By Brady Huggett

Genentech Inc. and Actelion Ltd. got negative results in their RITZ-1 trial of Veletri, giving them a split of their two pivotal Phase III trials for the acute heart failure drug and putting the product in limbo.

The trial did not meet its primary objective of significantly improving symptoms of dyspnea associated with acute heart failure, while the other Randomized Intravenous Tezosentan study ¿ the 292-patient RITZ-2, released last month ¿ met its primary endpoint of showing a statistically significant improvement in cardiac index. The discrepant results have thrust the product¿s future into uncertainty while the companies pore over data from both trials.

Company officials from Actelion, of Allschwil, Switzerland, said in a conference call that the companies are weighing several options, such as decreasing the dose and designing a new trial using the new information. Originally, the companies anticipated a new drug application filing by the end of the year, but Actelion officials said now a delay of about 18 months can be expected.

News of the negative results dropped Genentech¿s stock (NYSE:DNA) $5 Friday, or nearly 9 percent, to close at $52. Actelion¿s stock (SWX:ATLN) took the news much harder. Its stock on the Swiss exchange spiraled down 62 percent Friday.

Cory Kasimov, an analyst for Gruntal & Co. LLC in New York, said for Genentech¿s bigger picture, Veletri simply does not significantly affect its bottom line.

¿In the whole scheme of things, it is not that negative for the company,¿ Kasimov said. ¿It¿s definitely negative news, but the point I am making is we believe Genentech has other products in its pipeline of far greater value than Veletri.

¿We are eliminating [Veletri] from our model until we can get a better clarification of this product¿s potential,¿ he added. ¿It only had a potential of a couple hundred million per year. The significance isn¿t there. We are still very high on the company.¿

Oddly, improvement of dyspnea also was measured as a secondary endpoint in the RITZ-2 trial, with positive results. Shelley Schneiderman, corporate communications manager of cardiovascular products at Genentech, said that is why the 675-patient RITZ-1 trial data were unexpected.

¿This was a surprise result,¿ she said. ¿In [RITZ-2] we saw what we wanted to see; we had seen positive dyspnea improvement trends. Clearly [RITZ-1] is telling us that the drug was not statistically significant in this indication.¿ Schneiderman said one difference between the RITZ trials was the measuring of endpoints. Measuring improvements in hemodynamics ¿ blood circulation to and from the heart ¿ is a quantifiable, objective measurement, while measuring improvements in dyspnea is done by a patient-assessed method: The patients describe how they feel using a seven-point range. Dyspnea measurements give much less concrete results, Schneiderman said.

Two other trials round out the RITZ program ¿ RITZ-4 and RITZ-5. These trials are basically exploratory, Schneiderman said, but they will now be examined as well as RITZ-1 and RITZ-2 when determining Veletri¿s fate.

¿I think [RITZ-4 and RITZ-5] have been completed, and our scientists will look at them and analyze the four studies,¿ she said. ¿Data has not been released yet. I don¿t want to be falsely optimistic, but we have a number of trials to wade through and that is the immediate task of the companies.¿

The analysis most likely will focus on Veletri¿s dosing, something Actelion officials said was ¿obviously a very important aspect with this drug.¿ The RITZ-1 trial evaluated the ability of 50 mg/hour of Veletri, plus standard treatment, to reduce the clinical symptoms of acute heart failure, based on the patient¿s assessment of dyspnea in the absence of hemodynamic evaluation. Secondary endpoints in the study, including time to death or worsening of heart failure, did not reach statistical significance.

But among those at Actelion and South San Francisco-based Genentech, which entered their $75 million agreement to co-promote Veletri in February 2000, the hope is a lower dose might still achieve endpoints. (See BioWorld Today, Feb. 16, 2000.)

¿What I can tell you from the RITZ-2 ¿ it studied the 50 mg/hour and 100 mg/hour ¿ was that the 100 wasn¿t any more efficacious than the 50,¿ Schneiderman said. ¿If we are learning from this product that more isn¿t always better, what could we learn from a lower dose?¿

Looking up these companies¿ cardiovascular pipeline, they are co-developing Tracleer, an oral endothelin receptor antagonist, that is being evaluated in two Phase III trials, ENABLE-1 and ENABLE-2 (Endothelin Antagonist Bosetan for Lowering Cardiac Events in Heart Failure), in more than 1,600 patients with coronary heart failure. Results from those trials are expected by the end of 2001, Schneiderman said.

For now, the task at hand is working through the figures. Only then can a clear decision be made, Schneiderman said.

¿That¿s the challenge moving forward,¿ she said. ¿The data has to be understood. Now we have two Phase III trials, one positive and one negative. Is the product dead? It¿s too early to tell.¿

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