Monday, May 9, 2011

Avibactam at ECCMID

Image representing Novexel as depicted in Crun...Image via CrunchBase

I hope all of you are wondering what on earth avibactam is.  It is the generic name for Novexel’s (was Sanofi-Aventis’, now Astra-Zeneca and Forest’s) non-beta-lactam broad spectrum beta-lactamase inhibitor previously designated NXL-104.  At the ongoing ECCMID meetings in Milan, Astra-Zenca presented two abstracts describing the results of two phase II trials with ceftazidime combined in a 4:1 ratio with avibactam.  Avibactam is a potent inhibitor of both class A and C beta-lactamases including ESBLs.  Of great interest, it works well against the class A carbapenemase, KPC as well.

Once again, I get a chance to brag about compounds that I consider at least partly mine.  I spent the years from 2006-2009 working hard for Novexel and NXL-104 (among other compounds) while consulting for them and serving on their Board.  I always thought, and stated from my initial evaluation of their portfolio, that NXL-104 was their star.  The data from phase II is consistent with this belief.  Once again I get to say how proud I am of everyone who worked at Novexel and their relentless and aggressive pursuit of developing NXL-104 and in their early identification of partners (first Forest and later Astra Zeneca) for this novel and promising compound.

Poster 1532 by Lucasti et. al.,  presented the data on a prospective randomized double blind trial of ceftazidime-avibactam plus metronidazole vs. imipenem for the treatment of complicated intra-abdominal infections (cIAI).  Of the 101 and 102 patients randomized to the two groups resp., 68 and 76 were microbiologically evaluable. The mean APACHE II score was <10.  E.coli was by far the most common pathogen occurring with 52 and 53 isolates in the ceftaz-avi and imipenem groups.  In the ceftaz-avi group, of 26 infections involving ceftaz resistant (MIC 8 mg/L or more) but ceftaz-avi susceptible Gram negatives, 25 were cured.  Almost half of the Gram negative enterics isolated in this study appear to have been resistant to ceftazidime.  To me this is an astounding figure. Given the global nature of the study, a breakdown of resistant isolates geographically would be more than interesting. Overall, 91 of patents treated with cetaz-avi and 93% of those treated with imipenem were cured at test of cure.  There were no outstanding safety issues for either treatment arm.

Poster 1533 by Vazquez et. al., presented data on a randomized, investigator-blinded trial of ceftaz-avi in a 4:1 ratio compared to imipenem in the treatment of complicated urinary tract infections (cUTI).  In this case, the “urinary” dose of ceftazidime had to be used – 500 mg q 8 hours.  Therefore, the dose of cetaz-avi was 500/125 mg q 8 hours.   It was striking to me that the numbers enrolled in this trial were smaller and that the number of microbiologically evaluable patients were quite small – 27/49 and 35/54 patients completing therapy respectively.  One can only imagine how difficult it must have been to complete such a trial with drugs that could only be administered intravenously.  The microbiological response rates were 70.4 and 71.4% in both groups.  The microbiological response of patients with ceftaz resistant Gram negatives treated with ceftaz-avi was >80% - no different than imipenem therapy in this trial.  Again – no particular safety issues were identified.

These data suggest that ceftazidime-avibactam should be pursued further in pivotal phase III trials.  Avibactam is being developed by Forest in combination with ceftaroline as well.  These Phase II data should provide them with a very positive signal as well.

There is so much potential for this compound and for others like it to address the Gram negative bacterial resistance problems that challenge us today and will do so for years to come. It just seems like forever to me for us to get this drug through trials and to the patients that need it.  I am getting impatient!  One can only hope that a feasible way forward for phase III will be forthcoming both in the US and in Europe.  
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