On September 7, the FDA Anti-infectives Advisory Committee will review the New Drug Application for ceftaroline submitted by Cerexa/Forest. Although I do have a consulting contract with Cerexa, I haven’t spoken with them in over a year and have absolutely no confidential knowledge of their data or anything else around ceftaroline’s phase III program. What I will discuss here is what is available publicly based on meeting presentations and a recent publication describing the data in their skin infection trials. In this regard, see my previous blogs about the FDA and clinical trial designs in pneumonia (http://antibiotics-theperfectstorm.blogspot.com/2009/12/fda-pneumonia-and-new-antibiotics.html) and in skin infections (http://antibiotics-theperfectstorm.blogspot.com/2010/04/skin-infections-follow-up.html; http://antibiotics-theperfectstorm.blogspot.com/2010/06/skin-no-4-word-turns.html).
Cerexa carried out two phase III trials in CAP comparing ceftaroline to ceftriaxone in over 1300 patients. Only PORT score III and IV patients were eligible making this the most comprehensive study of antibiotic efficacy in seriously ill, hospitalized patients with community-acquired pneumonia to be performed (to my knowledge). In these seriously ill patients, they showed that ceftaroline cured 84.3% compared to ceftriaxone with 77.7% in the clinically evaluable population. It looks like a fair percentage of patients received at least some prior antimicrobial therapy but that the numbers were similar in the two groups. It also looks like about 20% of patients had documented infection caused by S. pneumoniae. Cure rates for these patients were 85% and 69%, respectively. Adverse events appeared similar between the two groups and only led to rare discontinuations of therapy. The issue for the FDA will be the relatively small number of documented bacterial infections and the number of patients who received prior therapy. I am sure that Cerexa has analyzed the latter group separately, but I am unaware of those results. The FDA is now targeting earlier endpoints, specifically lack of fever and “clinical improvement” at 72 hours rather than the 8-15 days post therapy test of cure used by Cerexa. They also target documented bacterial infections. Nevertheless, the Cerexa data are robust and were derived from seriously ill patients.
Cerexa also carried out two phase III trials in patients with complicated skin infections. The data are published by Corey et. al. in Clinical Infectious Diseases available online as of August 9. The trail was again carried out in over 1300 patients comparing ceftaroline to vancomycin plus aztreonam. The test of cure visit was 8-15 days after completion of therapy. About one third had major abscess – this will be problematic for the FDA unless Cerexa can show they also had accompanying cellulitis. Cerexa did require at least 2 cm of surrounding erythema to include patients with abscess. Another third did have cellulitis. About 12-15% had infected wounds. The next most common infection was infected ulcer. Overall, lesions measured 150 sq. cm in both arms of the study. Almost 40% had at least some prior antimicrobial therapy. I could not find data stratifying cure rates by prior antimicrobial therapy. About one third had an elevated white blood cell count and one third had fever at baseline. Almost two thirds of patients had a microbiologically documented infection and almost 500 patients total had MRSA infections with cure rates around 94%. Cure rates were similar for the two arms of the study across all different infection types. Adverse events were also similar between the two study arms. Again, these were large trials with robust data.
For cSSSI (now ABSSSI according to the FDA), the FDA would like to see studies focusing on cellulitis. So, if there is an abscess, a wound infection, etc., surrounding cellulitis would be required and the endpoint for therapy would be related to the response of the cellulitis. The FDA would like to see an endpoint at 72 hours with halting lesion progression and with patients afebrile. They would like to eliminate prior antimicrobial therapy. So the new FDA view of skin infection trials, like pneumonia trials, is different from the large trials carried out by Cerexa (after agreeing the design with the FDA at the time).
So, what will the FDA do with these data? The data are robust. The patients were clearly seriously ill in both the cSSSI and CAP trials. And Cerexa designed these trials in concert with FDA review before embarking on the trials. The FDA has just changed its mind in the last year or so. Perhaps a post-hoc analysis of the data in light of the new FDA thinking will provide reassurance to the agency. In my view, if the FDA analysis of the data agrees substantially with the analysis by Cerexa, they must approve ceftaroline. A failure to approve this drug will be Waterloo for antibiotics. We can kiss investors and probably several other companies goodbye. In the worst of all possible cases, they might ask for additional phase II type data linking the Cerexa trial endpoints with some new endpoint (still not even defined for CAP). This might not be good, but at least it would not be the disaster that requiring new phase III trials would be.
September 7, therefore, is a watershed moment for the FDA. Lets hope that it’s not Waterloo for antibiotics.
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