Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies VERITAS Trial Presented at The American College of Cardiology Scientific Sessions 2004 Presented by Dr. John J. V. McMurray

www. Clinical trial results.org IV Tezosentan 5 mg/hr for 30 minutes followed by 1 mg/hr for 24-72hours n=727 IV Tezosentan 5 mg/hr for 30 minutes followed by 1 mg/hr for 24-72hours n=727 Primary Endpoint (VERITAS 1 & 2): Change in dyspnea from baseline over the first 24 hours, as assessed by area under the curve Primary Endpoint (pooled trials): Death or worsening heart failure at 7 days Primary Endpoint (VERITAS 1 & 2): Change in dyspnea from baseline over the first 24 hours, as assessed by area under the curve Primary Endpoint (pooled trials): Death or worsening heart failure at 7 days VERITAS Trial Presented at ACC 2005 Placebo 5mg/hr for 30 minutes followed by 1 mg/hr for hours n=708 Placebo 5mg/hr for 30 minutes followed by 1 mg/hr for hours n=708 1,449 patients with acute heart failure requiring IV therapy And received at least 1 dose of an IV diuretic, age>18 years, dyspnea at rest, enrollment within 24 hours of hospital admission 40% female, mean age 70 years 68% patients had EF=29% and ischemic heart disease, 99% used IV loop diuretics, 62% used ACE Inhibitor or angiotensin receptor blockers, 47% used beta-blockers 1,449 patients with acute heart failure requiring IV therapy And received at least 1 dose of an IV diuretic, age>18 years, dyspnea at rest, enrollment within 24 hours of hospital admission 40% female, mean age 70 years 68% patients had EF=29% and ischemic heart disease, 99% used IV loop diuretics, 62% used ACE Inhibitor or angiotensin receptor blockers, 47% used beta-blockers

www. Clinical trial results.org VERITAS Trial: Primary Endpoint There was no difference in death or worsening heart failure between the Tezosentan group compared to the placebo group at both 7 and 30 days. For the primary endpoint of dyspnea at 24 hours, there was no difference between the treatment groups in either of the VERITAS trials individually or together. Primary endpoint of death or worsening heart failure at 7 and 30 days Presented at ACC days p= days p=0.95

www. Clinical trial results.org VERITAS Trial: Adverse Events Presented at ACC 2005 p=NS There was not a significant difference in the number of serious adverse events that occurred within the Tezosentan group compared to the placebo group. Hemodynamic parameters did improve with the tezosentan group group, with a 6mmHg decline in systolic blood pressure over the placebo group at 72 hours and improvements in cardiac index. There was no difference in survival at 6 months.

www. Clinical trial results.org VERITAS Trial: Summary Among patients with acute heart failure, treatment with the endothelin receptor inhibitor tezosentan was associated with no difference in dyspnea by 24 hours or in death or worsening heart failure by 7 days compared with placebo, prompting an early termination of the trials despite no increase in adverse events. The lack of clinical benefit occurred despite improvements in hemodynamic parameters, including systolic blood pressure and cardiac index. Among patients with acute heart failure, treatment with the endothelin receptor inhibitor tezosentan was associated with no difference in dyspnea by 24 hours or in death or worsening heart failure by 7 days compared with placebo, prompting an early termination of the trials despite no increase in adverse events. The lack of clinical benefit occurred despite improvements in hemodynamic parameters, including systolic blood pressure and cardiac index.