Washington Editor

Theravance Inc. filed for FDA approval of its partnered antibiotic telavancin as a treatment of complicated skin and skin structure infections (cSSSI) caused by Gram-positive bacteria.

If approved, the rapidly bactericidal injectable could provide a new entry in an area clearly in need of new products. And for the South San Francisco company, which was incorporated a decade ago this month, the filing represents a significant milestone.

"We're very excited," said David Brinkley, Theravance's senior vice president of commercial development, noting that the company has applied for priority review of the fast-track product. That means a decision could come between the middle and end of next year.

The new drug application is based on two pivotal studies known as ATLAS 1 and 2, both of which demonstrated telavancin's non-inferiority to vancomycin (Vancocin, from ViroPharma Inc.) in treating cSSSIs, the trials' primary endpoint.

In the double-blind, randomized Phase III studies that enrolled a total of 1,867 patients, 719 of whom were infected with methicillin-resistant Staphylococcus aureus (MRSA), telavancin compared favorably to that standard therapy in clinical cure, microbiological eradication and overall therapeutic response rates. (See BioWorld Today, Aug. 24, 2006.)

But despite those data, FDA clearance might not be a slam dunk, because the agency has recently shifted its reliance on non-inferiority for approving antibiotics. Two times in the past couple of months, FDA actions have indicated this change.

Six weeks ago Louisville, Colo.-based Replidyne Inc.'s application to market faropenem was rejected even though the drug had met non-inferiority endpoints, which previously had the agency's blessing, and a month before that an FDA advisory committee voted against Waltham, Mass.-based Oscient Pharmaceuticals Corp.'s bid to expand the label for Factive (gemifloxacin) on the same basis.

In both cases, superiority trials were requested to better define the margin of those two antibiotics' benefit. (See BioWorld Today, Sept. 13, 2006, and Oct. 24, 2006.)

But Brinkley noted a distinction for Theravance's application: cSSSIs, especially when they involve MRSA, represent serious, life-threatening infections. Just as notably, the level of non-inferiority exhibited in ATLAS 1 and 2 was more than 20 percent in most measures.

"We had to have a tighter margin than previous drugs did, and we did," he said, though he hedged by saying that he didn't "want to speculate on what the FDA might or might not do."

The mechanism of action of telavancin, a lipoglycopeptide that was discovered internally at Theravance, involves the inhibition of bacterial cell wall synthesis as well as the disruption of the functional integrity of the bacterial cell membrane.

Additional findings from ATLAS 1 and 2 showed it to be better than vancomycin in the clinical cure rate of cSSSIs caused by Gram-positive bacteria, generating a 90.6 percent cure rate compared to vancomycin's 86.4 percent (p=0.060). In addition, its microbiological eradication rate was better, with telavancin achieving 89.9 percent compared to vancomycin's 85.4 percent (p=0.053).

The product is partnered with Tokyo's Astellas Pharma Inc. in a worldwide collaboration. Terms of this nearly $235 million arrangement have Theravance leading telavancin's development for cSSSIs and hospital-acquired pneumonia. A Phase III trial in that latter indication is scheduled to complete enrollment next year. In addition, both companies will work together on U.S. marketing for the first three years.

Upon FDA acceptance, Theravance stands to receive a milestone payment of an undisclosed amount.

Astellas is leading all other development, regulatory, manufacturing, sales and marketing activities for any other indications. In addition to telavancin rights, Astellas also received an option to further develop and commercialize TD-1792, Theravance's Phase I heterodimer antibiotic. (See BioWorld Today, Nov. 9, 2005.)

If approved for cSSSIs, telavancin would compete with Cubicin (daptomycin, from Cubist Pharmaceuticals Inc.), which contributed greatly to the company's $50.3 million in net product revenues last quarter, a 66 percent increase. Another possible competitor is Zeven (dalbavancin, from Pfizer Inc.), which remains under FDA review.

On Friday, shares in Lexington, Mass.-based Cubist (NASDAQ:CBST) lost $1.61 to close at $18.82. Theravance's stock (NASDAQ:THRX) lost 20 cents to close at $30.40.