Washington Editor

Still hoping to find a partner for its Alzheimer's disease drug Phenserine, Axonyx Inc. released positive data supporting further studies at higher doses that could spark a deal.

"It's really the [total] data package that we will have available that should be of interest to [potential partners]," Colin Neill, the company's chief financial officer, told BioWorld Today. "What the new data show, really, is that the drug potentially can work."

The results stem from an additional analysis of two curtailed Phase III trials of the selective acetylcholinesterase inhibitor, which has been in development for mild to moderate forms of the neurodegenerative disease. Those studies, labeled AX-CL-09 and AX-CL-010, had been cut short after an initial Phase III trial failed to hit statistical significance on its primary endpoints.

Neill said it was impossible to tell whether the studies would have hit their endpoints if they had been completed as originally planned. Previously, the three Phase III studies had been moving forward simultaneously.

"We thought the issue was that we were not getting enough drug into the brain with the existing dose," Neill said. "That prompted us to think about reformulating the drug to an extended-release or slow-release formulation."

But now the New York company has said that a subgroup of patients who received 15mg of Phenserine twice daily demonstrated a statistically significant benefit over placebo based on an oft-used measure of the disease, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), and also showed a positive trend toward improvement in the Clinical Interview Based Impression of Change (CIBIC+) test. They were treated for more than 12 weeks, and there were no unexpected safety or tolerability concerns associated with Phenserine, so Axonyx concluded that the findings support the belief that higher doses could potentially be effective in future potential Phase III trials that last 26 weeks.

Neill added that the findings were "very interesting to include in the data package as we present it to potential marketing partners," though he said there was no imminent agreement forthcoming. Still, reports of the new data increased the company's stock (NASDAQ:AXYX) by 12 cents, to 97 cents.

But since additional trials would be needed to confirm those results, Axonyx needs a deal. A month ago, the company indicated it would not commit further resources to the Phenserine program and would seek a partner for the compound. That decision came less than two months after Axonyx unveiled top-line results showing that there was no statistically significant benefit associated with Phenserine over placebo after 12 weeks of treatment in either the ADAS-cog or CIBIC+, the primary efficacy endpoints. (See BioWorld Today, Sept. 21, 2005.)

Such setbacks aren't uncommon in this space, Neill noted, adding that all four FDA-approved Alzheimer's drugs failed studies during their development. "Nobody gets it right the first time," he said, especially given the subjective nature of study endpoints for Alzheimer's.

The AX-CL-09 and AX-CL-010 trials initially were each designed to enroll 450 patients for a 26-week treatment period, but after the first Phase III miss, the company halted recruitment and cut the treatment duration so they evaluated a total of 255 patients after 12 weeks. That first Phase III trial produced no statistically significant differences between Phenserine and placebo in areas of cognition, global function, behavior and daily living activities, cutting the company's stock value from more than $6 at the beginning of this year. (See BioWorld Today, Feb. 8, 2005, and March 15, 2005.)

"It's just too expensive to go forward on our own," Neill said. "If the drug has potential, it's going to have to be done in conjunction with somebody else who has a bigger checkbook."

Axonyx posted a $5.7 million net loss for the third quarter ended Sept. 30, at which time it had $63.2 million in cash, cash equivalents and investments.

The additional analysis was completed as part of the company's efforts to find a partner. It included 182 patients who received 15 mg of Phenserine or placebo for a period longer than 12 weeks but not more than 26 weeks. Patients who received 10 mg of Phenserine twice daily did not show a statistically significant benefit compared to placebo.

Phenserine, which is licensed from the National Institutes of Health in Bethesda, Md., also had been the subject of a Phase IIb study this year, but that trial was stopped as interim data have underscored the efficacy of the twice-daily 15 mg dose.

Going forward, the company has turned its eyes more squarely to two other Alzheimer's products in its pipeline.

Posiphen, a positive isomer of Phenserine that is designed to reduce beta-amyloid precursor protein levels, is in Phase I. Importantly, it lacks Phenserine's limiting side effects of nausea and vomiting, and potentially can be dosed as much as 10 times higher. At an earlier stage of development is BisNorCymersine, a highly selective butyrylcholinesterase inhibitor for moderate to severe Alzheimer's. It is scheduled to begin Phase I next quarter.