Assistant Managing Editor

 

It's been a bumpy ride lately for Theravance Inc., and, in many ways, for the antibiotic space in general.

Following an approvable letter in October for its antibiotic candidate, telavancin, in complicated skin and skin structure infections (cSSSI), the company reported that the FDA scheduled an unexpected advisory panel meeting Feb. 27 to review the application, only to cancel the panel at the last minute. A week later, Theravance told investors that the agency wanted time to evaluate apparent "data integrity" and "study monitoring issues."

Theravance isn't the only firm with a late-stage antibiotic to get mired in the regulatory review process. Witness Replidyne Inc.'s faropenem and Oscient Pharmaceuticals Corp.'s Factive (gemifloxacin) were met with rejection in 2006 in acute bacterial sinusitis as the FDA started seeking more conclusive efficacy data beyond the previous non-inferiority requirements. Pfizer Inc.'s dalbavancin was deemed approvable in hospital-acquired infections, but needs additional study data as per new draft guidelines. But Theravance might face the biggest obstacles to market approval, many of its own making.

In a press release last week, the firm reported, for the first time, the removal of a portion of data generated from one of the trial sites from the telavancin new drug application due to integrity issues. Theravance assured investors that the removal had no impact on the overall data set, in which telavancin, a lipoglycopeptide injectable antibiotic, demonstrated noninferiority to vancomycin in cSSSI. But the problem at one trial site was enough to prompt the FDA to investigate additional study sites, leaving many analysts skeptical about the modified new drug application's chances for final approval and wary of the new July 21 PDUFA date.

The Division of Scientific Inquiry at the FDA will handle the clinical site investigation and "can delay FDA action if it has not reached satisfactory conclusions," analyst Rachel McMinn, of Cowen and Co., wrote in a research note.

Michael Aberman, of Credit Suisse Securities LLC, went further, writing that "any impression that the PDUFA date sets a timeline is false," adding that the review of trial sites and resolution of manufacturing issues "will likely take longer than five months."

The day Theravance reported the FDA investigation, its shares (NASDAQ:THRX) sank to a record low, closing at $12.25.

McMinn attributed the drop to "management credibility issues," and to the fact that Theravance delayed disclosing to investors that regulators uncovered problems with the data at one trial site in the telavancin Phase III program.

"This is something they knew about Jan. 30," she told BioWorld Financial Watch, "and it's very upsetting because this was the issue the FDA had with Ketek," an antibiotic from Sanofi-Aventis that won approval in 2003 after a controversial turn with the FDA. It has continued to prove a headache for regulators, with allegations of data fabrication and manipulation at trial sites and a black box warning that was added a year ago after reports of deaths and liver toxicities linked to use of the drug.

Ketek (telithromycin) is approved in community-acquired pneumonia.

"There's clearly an increased regulatory focus in general, and for antibiotics in particular," McMinn said. The FDA is "under so much pressure following the whole Ketek debacle."

At the same time, the need for antibiotics continues to make headlines, as new outbreaks of drug-resistant bacterial infections, particularly the dreaded MRSA (methicillin-resistant Staphylococcus aureus), send health officials clamoring for alternative treatments. But whether the safety-conscious FDA's reluctance to clear new antibiotic products continues is anyone's guess.

"I think we'll have a better view of that when ceftobiprole" comes up for approval later this month, McMinn said.

A cephalosporin antibiotic from Basel, Switzerland-based Basilea Pharmaceutica Ltd. and Johnson & Johnson, ceftobiprole is under review for use in cSSSIs, including diabetic foot infections, with a PDUFA date of March 18. An advisory panel meeting for ceftobiprole, set for Feb. 28, was canceled along with the telavancin meeting, so "it will be interesting to see if that product also gets an approvable letter," McMinn said.

Cambridge, Mass.-based Targanta Therapeutics Corp. submitted an NDA last month for oritavancin, a semisynthetic lipoglycopeptide, against Gram-positive bacteria. A short-course antibiotic, oritavancin demonstrated efficacy in two pivotal trials, clearing infection at three to seven days of treatment compared to existing antibiotic treatment, which generally takes seven to 14 days.

Targanta has requested a six-month priority review, but even at the standard 10-month review process, anticipates FDA action in 2008, followed by a prospective launch in 2009.

In late February, another potential competitor, Swiss firm Arpida Ltd., said its rolling NDA for intravenous iclaprim in cSSSi will be completed within a few weeks. That product, a diaminopyrimidine, met in primary endpoint in the second of two pivotal trials in July, showing noninferiority to Pfizer's marketed antibiotic Zyvox (linezolid).

And Advanced Life Sciences Holdings Inc. is proceeding with its NDA for cethromycin in community-acquired pneumonia after results of the second of two pivotal clinical trials showed that the ketolide antibiotic met its primary endpoint of statistical noninferiority cure rates.

In addition to Zyvox, existing drugs for Gram-positive infections include vancomycin and Cubist Pharmaceuticals Inc.'s Cubicin (daptomycin). Lexington, Mass.-based Cubist's drug, approved in cSSSI in 2003 and later expanded into certain bloodstream infections, brought in sales revenue of $85.1 million for the fourth quarter, an increase of 51 percent over the previous year.

"In a perfect world, their stock would be getting a boost" from all the negative news surrounding telavancin, McMinn said, "but they have their own company-specific issues."

Among those issues is a potential patent challenge on Cubicin, which, if successful, essentially would wipe out the firm's primary revenue source. Beyond Cubicin, the remainder of the firm's pipeline consists of preclinical programs in Gram-positive and Gram-negative infections, Clostridium-difficile-associated diarrhea and hepatitis C infection.

In addition to cSSSI, Theravance's telavancin also is in development for hospital-acquired pneumonia (HAP), for which the firm reported positive Phase III data in December.

The drug is partnered with Tokyo-based Astellas Pharma Inc., but Theravance is responsible for leading development in cSSSI and HAP, and the companies will work together on U.S. marketing for the first three years upon approval.

Theravance, which posted a net loss of $32.4 million for the third quarter, had cash totaling $166.5 million, as of Sept. 30.