Washington Editor

Mixed data caused Axonyx Inc. to halt Phase III development of its Alzheimer's drug, Phenserine, despite plans to move forward with a Phase IIb trial.

The company reported Phase III findings over the weekend at an international conference in Italy that corroborated top-line data released a month ago - no statistically significant differences between the efficacy of the active and placebo groups were observed in areas of cognition, global function, behavior and daily living activities. But at the same time, the drug, in development for mild to moderate Alzheimer's disease, demonstrated trends toward efficacy in those same endpoints.

"There are a lot of data swirling around," Colin Neill, Axonyx's chief financial officer, told BioWorld Today. "It made sense to halt those [studies] until we understand exactly the best way to go forward or restructure as necessary, rather than go down a road that we may have to back-track."

Nevertheless, the resulting lack of Phase III statistical significance mirrored previously released data from the study, as did a drop in Axonyx's stock value Monday. Its shares (NASDAQ:AXYX) fell 44 cents, or 25.2 percent, to close at $1.30. Last month, the shares lost nearly two-thirds to close at $1.81. (See BioWorld Today, Feb. 8, 2005.)

A Phase III pause could allow the New York-based company time to decipher its riddle; those treated with 10-mg and 15-mg doses of Phenserine fared better than placebo-treated patients, but there was a higher-than-expected placebo response.

"The drug arms definitely had a drug response," Neill said. "As you'd expect, the 15 mg was a little better than the 10 mg."

He suggested that the study's duration might not have been long enough to maximize the drug's effects, and also speculated that a disproportionately high number of patients included in the study might fall on a more functional side of those diagnosed with the disease. Assessed on a 30-point scale, with 30 indicating full functionality, the trial included patients with a score between 13 and 23.

A separate phenomenon also might have been at work, said Axonyx CEO Gosse Bruinsma. He explained that recent studies of Alzheimer's patients have shown that they maintain levels of functionality longer than in the past.

"This seems to be something that is more and more often arising in the general Alzheimer's disease population," Bruinsma told BioWorld Today. "This might be very well because of generally better levels of care, perhaps better levels of nutrition, perhaps all sorts of other things going on, such as multi-vitamins, which we simply don't have a handle on and, in fact, no one has a handle on."

The company halted additional patient recruitment for its two other ongoing Phase III trials in order to evaluate clinical development plans for Phenserine, a selective acetylcholinesterase (AChE) inhibitor. Still forging ahead, though, Axonyx said it would continue patient enrollment in a Phase IIb study evaluating Phenserine's effects on cerebrospinal fluid levels of beta-amyloid and other biomarkers in mild to moderate Alzheimer's patients, despite a lack of statistical significance among dose levels tested in that trial.

But Axonyx will continue to study patients receiving 15 mg of the drug twice daily, a dose that showed about a 58 pg/ml difference from placebo following six months of treatment. The higher dose might reach statistical significance, but those same interim results suggested that further enrollment in the 10-mg group was not justified, as its 23 pg/ml difference from placebo would not achieve statistical significance.

"There was, most certainly, a response seen in both treatment arms," Bruinsma said, "which was opposite to the placebo group."

The data were culled from the first 37 patients in the double-blinded study, which is comparing both doses to placebo, and the company scheduled its interim analysis to assess the benefit of continuing enrollment. The enrollment period is expected to conclude next quarter, with final results in the last quarter of this year.

It had been scheduled to recruit 150 patients.

The Phase III trial involved 375 patients at 11 European sites. They were randomized to receive six months worth of placebo, Phenserine 10 mg or 15 mg twice daily. The primary efficacy parameters were the Alzheimer's Disease Assessment Scale, cognitive subscale and the Clinical Interview-Based Impression of Change with caregiver input scale. Additional study endpoints included the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale and the Neuropsychiatric Inventory.

"Clearly we are evaluating the best way to move the product forward," Bruinsma said. "The fact remains that Phenserine had a treatment effect that certainly makes the drug promising, in light of the fact that there was also a reduction of beta-amyloid."

Unlike other AChE inhibitors, which only suppress the activity of the enzyme, Phenserine has been shown to have two mechanisms of action: the inhibition of the AChE enzyme, and in preclinical studies, the inhibition of the synthesis of beta-amyloid. The drug was licensed from the National Institute on Aging, part of the National Institutes of Health in Bethesda, Md.