Actelion Ltd announced initial positive results from a dose-optimization study evaluating Veletri (tezosentan), an intravenous dual endothelin receptor antagonist, in patients suffering from acute heart failure (AHF). Important hemodynamic effects were achieved at doses of 5 mg/h and 25 mg/h. The primary endpoint of the study, improvement of cardiac index, was statistically significant for both doses. Effects of similar magnitude were also achieved in terms of reduction of pulmonary capillary wedge pressure (PCWP), another important hemodynamic parameter. At these doses, the drug was also well tolerated.
Based on these results and taking into consideration the need for an AHF drug providing more than symptomatic relief, Actelion has decided to proceed with a registration study (Phase III) with Veletri, evaluating mortality/morbidity benefits.
Final decisions on the trial design will be made following full data analysis and modeling as well as discussions with clinical experts and regulatory authorities worldwide. With preparations already substantially advanced and the results of the dose-optimization trial slightly ahead of schedule, the registration study is expected to be initiated by year-end and last between 18 and 24 months.
The dose-optimization study with Veletri (tezosentan) was a randomized, double blind, placebo-controlled, multi-center, parallel design trial of 129 patients hospitalized for Acute Heart Failure (AHF). Patients were randomized to receive either tezosentan (0.2, 1, 5 or 25 mg/hr) or placebo in addition to standard therapy. Patients were treated for 24 hours and were monitored for 30 days. Both hemodynamic and clinical parameters were evaluated in this trial, with the primary endpoint defined as change from baseline cardiac index at 6 hours after drug initiation. Data from this trial was submitted for presentation at an upcoming scientific meeting in 2003.
The dose-optimization trial was undertaken, following detailed analysis of the earlier studies in the RITZ-program. In these trials, treatment with much higher doses of tezosentan (50 and 100mg/h) resulted in hemodynamic benefits, but with concomitant increases of problematic vasodilatory side effects such as hypotension and headache.
AHF is a life-threatening condition in which the ability of the heart to pump enough blood to meet the body's metabolic needs is rapidly and seriously impaired. Each year, nearly one million people in the U.S. are hospitalized with AHF. Patients suffering from AHF typically experience symptoms such as dyspnea, edema, and fatigue, and often present with signs of poor blood flow.
In some cases, the onset of AHF is abrupt, with rapid fluid build-up in the lungs (pulmonary edema), which can impair breathing so drastically that the patient requires intubation and a ventilator for assisted breathing. In other cases, AHF can lead to cardiogenic shock, an abrupt disruption of blood flow that can follow a massive heart attack or surgery.
Actelion signed a U.S. co-promotion agreement for tezosentan with Genentech, Inc. in February 2000, with Actelion taking the lead in developing the drug. Following a successful conclusion of the Phase III program with Veletri in acute heart failure, Genentech can opt-in to become a co-promotion partner for Veletri in the United States.