12:00 AM
Sep 13, 2010
 |  BioCentury  |  Regulation

Complicated but uncontroversial

Forest's Ceftaroline clears higher FDA hurdles for pneumonia, skin infections

Last week's FDA panel meeting to discuss ceftaroline from Forest Laboratories Inc. was devoid of the controversy that has surrounded reviews of other antibiotics to treat either community-acquired bacterial pneumonia or complicated skin and skin structure infections.

The keys to the compound's ability to sail through the Anti-Infectives Drugs Advisory Committee were the same for both indications. Most importantly, the compound clearly works: it not only met the prespecified endpoints of the company's studies, but also held up to FDA's post hoc analyses, which were based on guidances issued after the trials had been designed.

Second, the company selected the appropriate patients, based on disease severity and type of infection, to enroll in Phase III.

The committee voted 21-0 and 18-0 that ceftaroline is a safe and effective treatment for community-acquired bacterial pneumonia (CABP) and complicated skin and skin structure infections (cSSSIs). Three of the panelists were present only for the CABP portion of the meeting.

Conquering cSSSIs

Two weeks before the meeting, FDA issued new draft guidance on development of drugs to treat acute bacterial skin and skin structure infections (ABSSSIs), which includes cSSSIs (see "The Skinny on Endpoints," A21).

The two Phase III trials Forest conducted to support the NDA were completed in 2007, and the endpoints recommended in the guidance were not included in the study protocols.

In addition to FDA's post hoc analyses, the company presented its own exploratory analyses that demonstrated the compound's effect on several different parameters of efficacy and in subgroups of patients with different types of infections. Forest conducted these analyses post hoc at the request of FDA.

In the company's two randomized, double-blind active-controlled trials - P903-06 and P903-07 - vancomycin plus aztreonam was the active control.

According to G. Ralph Corey, director of infectious disease research at Duke University Clinical Research Institute, vancomycin is considered the gold standard for treating cSSSIs. However, because ceftaroline has activity against both Gram-positive and Gram-negative organisms while vancomycin has activity only against the former, Forest added a second active control, aztreonam, to treat infections caused by Gram-negative organisms.

Corey spoke to the panel on behalf of Forest.

According to the company's briefing materials, ceftaroline's broad-spectrum activity comes from its strong affinity for penicillin binding protein (PBP) 2a and PBP2x. It also is able to bind modified PBPs, which confer resistance.

Vancomycin interacts with peptidoglycan to disrupt the cell wall.

To be enrolled in the Phase III program, patients were required to have an infection that either involved deeper soft tissue or required surgical...

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