Looking to take the sting out of pain, DOV Pharmaceutical Inc. is marching forward with the first of four pivotal trials of its investigational analgesic product, bicifadine.

The Hackensack, N.J.-based company will test the molecule in about 480 patients with moderate to severe acute pain following bunionectomy surgery. The placebo-controlled Phase III study is designed to assess the efficacy and safety of three dose levels of bicifadine for a five-day period, incorporating the analgesic tramadol as an active control.

"This is the first in a series that we'll be starting toward getting that [new drug application submission]," Barbara Duncan, DOV's chief financial officer, told BioWorld Today. "I don't know if you want to say it's the beginning of the end, but we're getting this program started and we are now on track for what we have put forth as a potential for an NDA filing very late in '06."

The study's primary efficacy endpoint is the summed pain relief and intensity difference score, a measurement of analgesia. Secondary endpoints include time-to-use of rescue medication, clinical global evaluations and other measures. Enrollment likely will take between six and nine months.

In March, DOV and the FDA reached agreement on a plan for the balance of the Phase III bicifadine program necessary to submit a new drug application for both acute pain and chronic lower back pain.

To support an acute pain NDA, DOV said it would select two additional acute pain models, both of which would target moderate to severe pain. It plans to begin them in the first half of next year. The bunionectomy study also is focused on moderate to severe pain, and will be mirrored down the road as the final of four pivotal trials required to support the submission for the management of acute pain.

Later this quarter the company plans to begin the first of two pivotal studies in chronic lower back pain patients for an NDA in that indication. In the first quarter of next year, DOV also plans to begin long-term safety trials necessary to support both the acute pain and the chronic lower back pain NDAs.

"[The NDAs] could probably be done around the same time because the rate-limiting factor will be the long-term safety database," Duncan said. "This will be in addition to what we've already done, so the FDA has asked for a number of patients on the drug for one year and another number of patients on it for six months. That's typical of what the FDA is looking for in terms of pain medications these days."

Two prior clinical trials of bicifadine demonstrated it to be an effective analgesic in a dental pain model, with efficacy superior to placebo and comparable to, or better than, codeine and tramadol. One of the studies, a 750-patient trial completed in August 2002, showed that bicifadine produced a dose-dependent pain reduction compared to placebo, and comparable to codeine. In the other trial, a 540-patient study completed a year ago, bicifadine produced a statistically significant reduction in pain in a dose-dependent fashion compared to placebo, as did tramadol.

"In these prior studies, both 200-mg and 400-mg dose arms were effective," Duncan said. "Here [in the bunionectomy study], we are using 200, 300 and 400 mg, and we believe that they will all be effective. We're still looking at the dose-response curve and adverse-event profile."

Bicifadine is not a narcotic, and might prove to have fewer limitations than many current pain therapies. Preclinical studies have shown that it does not to act at any opiate receptor, and in animal models, it does not demonstrate a potential for abuse, addiction or dependence. But Duncan said the company is not sure as to its mechanism of action.

"We do know that it is a dual uptake inhibitor of norepinephrine and serotonin," she added. "However, there are other drugs that are dual uptake inhibitors that are not analgesic. But something about its mechanism is clearly making it analgesic."

Beyond bicifadine, DOV expects to have another active Phase III program in the near term. Next quarter, the company expects to start a pivotal trial of ocinaplon for anxiety after finalizing a revised clinical trial protocol with the FDA. About a year ago the agency placed a hold on a pivotal trial of ocinaplon, asking for more safety data. (See BioWorld Today, Oct. 6, 2003.)

Deeper in its pipeline, DOV expects to progress DOV 102,677 into clinical studies early next year after filing an investigational new drug application. It could potentially be used for depression.

On Friday, the company's stock (NASDAQ:DOVP) gained 20 cents to close at $16.23.

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