1 Bosentan Therapy Bosentan Therapy for Pulmonary for Pulmonary Arterial Hypertension Arterial Hypertension Isaac Kobrin, MD Isaac Kobrin, MD Head of Clinical Development Head of Clinical Development Actelion Pharmaceuticals Actelion Pharmaceuticals 9001.01
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1 Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01.
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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
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
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
9008.01
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Preclinical ObservationsPreclinical ObservationsRelevant to Human SafetyRelevant to Human Safety
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
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
9012.01
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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
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
Bosentan 250 mg bidBosentan 250 mg bid
ScreenScreen
PlaceboPlacebo
Bosentan 125 mg bidBosentan 125 mg bid
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
9845.01
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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
9846.01
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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
9017.01
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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
9018.01
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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
9019.01
24
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
Percent or mean Percent or mean SD SD
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)
9020.01
25
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)
9021.01
26
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
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
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
42
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
– 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
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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
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)
Mean change Mean change SEM or percent SEM or percent
PlaceboPlacebo(N = 80)(N = 80)
0.2 0.2 0.5 0.5
3.1 3.1 0.7 0.73.0 3.0 0.4 0.4
PlaceboPlacebo(N = 288)(N = 288)
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
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
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
PlaceboPlacebo(N = 269)(N = 269)
0.920.921.321.32
56.856.8 32.032.0 5.65.6 2.22.2
BosentanBosentan(N = 618)(N = 618)
Incidence of Decreased Hb ConcIncidence of Decreased Hb Conc8 Placebo-controlled Studies8 Placebo-controlled Studies
Placebo-Placebo-subtractedsubtracted
LL = < 11.0 g/dl and >15% decrease from baselineLL = < 11.0 g/dl and >15% decrease from baseline
9078.01
87
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
0.960.961.09 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
PlaceboPlacebo(N = 79)(N = 79)
Placebo-Placebo-subtractedsubtracted
0.960.961.571.57
65.265.2 22.722.7 3.03.0 2.42.4
BosentanBosentan(N = 161)(N = 161)
Incidence of Decreased Hb ConcIncidence of Decreased Hb ConcAC-052-351 and AC-052-352AC-052-351 and AC-052-352
LL = < 11.0 g/dl and >15% decrease from baselineLL = < 11.0 g/dl and >15% decrease from baseline
9079.01
88
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
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
LL = < 11.0 g/dl and >15% decrease from baselineLL = < 11.0 g/dl and >15% decrease from baseline
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 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
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)
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
Increased risk of acute liver failure in patientsIncreased risk of acute liver failure in patientswith predominantly hepatocellular disease:with predominantly hepatocellular disease:
ALT/AST > 3 x ULNALT/AST > 3 x ULN
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
——* 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)
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?
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
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.
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
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.