Actelion and Genentech Announce First Endothelin Receptor Antagonist Shows Positive Preliminary Results for Acute Heart Failure.

Business Editors/Medical Writers

ORLANDO, Fla.--(BW HealthWire)--March 20, 2001

Positive Results Announced In First of Two Phase III

Trials of VELETRI(TM) (Tezosentan)

Actelion Ltd (SWX New Market:ATLN) and Genentech, Inc. (NYSE:DNA), announced positive results today from a Phase III trial of the first intravenous, dual endothelin receptor antagonist Veletri(TM) (tezosentan) in acute heart failure (AHF). In the RITZ-2 trial, Veletri demonstrated statistically significant hemodynamic (blood circulation) benefits in its primary efficacy measure, improvement in cardiac index (CI, the amount of blood pumped by the heart per minute/body surface area). Hemodynamic benefits were also realized in important secondary endpoints, including pulmonary capillary wedge pressure (PCWP).

RITZ-2 (Randomized Intravenous TeZosentan), a randomized, double-blind, placebo-controlled, multi-center trial of 292 patients hospitalized for AHF, was designed to evaluate the ability of Veletri to improve hemodynamics. Results were presented by Guillermo Torre-Amione, MD, Ph.D., Assistant Professor, Baylor College of Medicine, during the 50th Annual Scientific Session of the American College of Cardiology in Orlando.

In RITZ-2, the hemodynamic effects of two doses of Veletri (50 mg/hr and 100 mg/hr) were compared to placebo on top of conventional therapy over 24 hours. The primary endpoint was achieved, with a statistically significant change from baseline in cardiac index at six hours with both doses of Veletri relative to placebo (50 mg/hr, 21.4%; 100 mg/hr, 21.5%; placebo 2.0%; p less than 0.0001).

Statistically significant improvements were also observed in other secondary hemodynamic parameters in patients treated with Veletri relative to placebo, including decreases in PCWP (50 mg/hr, 18.4%; 100 mg/hr, 18.8%; placebo, 2.3%; p less than 0.0001). A decrease in this parameter is understood to improve the efficiency of the heart in patients with heart failure. In addition, a combined analysis of patients treated with both Veletri 50 mg/hr and 100 mg/hr showed improvement versus placebo in dyspnea (shortness of breath) at 24 hours, a clinically relevant secondary endpoint of the study.

The effect of Veletri on CI and PCWP -- achieved without an increase in heart rate -- was maintained for the duration of the 24-hour treatment period and for at least six hours after cessation of therapy. In addition, when time to death or worsening heart failure was assessed during the first 24 hours of the study, there was a trend in favor of the Veletri-treated patients compared to patients receiving conventional therapy alone (p=0.06).

"The RITZ-2 trial results demonstrate that Veletri may have great promise as a treatment for acute heart failure," said Isaac Kobrin, MD, head of Clinical Development for Actelion.

The overall pattern of serious adverse events was similar across the three treatment groups during the 28-day follow-up. Veletri 50 mg/hr had a similar adverse event profile to placebo during treatment, with the exception of an increase in reported cases of moderate to severe headache (placebo, 0.0%; 50 mg/hr, 5.5%; 100 mg/hr, 7.0%). The higher dose of Veletri (100 mg/hr) did not provide additional benefits over 50 mg/hr, but was generally associated with an increase in adverse effects such as symptomatic hypotension (placebo, 3.2%; 50 mg/hr, 3.3%; 100 mg/hr, 5.0%), nausea (placebo, 2.1%; 50 mg/hr, 3.3%; 100 mg/hr, 7.9%), renal impairment (placebo, 1.1%; 50 mg/hr, 2.2%; 100 mg/hr, 5.0%) and vomiting (placebo, 3.2%; 50 mg/hr, 2.2%; 100 mg/hr, 8.9%).

RITZ-2 is the first of two pivotal studies included in the Veletri Phase III clinical trial program for AHF: The second is RITZ-1, a 670-patient study evaluating the ability of Veletri 50 mg/hr to alleviate the symptoms of AHF, including dyspnea. RITZ-4, evaluating Veletri in AHF patients with acute coronary syndromes, and RITZ-5, evaluating the therapy in patients with pulmonary edema, complete the Veletri clinical trial program as supportive pilot studies.

"We are pleased that RITZ-2 yielded positive hemodynamic results," said Hal V. Barron, MD, senior director, Cardiopulmonary Research, Genentech. "We look forward to receiving the full clinical trial program results later this year to confirm the potential of Veletri in acute heart failure."

Veletri has been specifically designed for intravenous administration and represents the first dual endothelin receptor antagonist (ERA) in late stage clinical development for AHF. Veletri works by competitively binding to the endothelin receptors to antagonize the deleterious effects of endothelin (ET). Endothelin is one of the most potent endogenous vasoconstrictors known and has been shown to have a deleterious role in cardiopulmonary diseases, such as AHF. It has been implicated in the acute events associated with pathological conditions such as heart failure and is believed to have a significant role in disease progression -- characterized by cardiac fibrosis and hypertrophy -- and the potentiation of neurohormonal activation.

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.

In February 2000, Actelion and Genentech signed an agreement to develop and co-promote Veletri for the treatment of AHF, and to co-promote Genentech's new single bolus thrombolytic TNKase(TM) (tenecteplase). In December 2000, the companies announced the signing of a second agreement for the development and co-promotion of Actelion's oral endothelin receptor antagonist Tracleer(TM) (bosentan) for pulmonary arterial hypertension and congestive heart failure.

Actelion Ltd, a biopharmaceutical company headquartered in Allschwil, Switzerland, is the global leader in creative science related to the endothelium -- the single layer of cells separating every blood vessel from the blood stream. Actelion concentrates on developing and bringing innovative drugs to patients. Tracleer and Veletri, its two flagship drugs, are in late stage development for several cardiovascular disorders, including chronic and acute heart failure as well as pulmonary arterial hypertension. In addition, Actelion is conducting drug discovery programs in cardiovascular diseases, malaria, Alzheimer's disease and cancer. Actelion is quoted on the Swiss Stock Exchange (SWX New Market:ATLN).

Genentech, Inc. is a leading biotechnology company that discovers, develops, manufactures and markets human pharmaceuticals for significant unmet medical needs. Fourteen of the currently approved biotechnology products stem from Genentech science. Genentech markets nine biotechnology products directly in the United States. The company has headquarters in South San Francisco, California and is traded on the New York Stock Exchange under the symbol DNA.

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