Assistant Managing Editor

A twice-daily combination of tramadol and acetaminophen in acute low back pain missed its primary endpoint in a Phase III trial, sending shares of Labopharm Inc. sliding 10 percent, though the Laval, Quebec-based firm said positive results in certain pain measures could be sufficient for filings in areas outside the U.S.

Results from the 277-patient North American trial failed to demonstrate a statistically significant difference over placebo on the Sum of Pain Intensity Differences (SPID) over 50 hours when using the LOCF/BOCF (last observation carried/forward/baseline observation carried-forward) imputation methods, which was defined as the primary endpoint. But other analyses of the data, including an analysis of covariance, did reach statistical significance vs. placebo.

Labopharm President and CEO James Howard-Tripp attributed the miss to a "very robust placebo response."

Anytime a trial involves opioids, like tramadol, "you always have to be worried about the placebo response," he told BioWorld Today. In the Phase III study of the tramadol-acetaminophen formulation, which is designed to provide immediate and sustained relief of acute pain at less-frequent dosing intervals compared to existing products, the drug did demonstrate its expected effect.

"But that was confounded by the placebo issue," Howard-Tripp said.

Unfortunately for Labopharm, that means the pivotal study likely won't support a new drug application submission to the FDA.

Each regulatory agency has a "different bar you've got to reach" for the approval of pain drugs, Howard-Tripp said. "The U.S. has a particular way of looking at things," and right now, "we're not certain that we're going to meet the bar" set by the FDA.

Labopharm plans to meet with the FDA's Division of Anesthesia, Analgesia & Rheumatology Products to determine a path forward. But if the agency declines to accept the company's analyses of the data, another pivotal study will be needed for an NDA submission.

The news sent shares of Labopharm (NASDAQ:DDSS), dropping 22 percent in early trading, though they rebounded a bit to close Thursday at $1.16, down 13 cents.

But outside the U.S., Labopharm's data might be sufficient for regulatory review.

The company plans to present the Phase III analyses to agencies in Europe, Canada and the rest of the world, which have different standards for pain drug trials compared to the FDA, Howard-Tripp said.

An analysis of covariance from the study showed that tramadol-acetaminophen demonstrated a statistically significant difference over placebo on the SPID scale over 50 hours using LOCF as the imputation method. And a non-parametric analysis showed statistical significance using both LOCF and LOCF/BOCF as imputation methods. The difference from placebo on the Total Pain Relief score also was statistically significant.

On the safety side, 13 percent of patients in the Phase III study discontinued treatment in the tramadol-acetaminophen arm (12 percent of those due to adverse events) compared to 5 percent in the placebo group (2 percent due to adverse events).

But regardless of which way the FDA reacts to the tramadol-acetaminophen study, those data will not have any effect on the upcoming launch of the firm's first product, a once-daily version of tramadol that gained approval at the end of last year for use in chronic pain.

Labopharm's U.S. marketing partner, Purdue Pharma LP, of Stamford, Conn., has said it plans to get the drug on the market early this quarter, and "we're fully on track," Howard-Tripp said.

Once-daily tramadol already is marketed in 14 countries, including Canada and the five largest markets in Europe. Product sales brought in revenues totaling C$13.2 million (US$10.7 million) to Labopharm in 2008.

Under its deal with Purdue, the company expects to receive sales-based milestone payments of up to $110 million, as well as royalties of 20 percent to 25 percent on U.S. sales, and certain co-promotion rights.

Labopharm also is awaiting an FDA decision on its second product, a once-daily formulation of trazodone, a serotonin antagonist reuptake inhibitor, for major depressive disorder.

The PDUFA date is July 18, and the firm is preparing for that product's potential launch and is putting together a distribution partnership, Howard-Tripp said.

Earlier in its pipeline, Labopharm is working on abuse-resistant opioids and reformulated cancer drugs.

As of Dec. 31, 2008, the firm had about C$44.9 million in cash.