Bosentan Therapy for Pulmonary Arterial Hypertension

8/15/01


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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 Zimmermanís 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