BioWorld International Correspondent

Arpida Ltd. remains on track to file a new drug application in 2007 for its lead compound, iclaprim, which attained the primary endpoint in the first of two Phase III clinical trials by demonstrating statistical non-inferiority to linezolid (Zyvox) in the treatment of complicated skin and skin-structure infection (CSSSi).

Iclaprim, a diaminopyrimidine that inhibits the activity of prokaryotic dihydrofolate reductase, achieved an overall clinical cure rate of 85.5 percent vs. 91.9 percent for linezolid in the intent-to-treat population of 497 patients enrolled in the study.

Among clinically evaluable patients, the cure rates were 93.8 percent and 99.1 percent for iclaprim and linezolid, respectively, whereas for microbiologically evaluable patients, the cure rates were 94.7 percent and 98.8 percent for iclaprim and linezolid, respectively.

"The key message here is that iclaprim has shown a clinical cure rate at time-of-cure visit (seven to 14 days after treatment), which is statistically non-inferior to that of linezolid," Khalid Islam, president and CEO of Muenchenstein, Switzerland-based Arpida said on a conference call.

The compound, which Arpida originally licensed from Basel, Switzerland-based F. Hoffmann-La Roche Ltd., also demonstrated a safety profile that, Arpida said, "compared very favorably with that of linezolid."

"There were no serious adverse events, which were judged by the investigators to be probably or possibly related to treatment," Islam said. Adverse events included nausea, headaches, pruritis or itching, diarrhea and pyrexia or fever, but all occurred at a low frequency.

Because a previous study had indicated that iclaprim potentially could affect heart functioning, the patients in each treatment arm were monitored via electrocardiogram. Initially, patients with a pre-treatment QTc interval - a measure of cardiac repolarization corrected for heart rate - exceeding 470 milliseconds were excluded from the protocol. However, the requirement was dropped on the recommendation of the trial's data and safety monitoring board in March, following a review of the data from the first 200 recruits.

"There have been no cardiac events that have been attributed to QTc prolongation for either drug," Islam said. In the iclaprim arm, the mean maximal prolongation of the QTc interval from pre-treatment values was about 6.3 milliseconds. The equivalent figure for linezolid was 1.2 milliseconds. "Clearly we are well below the 20 milliseconds that the FDA and other authorities consider would be putting patients at risk," Islam said.

Although Arpida's stock peaked at CHF30.90 during trading on Nov. 30 - a rise of more than 14 percent on the previous day's close of CHF27 - it dropped back to CHF29 by the day's close and has remained around that level since.

"People just have not recognized the commercial potential of their lead product," said one analyst, who preferred to remain anonymous. The news "derisks the investment case substantially," he said, but it may take time for the share price to reflect this.

Germany-based Deutsche Bank AG upped its target price for the stock from CHF35 to CHF50. However, another analyst, who also preferred to remain anonymous, said that iclaprim still has "considerable hurdles" to overcome. "Not all questions were resolved, I would say," he said. "They didn't show the p' values of the result, and that's not transparent," he added.

Responding to analysts on this question, Islam said the result fell within a 95 percent confidence interval.

The same analyst also said that the lack of efficacy data in patients with CSSSi caused by methicillin-resistant Staphylococcus aureus also was a concern.

Iclaprim is undergoing a second Phase III trial, in a similar-sized population. That study, Islam said, is due to close out within the next few months, and top-line data will be available shortly afterward. It is powered independently, but the pooled data from the two trials will be even more strongly powered than either of the individual studies, he said.

Arpida has "unencumbered" global development, manufacturing and commercialization rights to iclaprim, for which it has yet to sign a deal.

"We have stated previously that we plan to commercialize the product in selected geographical areas. In view of the positive outcome, certainly that opinion has not changed," Islam said.