By Mary Welch

Aronex Pharmaceuticals Inc. said preliminary data from a Phase III trial of Nyotran failed to meet its primary endpoint in patients with confirmed cryptococcal meningitis.

The 261-person trial was designed to demonstrate equivalent efficacy and safety of Nyotran against amphotericin B. The composite primary endpoint consisted of the clearance of the cryptococcal meningitis as well as the investigators' assessment of clinical improvement. The drug's results were lower than those of amphotericin B in this endpoint.

"This is breaking news for us and it is important to remember that this is preliminary data," said Geoffrey Cox, Aronex's chairman and CEO. "I don't think we can or would want to duck the fact that we didn't meet our primary endpoint. But we are encouraged by the survival data and its safety profile."

The stock market reacted quickly to the news. Aronex shares (NASDAQ:ARNX) closed Wednesday at $2.75, down $1.625, or 37 percent.

Nyotran is a proprietary liposomal formulation of nystatin, which has been used as a topical treatment because it was too toxic to be taken systemically for the treatment of systemic fungal infections. Nyotran belongs to a class of drugs known as polyene derivatives, which includes amphotericin B, the standard treatment for systemic fungal infections.

There was encouraging data on the other endpoints, Cox pointed out.

In the secondary endpoint of survival at 70 days, there was no difference between the two drugs. Preliminary safety data suggested a favorable renal toxicity profile. The two drugs also seem comparable in overall infusion toxicity.

"We can't talk about numbers at this stage," Cox said. "This is just one of a number of trials designed to show the performance of the drug against different organisms. This is one trial of a package. We expect to collect all the data and analyze it - including the safety profile. We will then more thoroughly review the detailed analysis along with our other clinical trials and meet with the FDA. Following these discussions, we will be able to more accurately determine our regulatory strategy and the basis on which we can progress our commercial filings both in the U.S. and Europe. Our intent is to move this drug forward."

Cox noted that in three previous trials, some of which included refractory and resistant organisms, Nyotran showed clinical utility.

"We are encouraged by the survival data from this study against cryptococcal meningitis involving a clinically challenged population of HIV patients," he said. "We are pleased with the renal and infusion toxicity profiles of Nyotran, despite having doubled the dosage of Nyotran used in our previous Phase III trials.

The current trial was started in January 1999 with patients dosed over a four-hour infusion period with either Nyotran at 4 mg/kg/day or amphotericin B at 0.7 mg/kg/day. The patients, most of whom had HIV, were recruited in South Africa, South America and Thailand. The trial ended late last year.

Nyotran has already completed a comparative Phase III trials in presumed fungal infection, and a Phase II trial in Candidemia (yeast-based infections). A Phase II trial in salvage Aspergillus, a mold-based infection, is in progress.

In the previous Phase III trial of Nyotran, results showed that the liposomal formation of nystatin was equivalent to amphotericin B but had less renal toxicity in treating patients with systemic fungal infections. (See BioWorld Today, Sept. 27, 1999, p. 1.)

Aronex signed a $40 million deal last year with Abbott Laboratories, of Abbott Park, Ill., for the worldwide rights to Nyotran. (See BioWorld Today, Nov. 17, 1999, p. 1.)

"We have updated Abbott," Cox said.

The company is already weathering disappointing news from late last year.

In September, Aronex received a non-approvable letter from the FDA for its lead product, Atragen, as a therapy for acute promyelocytic leukemia. Atragen is an injectable liposomal formulation of all-trans retinoic acid (tretinoin), a vitamin A derivative. (See BioWorld Today, Sept. 28, 1999, p. 1.)

In December, the company said it met with the FDA and plans to submit an amendment to the new drug application for Atragen, seeking approval for the treatment of patients with acute promyelocytic leukemia for whom therapy with tretinoin is necessary but for whom an intravenous administration is required. Aronex said it planned to submit the application in the first half of this year.