Following the release of data from two U.S.-based Phase III trials in which one missed its primary endpoint, Labopharm Inc. said it is preparing a new drug application for its lead product, a once-daily formulation of the analgesic tramadol for moderate to moderately severe pain that might be associated with osteoarthritis, lower-back spasm, cancer and other acute and chronic conditions.
Labopharm's stock (TSE:DDS) fell C$1.35 Thursday, or 17.3 percent, to close at C$6.45 (US$4.85) when the Laval, Quebec-based firm reported that one of the trials hit its primary endpoints while the other missed.
The company made a new version of the immediate-release formulation of tramadol by using its technology, called Contramid, to improve the drug, a painkiller that has been sold in Europe for 27 years and currently is marketed in the U.S. as Ultram by Johnson & Johnson, of New Brunswick, N.J. Ultram, for which the patent has expired, is dosed at 50 mg, four to six times daily.
Labopharm's Contramid technology is a controlled-release drug delivery system, based on a cross-linked high amylose starch developed for the controlled and targeted delivery of oral solid-dosage forms, the company said.
As for the proposed once-daily formulation of tramadol, James Howard-Tripp, the company's president and CEO, said he expects FDA action on the new drug application roughly one year after it's filed. The targeted date of the filing has not been determined.
"Tramadol is a very soluble molecule, so it is not the easiest product in the world to turn into a controlled-release formula," Howard-Tripp said. "A significant number of companies have tried, without getting it right. We believe we've got it right and that we have a very attractive product."
Labopharm will file the NDA under the 505B2 section, which requires that a sponsoring company must demonstrate safety and efficacy, but does not stipulate the number of trials a company must conduct.
The firm actually expects to file data on three Phase III trials, including the one that missed its endpoints. On Thursday, Labopharm released the U.S. trials, referred to as MDT3-002 and MDT3-003. (The other Phase III study was a successful European trial of 450 patients.)
A total of 1,100 patients enrolled in the U.S. trials, which were designed in a similar manner to compare safety and efficacy of the once-daily formulation of tramadol to placebo during a 12-week period.
Trial MDT3-003 achieved statistical significance for its three co-primary endpoints: reduction in pain, improvement in physical function and the patient's global assessment of the product's effectiveness.
While MDT3-002 ended with some patient improvement, Howard-Tripp told BioWorld Today: "We had an abnormally high placebo response. One would hope you don't get these things, but unfortunately, this is a human trial and these thing happen periodically."
Tramadol reduces pain by binding to micro-opioid receptors and by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin.
Enrollment in the trials consisted of patients who were 40 years to 75 years of age, diagnosed with moderate to severe pain associated with osteoarthritis of the knee. At the start of each trial, eligible patients were randomly assigned to one of the four arms (three active treatment arms and a placebo arm). Patients in the three active arms received either a 100-mg dose, a 200-mg dose or a 300-mg dose of Labopharm's tramadol. Patients in the 100-mg active treatment arm took 100 mg for the duration of the trial, whereas for patients in the 200-mg and 300-mg arms, the dose was titrated up every two to three days. Patients in the control arm received placebo for the duration of the trial, the company said.
Statistical significance was achieved in MDT3-003 at the 200-mg and 300-mg doses.
The controlled-released formulation also caused fewer adverse events (in all three trials) as compared to the immediate-release drug, the company said.
Labopharm filed for approval in Europe last March, and Howard-Tripp said it expects news in the near future.
Howard-Tripp said the company has signed European partners, including Esteve SA, of Barcelona, Spain, for Spanish and Portuguese markets; Aventis SA, of Strasbourg, France, for France; and Gruppo Angelini, for the Italian market.
Howard-Tripp said the company is in discussions with an undisclosed partner for the U.S.