Staff Writer

Three months after placing plans for a $96.6 million initial public offering on hold until it could get its Phase III program for torezolid into compliance with new FDA guidelines on noninferiority trials, Trius Therapeutics Inc. appears to be back on track.

The San Diego biotech updated its SEC paperwork and issued a press release revealing that it has reached agreement with the FDA on a special protocol assessment covering the first of two planned Phase III trials for torezolid in acute bacterial skin and skin structure infections (ABSSSI).

Torezolid is a second-generation oxazolidinone antibiotic for Gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA). The drug is intended to improve on Pfizer Inc.'s first-generation oxazolidinone antibiotic Zyvox (linezolid), which generated $1.1 billion last year.

Trius has previously stated that torezolid is eightfold more potent and sixteenfold slower to elicit resistance than Zyvox. It also offers less frequent dosing, an improved safety profile, and activity against Zyvox-resistant bacterial strains, according to the company. In a Phase II trial, the lowest dose of torezolid demonstrated a 98 percent cure rate in complicated skin and skin structure infections, with a 100 percent cure rate for patients with MRSA.

The Phase III trial designed under SPA will compare 200-mg torezolid administered orally once daily for six days, to 600-mg Zyvox administered orally twice daily for 10 days. The primary endpoint of the double-blind study will be the cessation of spread of infected lesions and absence of fever at 48 to 72 hours following initiation of treatment. If torezolid achieves noninferiority, it will also be evaluated for superiority.

Secondary endpoints will include sustained clinical response at the end of therapy visit, and the investigator's assessment of clinical response at all visits and clinical success at the post-treatment evaluation visit.

The Phase III trial is expected to begin in the second half of this year and deliver top-line data in early 2012.

A second Phase III trial for ABSSSI will start patients on intravenous torezolid and transition them to the oral formulation. Zyvox is currently the only MRSA drug available in both I.V. and oral doses, a key advantage that has allowed the compound to remain competitive against Vancocin (vancomycin, ViroPharma Inc.) as well as newer MRSA drugs like Cubicin (daptomycin, Cubist Pharmaceuticals Inc.).

ABSSSI is the preliminary indication for many antibiotics, and Trius plans to later evaluate torezolid in other indications such as community-acquired bacterial pneumonia, hospital-acquired pneumonia, ventilator-acquired pneumonia, bacteremia and osteomyelitis.

All of those programs should move forward more smoothly now that the FDA has provided drug developers with guidance on conducting noninferiority studies, which are often used for antibiotics.

Trouble in the field began in 2006, when the FDA rejected Replidyne Inc.'s new drug application for the antibiotic faropenem, calling for superiority trials even though noninferiority had been good enough in the past. Around the same time, an FDA advisory committee rejected the idea of expanding Factive (gemifloxacin, Oscient Pharmaceuticals Corp.) into acute bacterial sinusitis for similar reasons. (See BioWorld Today, Sept. 13, 2006, and Oct 24, 2006.)

From there, things went from bad to worse, as telavancin (Theravance Inc.), oritavancin (Targanta Therapeutics Corp.), ceftobiprole (Basilea Pharmaceutica AG), iclaprim (Arpida AG) and cethromycin (Advanced Life Sciences Inc.) all failed to gain a first-pass approval. Pfizer Inc. yanked the filing for its antibiotic, dalbavancin, after the FDA asked for a new trial.

Eventually, the FDA started working on draft guidance documents for antibiotics in several indications. And last September, the industry dared to hope that the field was finally making progress as Theravance got a long-awaited approval of telavancin for cSSSI (complicated skin and skin structure infections, now referred to as ABSSSI). But the drug got a complete response letter for hospital-acquired pneumonia a few months later. (See BioWorld Today, Sept. 15, 2009, and Dec. 1, 2009.)

In March, the agency released draft guidelines on noninferiority trials, specifying when those types of studies are appropriate and how to choose a margin and analyze the results. The move prompted Trius to put its IPO plans on hold as it reworked its Phase III program to ensure it met all of the FDA's recommendations. (See BioWorld Today, March 8, 2010.)

Earlier in its pipeline, Trius is working on a preclinical program using its focused antisense screening technology (FAST) discovery platform to develop antibiotics for Gram-negative bacterial infections. The work is funded under a $29.5 million contract with the Defense Department. (See BioWorld Today, May 20, 2010.)

A separate $27.7 million contract from the NIH is funding preclinical work on antibiotics that target both Gram-positive and Gram-negative bacteria.