Trius Therapeutics is headed into Phase III for its lead antibiotic candidate torezolid (TR-701) with an important advantage over other companies that have tried for a complicated skin and skin structure infections claim in the past year: Trius has a clear sense of the outcome FDA now expects to see in a non-inferiority study.

The "silver lining" coming out of the experience of companies that "suffered at the time the non-inferiority margin guidance was ambiguous ... is that there now is clarity," Trius CEO Jeff Stein said in an interview. "We know what the target is."

Trius released positive data June 8 from a dose-ranging study of oral torezolid in 188 patients with severe complicated skin and skin structure infections caused by gram-positive bacteria. The antibiotic was shown to be 98 percent effective at 200 mg, the smallest dose studied, though it also proved safe and effective at 300 mg and 400 mg doses, where the cure rate was 94 percent. Patients were treated once daily for five to seven days; the study took four months to enroll.

The higher efficacy of the lowest dose was a pleasant surprise, Stein said. "We don't consider this as statistically significant, given the numbers of patients in the trial, but it is nonetheless very comforting that we got the higher number in the lowest dose."

The firm also gained important evidence that torezolid is effective against Methicillin-resistant Staphylococcus aureus; gaining a specific claim against the superbug will be a key commercial factor for the product. MRSA was the primary pathogen in 72 percent of the 133 Phase II patients where a pathogen was cultured; the clinical cure rate for that entire group was 100 percent for 200 mg, 93 percent for 300 mg, and 96 percent for 400 mg.

No clinical relapses were found during 21-28 day follow-up visits. No one dropped out because of adverse events, and laboratory results showed no significant shifts from baseline in hematology or chemistry parameters, including platelet or liver enzymes.

With a good safety profile so far, Trius doesn't anticipate regulators asking for a Risk Evaluation and Mitigation Strategy, as they did with Theravance's cSSSI candidate telavancin (¹ Also see "Telavancin’s “Complete Response” Letter Calls For Pregnancy-Focused REMS" - Pink Sheet, 2 March, 2009. p. 21). "Given the nature of the results we have so far, we don't expect that, [and] they haven't brought that up in any of our correspondence," Stein said.

The comparator in the planned Phase III program will be Pfizer's first-generation oxazolidinone antibiotic Zyvox (linezolid), which was the comparator in Trius' Phase I torezolid study. In that 21-day study the 200 mg dose of torezolid was comparable to placebo, while the labeled dose of linezolid produced "the expected depletion of platelets and other cell lines," according to Trius. Zyvox is the only currently marketed antibiotic in the class.

Phase III program includes I.V. step-down study

Trius expects to submit its Phase III protocol to FDA by mid-June, Stein said. The plan calls for two parallel studies. The first, a U.S.-based trial, will test the oral 200 mg dose, while the second, an international hospital-based study, will initiate patients on the I.V. formulation then step them down to the oral antibiotic. The I.V. portion will probably be two to three days of a seven-day regimen, Stein explained. Having an antibiotic that can cross over from the hospital setting to outpatient use is also a commercial advantage.

The Phase III trials should launch in the first quarter of 2010.

By then privately held Trius hopes to have torezolid partnered, Stein said, citing increased interest based on the Phase II data. The company has funds to initiate the program but not enough to complete both trials, "so we hope to identify a partner before the end of the year," he said.

The company announced in March 2008 that it had closed a $30 million Series B financing led by Kleiner, Perkins, Caufield and Byers. New investor FinTech Global participated along with existing investors Sofinnova Ventures, Versant Ventures, InterWest Partners and Prism VentureWorks.

Other companies seeing more clouds than silver lining

The partnering talks will be a gauge of industry comfort with the category after a brutal meeting of FDA's Anti-Infective Drugs Advisory Committee in November 2008 sent a ripple of trepidation through the anti-infectives community. That meeting - which saw votes against products from Arpida, Targanta and Theravance -probably set antibiotic development back a year as firms caught in the turning regulatory tide considered whether their work could be salvaged or whether to stay in the field at all.

On the first day of that three-day meeting the committee voted unanimously that non-inferiority trials are acceptable for the cSSSI indication and that a non-inferiority margin of 10 percent was probably appropriate in most cases (² Also see "Industry’s Lesson On Non-Inferiority Margins In Anti-Infective Trials: Use 10%" - Pink Sheet, 24 November, 2008., p. 9). For Trius, that gives the firm a clear, current target for the nascent Phase III program for torezolid - but for the companies with applications already under review, it meant going back and redoing clinical trials.

The trial for Arpida's cSSSI candidate iclaprim used a non-inferiority margin of 12.5 percent, and the committee judged it neither safe nor efficacious. FDA followed up with a "complete response" letter, and, unable to fund the new study it required, Arpida retrenched to consider its options.

On May 7 the Arpida board recommended to shareholders that they sell off the company's assets, including iclaprim, separately because they are probably worth more than the company as a whole in the current economy. The results of the meeting are not yet public.

The second company, Targanta, was recently acquired by The Medicines Company, which is taking over negotiations with FDA regarding the oritavancin "complete response" letter and its requirement for a new study.

The third company, Theravance, filed a new application for telavancin, this time against hospital acquired pneumonia, where FDA has attempted to provide clearer advice (³ Also see "FDA Updating Antibiotic Guidances, But Is It Too Late For Some Sponsors?" - Pink Sheet, 9 February, 2009., p. 30). The firm announced April 24 that FDA accepted for review its response to the cSSSI "complete response" letter.

-Shirley Haley (s.haley@elsevier.com)

Trius Confident After Phase II Results Against Skin Infections That Include MRSA

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