirubingt 3 x ULN
• Education of physicians, nurses, pharmacists
• Information to patients, directly via drug
  distribution and through patient organizations

9107.01
117
Recommended Dosages
Starting dose bosentan 62.5 mg bid (4
weeks) Target dose

• No dose adjustment needed for most subgroups
• Not recommended for
• Pts with moderate to severe liver impairment
• Pts with ALT/AST gt 3 x ULN at baseline
• Pts on glibenclamide or cyclosporin A
• Pregnant women

bosentan 125 mg bid
9108.01
118
Overall Summary

• Treatment with bosentan is associated with
• Improvement in all clinical and hemodynamic
  efficacy measures
• Reduction in risk of clinical worsening
• Good tolerability
• Potential risks related to
• Modest decrease in Hb concentration
• Increase incidence of elevated liver enzymes
• Both can be managed by appropriate monitoring
  and education

9109.01
119
Risk Related to Elevated Liver Aminotransferases
Willis C Maddrey, MD Executive VP for Clinical
Affairs UT Southwestern Medical Center and
Aston Ambulatory Care Ctr
9110.01
120
Signals of Drug-induced Hepatotoxicity

• Major Development of acute liver
  failure Onset of
  clinically apparent jaundice
  Appearance of ascites, encephalopathy,
  coagulopathy
• Intermediate ALT gt 8 x ULN
  ALT gt 5 x ULN ALT gt
  3 x ULN
• Minor Any elevation in ALT (lt 3 x
  ULN) in an asymptomatic
  patient

9111.01
121
Relevance of Elevated Liver Aminotranferases

• Inexact correlations with injury
• Important role of associated signs and symptoms
• gt 3 x ULN equal to inflammation on liver
  biopsy
• gt 5 x ULN triggers considerably heightened
  awareness and follow-up
  (treatment withdrawal
  should be considered)
• Drugs associated with liver injury tend to havea
  signature pattern

9112.01
122
Drug-induced Hepatocellular JaundiceZimmerman
Observations / Rule

• In patients with drug-induced hepatoxicity
  whohave elevated aminotransferase levels (gt 3 x
  ULN),clinical jaundice (bilirubin gt 3 mg/dl),
  and arelatively little change in alkaline
  phosphatase,there is an approximately 10
  mortality rate.
• Drugs studied

Isoniazid 10 Methyldopa 10 Tienilic acid 10
9114.01
123
Bosentan-induced Hepatotoxicity

• Injury hepatocellular or mixed
• Incidence of elevated ALT/AST
• 11.2 with gt 3 x ULN
• 0.6 with gt 20 x ULN
• Onset usually (gt 90) within 16 weeks
• All elevations resolved upon drug withdrawal(97
  within 8 weeks)
• No cases of acute liver failure

9115.01
124
Risk ReductionBosentan Monitoring Guidelines

• Determination of biochemical tests of liver
• Pretreatment
• Monthly for 6 months
• Quarterly thereafter
• Discontinue treatment if
• ALT/AST gt 5 x ULN
• Increased ALT/AST is associatedwith symptoms of
  liver injury

9116.01
125

9117.01
126
Risks vs. Benefits
Lewis J Rubin, MDProfessor of MedicineDirector
of Pulmonary and Critical Care Medicine Univ
of California, San Diego
9118.01
127
Benefits of Bosentan Treatment

• Treatment with oral bosentan is associated with
• Improvement in 6-min walk test
• Improvement in dyspnea score during exercise
• Improvement in WHO functional class
• Delay in time to clinical worsening
• Improvement in hemodynamic parameters
• Maintenance of treatment effect, with no evidence
  for tolerance

9123.01
128
Risks with Bosentan Treatment

• Treatment with bosentan is associated with
• Decreases in hemoglobin concentration
• Increased incidence of elevated liver
  aminotransferases

9125.01
129
Elevated Liver Aminotransferases

• Have been characterized
• Have been quantified
• Incidence
• Degree of severity
• Can be monitoredwithin PAH treatment paradigm

9126.01
130
Risks / Benefits Conclusion
Treatment with bosentan produces clinically
meaningful benefits that substantially outweigh
its characterized risks. Oral bosentan fulfills
an unmet medical need in patients with PAH.
9128.01
131