Washington Editor

Shares in Pain Therapeutics Inc. lost nearly 20% of their value on news that a Phase III study of Oxytrex was inadequate due to patient dropouts, meaning another trial is in order.

The number of those who completed the osteoarthritis study was lower than expected, and statistical significance was not reached in reducing opioid-related physical dependency, the trial's primary endpoint. The South San Francisco-based company had expected that up to 40 percent of patients would drop out before completing the study's three-month treatment period, but in fact dropout rates were 48 percent to 60 percent in the drug arms and 37 percent among placebo patients.

On Tuesday, its stock (NASDAQ:PTIE) sank $1.61, or 18.9 percent, to close at $6.90.

Still, there were encouraging and positive trends in the 775-patient trial, which began in March of last year.

"It's a classic case where the drug worked and the trial failed," Pain Therapeutics President and CEO Remi Barbier told BioWorld Today. "Clearly, the clinical effect is here. We saw it, and we've see it before, in two large trials, animal data and the mechanism of action. Why the heck we did not see it here is just a shame."

Oxytrex, a combination of oxycodone with ultra-low-dose naltrexone, reduced physical dependency by 28 percent compared to an equivalent dose of oxycodone, exceeding Pain Therapeutics' expectation of such a reduction by 25 percent or more, but well below the statistical significance threshold. The trial did hit statistical significance in a subgroup analysis, as Oxytrex reduced physical dependency by 75 percent in patients older than 50 (p=0.04).

Barbier said the company chose not to exclude patients younger than 50, though, because of the potential of label restrictions. But he blamed the study's high dropout rate on its inclusion of younger patients, many of whom aren't typical osteoarthritis patients but nonetheless appeared to have enrolled soon after last year's market withdrawal of the COX-2 inhibitor Vioxx (rofecoxib, Merck & Co. Inc.).

"We believe that a fair number of patients who used to be on Vioxx were inappropriately enrolled in our study," he said, "and if Vioxx treats your pain, you're not a good candidate for opioid therapy, and vice-versa."

Still, the study met its pre-defined secondary endpoint, as Oxytrex was non-inferior to oxycodone during the three-month treatment period. Specifically, Oxytrex patients reported slightly better pain relief than oxycodone patients and significantly better analgesia than placebo patients. In contrast, oxycodone did not separate from placebo, given the high dropout rate and placebo response.

However, Barbier acknowledged that another trial would be necessary, although he noted that it wouldn't significantly delay the pain drug's eventual market entry given that required open-label safety studies remain ongoing until the third quarter of next year. He predicted a potential six-month setback.

"I think what we're seeing [with the company's stock drop] today is not so much a reaction to our timelines as much as investors' collective sentiments to the P' word - pain," Barbier said. "I think investors are just tired of these pain trials, not just by us, but every pain company out there, which have at one point or another published disappointing trial results."

He attributed negative data to trial design rather than the inability of pain drugs to work. Studies fail to take into account that a single dose of particular drug works differently for different patients, high placebo effects (especially among younger patients) and difficult side-effect profiles among opioids, he said.

"So when you have no happy dose, large placebo responses and side effects," Barbier said, "it becomes very difficult to prove in a statistically meaningful way the value of a drug."

The just-reported trial was the second of two Phase III studies on which the company planned to file for approval. It enrolled 719 patients with severe, chronic lower-back pain, and those on the investigational drug 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.)

Pain Therapeutics plans to talk with the FDA early next year on designing clinical trials and titration studies that pre-screen patients to overcome the statistical limitations imposed by high dropout rates.

"I think this study proves almost definitively that fixed-dose studies rarely work with opioid painkillers," Barbier said, adding that the first Phase III trial of Oxytrex followed a titration design. "Going forward, not just us, but I think the whole industry will be looking toward titration designs."

Pain Therapeutics said the setback would not impede the closing of its recently reported alliance with King Pharmaceuticals Inc., of Bristol, Tenn., and thanks to that deal, Pain Therapeutics expects to move into next year with more than $200 million in cash. Looking into 2006, the company is eyeing a net cash burn rate of less than $15 million.

The new agreement with King is related to Remoxy, a long-acting oral oxycodone, and other abuse-resistant opioid painkillers. Terms include an up-front cash payment of $150 million to Pain Therapeutics, payable upon closing.

Elsewhere in the company, Pain Therapeutics said it remains on track to soon report results of a Phase III trial of PTI-901 in 600 women with irritable bowel syndrome.