Washington Editor

COLLEGE PARK, Md. - A panel of federal advisers Wednesday supported approval of Theravance Inc.'s injectable antibiotic telavancin, despite the potential for the drug to cause birth defects and kidney problems.

The South San Francisco-based firm and its partner, Deerfield, Ill.-based Astellas Pharma US Inc., are seeking approval to market telavancin, a semisynthetic lipoglycopeptide antibiotic active against Gram-positive organisms, to treat complicated skin and skin structure infections (cSSSI), such as methicillin-resistant Staphylococcus aureus (MRSA).

The FDA's Anti-Infective Drugs Advisory Committee voted 21 to 5 that Theravance's study results demonstrated that telavancin was safe and effective in treating cSSSIs.

The firm's Phase III results demonstrated that telavancin was noninferior to vancomycin in treating cSSSIs. However, telavancin did not demonstrate superiority in the treatment of patients with MRSA.

Analyst Thomas Russo, of R.W. Baird & Co., said the backing from the committee for telavancin in cSSSI also bodes well for the drug's prospects in hospital-acquired pneumonia (HAP), which he said provides a better commercial opportunity for Theravance.

The company plans to submit an application for the drug in HAP later this year or in early 2009.

The world is in the midst of an "emerging crisis" where the available arsenal of antibiotics increasingly are becoming resistant to infectious organisms, such as S. aureus, said Ralph Corey, professor of medicine at the Duke Clinical Research Institute, who led the Phase III studies on telavancin.

More than 60 percent of S. aureus infections are MRSA, he noted, calling the infection the "Darth Vader of organisms." MRSA, which infects about 94,000 people each year resulting in about 19,000 deaths annually, is an "evil and clever organism," he declared. "We need new effective antibiotics for cSSSIs due to MRSA."

Currently, only vancomycin, daptomycin, linezolid and tigecycline are approved in the U.S. to treat suspected or confirmed MRSA. Ertapenem, meropenem, levofloxacin and piperacillin-tazobactam are approved by the FDA for other cSSSIs.

Despite animal studies that showed telavancin is a multispecies teratogen, with limb malformations being the primary terata, panelists voted 18 to 5, with three abstentions, that there could be clinical situations when the benefits of using the drug in a pregnant woman outweigh the risks, such as if the patient is in a life-threatening circumstance and all other antibiotics have failed.

However, the committee voted 25 to 1 that the FDA mandate a risk-management program designed to prevent the unintended use of telavancin in women who are pregnant or of childbearing potential.

Nonetheless, said panelist Arthur Levin, director of New York-based advocacy group the Center for Medical Consumers, given the concerns of teratogenicity and the fact that there are at least eight approved antibiotics on the U.S. market for cSSSIs, "I can't conceive a situation" when it would be appropriate to use telavancin in a pregnant woman.

South San Francisco-based Theravance reported that nine patients treated with telavancin died during the reporting period for its drug trials, with five additional deaths occurring in telavancin-treated patients outside the reporting period. The FDA deemed eight of those deaths as "possibly related" to the drug, which included the deaths of two patients who had taken a dosage lower than the proposed 10 mg/kg.

Three of the deaths possibly related to telavancin were from acute renal failure or renal insufficiency, said Janice Pohlman, acting medical team leader in the FDA's Division of Anti-Infective and Ophthalmology Products. However, one of those three deaths also was attributed to respiratory failure, she noted.

The study data showed that 15 of the telavancin patients experienced serious adverse renal events compared with four in the vancomycin group.

Three of the telavancin-treated patients required hemodialysis, Pohlman said. In addition, she said, two to three times as many patients treated with telavancin developed clinically significant elevations in creatinine.

Study results also showed that telavancin prolongs the QT interval.

Nevertheless, most of the panelists agreed that the risks of fetal exposure, renal toxicity and adverse cardiovascular events could be managed by prescribers with careful patient monitoring and an effective risk management plan.

Theravance has proposed to distribute the drug only to wholesalers that primarily supply hospitals, inpatient hospital pharmacies and to pharmacies that supply home health care agencies.

The FDA's maternal health team recommended that, if approved for cSSSI, televancin should be assigned "pregnancy category X," a designation where studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit.

The maternal health team also called for a black-box warning on the drug's labeling alerting prescribers and patients that telavancin is a suspected human teratogen and should not be used in women of childbearing age, and said that Theravance should be required to include a pregnancy surveillance registry as part of a risk evaluation and mitigation strategy.

Panelists did not vote on the pregnancy category, what warnings should be included in telavancin's labeling or the specific elements for a risk-management program. However, most agreed that the labeling should include strong warnings about the use of the drug in pregnant women and the potential for adverse cardiac and renal events.

Wednesday afternoon, the panel reviewed the new drug application for Cambridge, Mass.-based Targanta Therapeutics Corp.'s antibiotic oritavancin. However, the committee had yet to vote by press time.

On Tuesday, the panel voted unanimously that noninferiority trials are acceptable for cSSSIs, with most agreeing that a 10 percent margin was appropriate. However, a majority of the committee said that simple abscesses should be excluded from future trials, given concerns over the limited treatment effect of antibiotics above simple drainage.