Washington Editor

Pain Therapeutics Inc. is trying again with Oxytrex.

A year after missing in a Phase III study of the oral painkiller, a combination of oxycodone with ultra-low-dose naltrexone designed to minimize physical dependence, the South San Francisco-based company began another Phase III study in chronic pain patients prone to opioid dependence. The double-blinded trial will enroll about 120 subjects, a sub-population of patients "in extreme pain," said President and CEO Remi Barbier, who also are inclined to physical addiction and withdrawal problems.

"They are on extremely high doses of opioids," he told BioWorld Today. "We think that corresponds to very high levels of physical dependence and withdrawal, so if it works in this patient population, it should work in everyone else."

The trial, labeled the Extreme Study, is recruiting patients who have been taking high daily doses of oxycodone - greater than or equal to 120 mg - for more than a year. Barbier said it typically takes many years for them to get to that dosing level, "so you simply don't want to muck around" with their opioid therapy. Therefore, they'll be randomized to receive twice-daily low doses of naltrexone (0.0001 mg), or matching placebo for two weeks as a sort of co-treatment with oxycodone.

After that, they check into a clinic to receive an injection of a high-dose opioid antagonist to precipitate withdrawal over the next 24 hours. Any after-effects would surface quickly, Barbier said, because any interruption to the opioid flow into their bloodstream would produce withdrawal signals "within 60 minutes."

During that phase, physicians will monitor and measure those patients for signs and symptoms of physical dependence and withdrawal using an observational method, the Subjective Opiate Withdrawal Scale. The study's primary endpoint is defined as physical dependence/withdrawal scores in the treated arm compared to placebo.

Its protocol allows an interim analysis.

Enrollment is under way and should take about a year, though that timeline could get complicated because many of the patients might be fearful of changes to their opioid dosing.

"We'll have to use kid gloves in explaining to them that there is no interruption," Barbier said. "If anything, there's a benefit."

The trial, coupled with a larger study scheduled to begin later next year, is designed to support a new drug application to the FDA. The Extreme Study should satisfy the agency's desire to see the effect of the low-dose antagonist isolated from the agonist, and the coming trial will include a broad set of patients who will be tested in a standard three-month pain study with a titration period. Before it gets under way, the company must continue to formulate the 0.0001-mg doses of naltrexone over the first half of next year until getting sufficient quantity.

Pain Therapeutics is eyeing a regulatory filing in 2009.

The last Phase III trial failed because of the high number of patient dropouts - there was no titration period - so statistical significance was not reached in reducing opioid-related physical dependency. But there were encouraging and positive trends, as Oxytrex reduced physical dependency by 28 percent compared to an equivalent dose of oxycodone. Still, the news knocked off a fifth of the company's stock value about a year ago. (See BioWorld Today, Nov. 23, 2005.)

An earlier Phase III study that enrolled 719 patients with severe, chronic lower-back pain proved more positive, showing that those who received Oxytrex reported about 50 percent fewer symptoms of physical dependence and withdrawal after stopping high-dose opioid use compared to patients on oxycodone. (See BioWorld Today, March 25, 2005.)

"No one has ever tried to reduce physical dependence, this is a first," Barbier said. "So we're pioneers, and as with any pioneering effort, it's highly exciting and energizing. But on the other hand, you're clearing the brush as you go along."

On Wednesday, its stock (NASDAQ:PTIE) added on 4 cents to close at $8.74.