Table of Contents
Bosentan Therapy for Pulmonary Arterial Hypertension
Advisors
Bosentan Therapy for PAH
Endothelin-1 (ET-1)
Rationale for ET Receptor Antagonism in PAH
Bosentan
Preclinical Observations Related to PAH
Preclinical Observations Related to PAH
Preclinical Observations Relevant to Human Safety
Preclinical Observations Testicular Changes
Pharmacokinetic Characteristics
Pharmacokinetic Characteristics
Metabolism and Excretion
Influence on Drug Metabolism
Warfarin DDI: Clinical Relevance AC-052-352
Efficacy in PAH Patients
PAH Studies for Efficacy Evaluation
Study Designs Placebo-controlled Studies
Patient Allocation to Periods 1 and 2 AC-052-351
Patient Allocation to Periods 1 and 2 AC-052-352
Main Inclusion Criteria
Main Exclusion Criteria
Demographics
Baseline Characteristics
Baseline Hemodynamics
Main Concomitant Medications for PAH
Patient Disposition AC-052-351
Patient Disposition AC-052-352
Efficacy Parameters
Efficacy Parameters
Statistical Analyses Primary Endpoint
6-minute Walk Test Mean Treatment Effect
Robustness of Results Primary Parameter
Change in Walk Distance During Period 1
Change in Walk Distance by Dose During Period 1 in AC-052-352
Walk Test in Subpopulations Mean Treatment Effect (AC-052-352)
Walk Test in Subpopulations Mean Treatment Effect (AC-052-352)
Walk Test in Subpopulations Mean Treatment Effect (AC-052-352)
Change in Borg Dyspnea Index Mean Treatment Effect
Time to Clinical Worsening Up to Treatment End
Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352)
Incidence of Clinical Worsening To End of Period 2
Improvement in WHO Class End of Period 1
Change in WHO Class AC-052-351 and AC-052-352
Changes in Hemodynamics Change to Week 12 (AC-052-351)
Increase in Therapy for PAH AC-052-352 (Period 1)
Patient Allocation to Periods 1 and 2 AC-052-351
Patient Disposition AC-052-351
Patient Allocation to Periods 1 and 2 AC-052-352
Disposition of Pts Scheduled for Period 2 AC-052-352
Maintenance of Efficacy Walk Test Up to 28 Weeks
Open-label Extension AC-052-353
6-minute Walk Distance Open-label Extension Study AC-052-353
WHO Functional Class Open-label Extension Study AC-052-353
Efficacy Conclusions
Efficacy Conclusions
PPT Slide
Safety and Tolerability
Bosentan Therapeutic Studies Safety Database
Bosentan Therapeutic Studies Safety Database
Bosentan Therapeutic Studies Safety Database
Bosentan Therapeutic Studies Safety Database
Subjects in the Database
Subjects in the Database 8 Placebo-controlled Studies
Exposure to Bosentan Overall and Placebo-controlled Studies
Patient Demographics 8 Placebo-controlled studies
Treatment-emergent AEs 8 Placebo-controlled Studies
AEs of Specific Interest 8 Placebo-controlled Studies
Worsening Heart Failure
Most Frequent (? 5%) Treatment-emergent AEs AC-052-351 and AC-052-352
Most Frequent (? 5%) Treatment-emergent AEs AC-052-351 and AC-052-352
AEs (? 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies
AEs Leading to Withdrawal AC-052-351 and AC-052-352
Reasons for Death (? 3 patients) 8 Placebo-controlled Studies
Reasons for Death AC-052-351 and AC-052-352
Vital Signs
Evidence for Rebound?
Outcomes in PAH Patients Started on Epoprostenol
Long-term Experience Open-label Extension Study AC-052-353
Long-term Experience Open-label Extension Study AC-052-354
Overall Exposure PAH Patients
Survival AC-052-351, AC-052-352 and OL Extensions
Additional Safety Observations
Decreases in Hemoglobin Concentration
Preclinical Observations Decreases in Hemoglobin
Incidence of Decreased Hb Conc 8 Placebo-controlled Studies
Incidence of Decreased Hb Conc AC-052-351 and AC-052-352
Incidence of Decreased Hb Conc Placebo-corrected Incidence
Among PAH Patients with Anemia
Time to Occurrence Decreases in Hemoglobin
Change in Hb Concentration NC15462 and NC15464B
Change in Hb Concentration AC-052-352
Unlikely Reasons Decrease in Hemoglobin
Possible Mechanisms Decrease in Hemoglobin
Risk Management Decrease in Hemoglobin
Increases in Liver Aminotransferases
Preclinical Observations
Elevated ALT/AST > 3 x ULN by Dose Safety Database
Severity of Elevated ALT/AST Safety Database
Elevated Aminotransferases AC-052-351 and AC-052-352
Time Course Elevated Aminotransferases
Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN
Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN
Time to First Occurrence Elevated Liver Aminotransferases
Time to First Occurrence Elevated Liver Aminotransferases
Associated Symptoms Elevated Liver Aminotransferases
Type of Liver Injury Council for Intl Org of Medical Science
Type of Liver Injury Council for Intl Org of Medical Science
Mechanism Elevated Aminotransferases
Risk Assessment Hyman Zimmerman’s Suggestions
Long-term Exposure to Bosentan
Risk Assessment with Bosentan
Clinical Picture Elevated Aminotransferases
Clinical Picture Elevated Aminotransferases
Is the Risk of Increased Liver Aminotransferases Manageable?
Is the Risk of Increased Liver Aminotransferases Manageable?
Recommended Dosages
Overall Summary
Risk Related to Elevated Liver Aminotransferases
Signals of Drug-induced Hepatotoxicity
Relevance of Elevated Liver Aminotranferases
Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule
Bosentan-induced Hepatotoxicity
Risk Reduction Bosentan Monitoring Guidelines
PPT Slide
Risks vs. Benefits
Benefits of Bosentan Treatment
Risks with Bosentan Treatment
Elevated Liver Aminotransferases
Risks / Benefits Conclusion
PPT Slide
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