By Kim Coghill
Genentech Inc. and its partner, Swiss biotech company Actelion Ltd., said Tuesday a pivotal Phase III trial to study the effects of Veletri (tezosentan) on blood circulation in acute heart failure was positive.
The results were announced by Genentech, of South San Francisco, during the 50th Annual Scientific Session of the American College of Cardiology in Orlando.
Veletri, the first intravenous dual endothelin receptor antagonist in late-stage clinical development for acute heart failure, demonstrated statistically significant blood circulation benefits in its primary efficacy measure: improvement in cardiac index.
The results are from the RITZ-2 (Randomized Intravenous Tezosentan) trial, the first of two pivotal studies in the Veletri Phase III clinical program for acute heart failure. The RITZ-2 study was a randomized, double-blind, placebo-controlled, multicenter trial of 292 patients hospitalized for acute heart failure.
"These are early results. We are conducting another pivotal trial, as well as two ongoing trials that we call supportive studies," said Shelley Schneiderman, Genentech's manager for corporate communications. "We expect an NDA filing by the end of the year. This is a significant product because there has not been a drug approved for acute heart failure for some time. There's standard conventional treatment - but no new drugs."
The other Phase III pivotal trial Schneiderman spoke of is referred to as RITZ-1. Expected to be completed in mid-2001, RITZ-1 is a 670-patient trial to evaluate the ability of Veletri 50 mg/hr to alleviate the symptoms of acute heart failure, including dyspnea. The supportive studies are called RITZ-4, which evaluates Veletri in acute heart disease patients with acute coronary syndromes, and RITZ-5, slated to evaluate the therapy in patients with pulmonary edema.
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 percent; 100 mg/hr, 21.5 percent; placebo 2 percent; p<0.0001), the companies said.
Statistically significant improvements also were observed in other secondary hemodynamic parameters in patients treated with Veletri relative to placebo, including decreases in pulmonary capillary wedge pressure (50 mg/hr, 18.4 percent; 100 mg/hr, 18.8 percent; placebo, 2.3 percent; p<0.0001).
The effect of Veletri on pulmonary capillary wedge pressure and cardiac index was maintained for the duration of the 24-hour treatment period and for at least six hours after cessation of therapy. Also, 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 only conventional therapy (p=0.06).
Some adverse events in the trial included symptomatic hypertension, nausea, renal impairment and vomiting.
Genentech and Actelion are developing a related product, known as Tracleer, an oral endothelin receptor antagonist, which has received orphan designation from the FDA. Results of a pivotal Phase III trial comparing Tracleer to placebo for pulmonary hypertension were encouraging. (See BioWorld Today, Dec. 14, 2000.)
The product also is being evaluated in two Phase III trials, ENABLE-1 and ENABLE-2 (Endothelin Antagonist Bosetan for Lowering Cardiac Events in Heart Failure), involving more than 1,600 patients with coronary heart failure. ENABLE-1 is being conducted in Europe, Israel and Australia; ENABLE-2 in North America.
Genentech and Actelion, based in Allschiwil, Switzerland, entered their $75 million agreement to co-promote Veletri more than a year ago. (See BioWorld Today, Feb. 16, 2000.)
As part of the deal, Genentech was to pay Actelion $15 million in up-front licensing fees, plus milestone payments, a convertible loan and an equity investment in Actelion's initial public offering last April.
Then late last year, the two companies struck up an agreement for the development of Actelion's Tracleer. Under terms of the second deal, Genentech paid Actelion an up-front payment of $35 million in a deal that, with milestones, could make the total value $140 million. (See BioWorld Today, Dec. 14, 2000.)
Genentech's stock (NYSE:DNA) closed Tuesday at $47, down 50 cents. n