FDA Panel Splits on New Antibiotic Combo Treatment

Larry Hand

December 05, 2014

A US Food and Drug Administration (FDA) advisory committee has voted to recommend approval of a new combination antibiotic drug for two indications, but the committee is recommending that the drug not be approved for one other indication.

The Anti-Infective Drugs Advisory Committee voted 11 to 1 in favor of recommending approval of the combination of ceftazidime and avibactam (CAZ-AVI) for treatment of complicated intra-abdominal infections (cIAI) and 9 to 3 in favor of recommending approval of CAZ-AVI for treatment of complicated urinary tract infections.

Both recommendations, however, carry the wording "when limited or no alternative treatments are available."

In two separate votes, the committee voted against recommending approval of CAZ-AVI for treatment of gram-negative infections including hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) and bacteremia. Committee members voted unanimously against recommending approval when "limited or no alternative treatments are available" and 11 to 1 against recommending approval if "no alternative treatments are available."

Ceftazidime is a well-established ß-lactam inhibitor and avibactam is a novel ß-lactamase inhibitor. The combination is designed to meet current and future treatment needs for gram-negative infections, according to a document supplied by Cerexa, an Alameda, California, a subsidiary of Forest Laboratories.

Increasingly, infections have reduced the activity of ceftazidime, but introducing avibactam with ceftazidime restores that activity, the company says.

Cerexa applied for the new drug approval under the FDA's 505(b)(2) pathway, which allows the agency to make an accelerated decision based on the agency's prior finding of safety and efficacy of an approved drug (ceftazidime, FDA-approved in 1985) and phase 1 and 2 studies for CAZ-AVI, plus animal model data.

Cerexa requested approval based on intravenous dosing of CAZ-AVI for two hours at eight-hour intervals in hospitalized adults with infections.

Cerexa officials and consultants presented preliminary, top-line data from a phase 3 study of CAZ-AVI for treatment of cIAI that helped the company get positive votes on the first two indications requested. However, since the company only submitted supplemental data to the FDA regarding gram-negative bacteria on November 26, FDA officials had not had time to fully analyze the preliminary results.

Those phase 3 results showed CAZ-AVI to be noninferior to other treatments, phase 1 and 2 results showed that cure rates were comparable to other treatments, and studies in animal models showed CAZ-AVI to be effective against infections, Cerexa contended.

Other phase 3 trials are ongoing, and Cerexa plans to file supplemental data from those in late 2015.

"Urgent, Unmet Need"

CAZ-AVI has been exposed to 1735 patients globally in doses ranging from 0.625 grams to 5 grams, Angela Talley, MD, associate director of clinical development for Cerexa, told committee members. It is generally well tolerated, with adverse events similar to those of other treatment groups, and no drug-related deaths have occurred, she said.

David Friedland, Cerexa's vice president of clinical development, said, "The totality of data supports a positive benefit-risk profile for CAZ-AVI for the indications we are seeking," and that the filing was "based on an urgent, unmet need" to fight increasingly drug-resistant infections.

The FDA staff contended that while CAZ-AVI showed numerically higher differences in effect than other treatments, wide confidence intervals show a degree of uncertainty.

In voting yes for recommending the treatment of cIAI, Dean Follmann, PhD, chief of the Biostatistics Research Branch at the National Institute of Allergy and Infectious Diseases, said it was important to have the phase 3 data, and that information from the ongoing trials will offer even more information on dosing, cures, and mortality.

Capt. Monica E. Parise, MD, committee chair, and chief of the Parasitic Diseases Branch at the Centers for Disease Control and Prevention, said she voted yes on that question because the totality of the evidence was sufficient.

On the questions regarding HABP and VABP, however, Cerexa submitted no human data, and committee members in general said that's why they voted to not recommend approval for that indication.

No panel members reported any relevant financial relationships.


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