Washington Editor

EPIX Pharmaceuticals Inc. reported that its investigational 5-HT4 agonist PRX-03140 helped improve cognitive function and memory in patients with Alzheimer's disease after only two weeks of use.

Shares of Lexington, Mass.-based EPIX (NASDAQ:EPIX) climbed 35.4 percent Tuesday, or $1.05, to close at $4.02.

The drug was tested in a Phase IIa trial as a single agent and in combination with New York-based Pfizer Inc.'s Aricept (donepezil) in 80 patients with mild-to-moderate Alzheimer's disease at 17 U.S. sites. Patients who received a once-daily 150-mg oral dosage of PRX-03140 alone achieved a statistically significant mean 5.7 point improvement on the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog), the current standard for evaluating drug efficacy for cognition in Alzheimer's disease.

"These patients were taking no other cognitive-enhancing medications," CEO Michael Kauffman noted during a conference call.

Patients receiving placebo alone averaged a 0.2 mean worsening in memory and cognitive function, he said, adding that those on the 50-mg dosage of PRX-03140 showed a 1.1 point improvement on the ADAS-cog.

In the combination arm of the trial, 50 patients who were on a stable once-daily 10-mg dosage of Aricept for a minimum of three months prior to starting the trial were randomized to PRX-03140 at 5 mg, 25 mg, 50 mg, 100 mg or 200 mg or placebo.

Data showed that all 50 patients remained on their stable once-daily 10-mg dosage of Aricept throughout the trial, Kauffman said.

However, he added, ADAS-cog changes in the combination arm of the trial were not statistically significant.

"While we did not achieve a statistical significance in ADAS-cog in the combination arm, we were delighted to see the statistically significant improvement in cognitive function in the monotherapy arm of the trial," Kauffman told investors.

PRX-03140 is an agonist or activator of the Type 4 serotonin receptor, commonly known as the 5-HT4 receptor, which stimulates the production and release of acetylcholine, the key neurotransmitter in the nervous system believed to be responsible for the cognitive and memory decline seen in Alzheimer's patients.

"By activating 5-HT4, 3140 not only stimulates the production and release of acetylcholine, which may improve cognitive symptoms of Alzheimer's disease, but it also stimulates the alpha-secretase pathway increasing soluable amyloid precursor protein alpha, reducing Abeta 1-42, and thereby potentially slowing disease progression," Kauffman explained.

Current Alzheimer's therapies are focused on blocking the breakdown or loss of acetylcholine, he added.

To increase the levels of acetylcholine in an Alzheimer's patient's brain, therapies like Aricept or cholinesterase inhibitors that prevent the loss of acetylcholine "block the drain," like in a kitchen sink, Kauffman said. In contrast, PRX-03140 stimulates the production and release of acetylcholine, or "turns the faucet on in the brain."

To put PRX-03140's two-week, 5.7-point improvement in context of currently marketed Alzheimer's therapies, Kauffman said, those other drugs demonstrated a 3 to 4 point improvement after 12 to 24 weeks in clinical studies.

"This further underscores the compelling nature of our findings," he declared.

To date, EPIX has completed Phase I and Phase IIa trials in more than 180 subjects, with PRX-03140 "proving to be well tolerated with a favorable side effect profile," Kauffman said.

Based on the "encouraging" Phase IIa data, he said, the firm plans to start a Phase IIb trial in the first half of 2008, with ADAS-cog as the primary endpoint.

"We believe that PRX-03140 is poised to meet a critical unmet medical need," Kauffman said, noting that Alzheimer's disease affects about 5 million people in the U.S. alone. "For these patients, current treatment options are limited, with few approved drugs currently prescribed for Alzheimer's patients," he said.

The global market for Alzheimer's disease drugs was about $4 billion in 2006 and is projected to grow to at least $5 billion by 2010, Kauffman said.

EPIX is developing PRX-03140 as part of a worldwide collaboration with London-based GlaxoSmithKline plc. As a result, Kauffman noted, GSK has the exclusive option to license the compound, which would trigger milestone payments and provide EPIX with the potential for tiered double-digit royalties in addition to option fees and additional milestone payments.

While the trial of PRX-03140 was small, said analyst Alan Carr of Needham and Co. of New York, "we are encouraged by the surprisingly strong reported mean activity on the ADAS-cog scale at only two weeks."

However, he cautioned in an investor note, "the changes in score for two patients on drug may have been responsible for much of the signal. Furthermore, we would have anticipated a stronger effect in combination with Aricept."

While the Phase IIa data suggested early promising signs of activity, Carr said data from a six-week-plus trial "may provide a more reliable indication of activity in this disease."